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© American College of Medical Genetics and Genomics
ACMG StAndArdS And GuidelineS
PURPOSE
is guideline is intended as an educational resource. It high-
lights current practices and therapeutic approaches to the
diagnosis and management of GSD I and its early and long-
term complications.
GENERAL BACKGROUND
History
In 1929, von Gierke described glycogen storage disease type
I (GSD I) aer reviewing the autopsy reports of two children
whose livers and kidneys contained excessive amounts of
Submitted 12 August 2014; accepted 12 August 2014; advance online publication 6 November 2014. doi:10.1038/gim.2014.128
Genet Med
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Genetics in Medicine
10.1038/gim.2014.128
ACMG Standards and Guidelines
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© American College of Medical Genetics and Genomics
6November2014
Purpose: Glycogen storage disease type I (GSD I) is a rare disease of vari-
able clinical severity that primarily aects the liver and kidney. It is caused
by decient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a
deciency in the microsomal transport proteins for glucose 6-phosphate
(GSD Ib), resulting in excessive accumulation of glycogen and fat in the
liver, kidney, and intestinal mucosa. Patients with GSD I have a wide spec-
trum of clinical manifestations, including hepatomegaly, hypoglycemia,
lactic acidemia, hyperlipidemia, hyperuricemia, and growth retardation.
Individuals with GSD type Ia typically have symptoms related to hypo-
glycemia in infancy when the interval between feedings is extended to
3–4 hours. Other manifestations of the disease vary in age of onset, rate of
disease progression, and severity. In addition, patients with type Ib have
neutropenia, impaired neutrophil function, and inammatory bowel dis-
ease. is guideline for the management of GSD I was developed as an
educational resource for health-care providers to facilitate prompt, accu-
rate diagnosis and appropriate management of patients.
Methods: A national group of experts in various aspects of GSD I
met to review the evidence base from the scientic literature and pro-
vided their expert opinions. Consensus was developed in each area of
diagnosis, treatment, and management.
Results: is management guideline specically addresses evalua-
tion and diagnosis across multiple organ systems (hepatic, kidney,
gastrointestinal/nutrition, hematologic, cardiovascular, reproductive)
involved in GSD I. Conditions to consider in the dierential diag-
nosis stemming from presenting features and diagnostic algorithms
are discussed. Aspects of diagnostic evaluation and nutritional and
medical management, including care coordination, genetic counsel-
ing, hepatic and renal transplantation, and prenatal diagnosis, are
also addressed.
Conclusion: A guideline that facilitates accurate diagnosis and
optimal management of patients with GSD I was developed. is
guideline helps health-care providers recognize patients with all
forms of GSD I, expedite diagnosis, and minimize adverse sequelae
from delayed diagnosis and inappropriate management. It also helps
to identify gaps in scientic knowledge that exist today and suggests
future studies.
Genet Med advance online publication 6 November 2014
Key Words: glycogen storage disease; glycogen storage disease type I;
von Gierke disease
1Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA; 2Division of Metabolic Disorders, Children’s Hospital of Orange County, Orange,
California, USA; 3Division of Genetics, Nemours Children’s Clinic, Jacksonville, Florida, USA; 4Departments of Pediatrics and Medicine, Columbia University Medical Center,
NewYork, New York, USA; 5Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida, USA; 6Department of Medicine, University of Washington,
Seattle, Washington, USA; 7Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA; 8American College of Medical Genetics and Genomics, Bethesda,
Maryland, USA. Correspondence: Michael S. Watson (mwatson@acmg.net)
Diagnosis and management of glycogen storage disease
type I: a practice guideline of the American College of
Medical Genetics and Genomics
PriyaS.Kishnani,MD1, StephanieL.Austin,MS, MA1, JoseE.Abdenur,MD2, PamelaArn,MD3,
DeekshaS.Bali,PhD1, AnneBoney,MED, RD1, WendyK.Chung,MD, PhD4, AditiI.Dagli,MD5,
DavidDale,MD6, DwightKoeberl,MD, PhD1, MichaelJ.Somers,MD7, StephanieBurnsWechsler,MD1,
DavidA.Weinstein,MD, MMSc5, JosephI.Wolfsdorf,MB, BCh7 and MichaelS.Watson, MS, PhD8
Disclaimer: is guideline is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this guideline
is completely voluntary and does not necessarily ensure a successful medical outcome. is guideline should not be considered inclusive of all proper procedures and
tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specic procedure
or test, the clinician should apply his or her own professional judgment to the specic clinical circumstances presented by the individual patient or specimen. Clini-
cians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this guideline. Clinicians also are
advised to take notice of the date this guideline was adopted and to consider other medical and scientic information that becomes available aer that date. It also
would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.
GENETICS in MEDICINE
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KISHNANI et al | GSD I guideline
ACMG StAndArdS And GuidelineS
glycogen.1 In 1952, Cori and Cori2 reported six similar patients
and discovered that the absence of the enzyme glucose-6-phos-
phatase (G6Pase) caused von Gierke disease, establishing the
rst metabolic disorder in which an enzyme defect was identi-
ed. Two patients had almost total deciency of hepatic G6Pase;
the remaining four patients had normal enzyme activity.
Early on, the authors recognized the variability of the hepatic
GSDs. In 1978, Narisawa et al.3 explained the paradox of the
four patients with GSD and normal enzyme activity when he
described GSD type Ib (GSD Ib) and showed that it was caused
by deciency of the transporter enzyme glucose-6-phosphate
translocase (G6PT). Deciency of the enzyme G6Pase results in
GSD Ia, and deciency of G6PT results in GSD Ib.
e human G6Pase gene, G6PC, is a single-copy gene
(OMIM# 613742) located on chromosome 17q21, which was
cloned in 1993 by Lei et al.4 e group identied mutations
causing GSD type Ia (GSD Ia) and generated a G6Pase-decient
mouse model in 1996.5 G6PC spans ~ 12.5 kb and consists of
ve coding exons. e human G6PT gene, SLC37A4 (OMIM#
602671), which causes GSD Ib, was cloned and found to be
located on chromosome 11q23. SLC37A4 spans ~ 5.3 kb and
contains nine exons. Approximately 80% of people with GSD I
have type Ia and 20% have type Ib.
Overview and general background
G6Pase is a multipart enzyme system located in the endoplas-
mic reticulum membrane. G6Pase together with the glucose-
6-phosphate transporter (SLC37A4/G6PT) forms the complex
responsible for glucose production by catalyzing the terminal
step of both glycogenolysis and gluconeogenesis. It is a key
enzyme in regulation of blood glucose (BG) levels. Deciency
of glucose 6-phosphatase activity or its microsomal transport
proteins results in excessive accumulation of glycogen and fat
in the liver, kidney, and intestinal mucosa.
e presenting symptoms of GSD Ia vary according to the
patient’s age. Patients with GSD I may present during the neo-
natal period with hypoglycemia and lactic acidosis; however,
they more commonly present at 3 to 6 months of age with hepa-
tomegaly and/or signs and symptoms of hypoglycemia, includ-
ing seizures. Clinical characteristics include doll-like facies,
poor growth, short stature, and a distended abdomen due to
pronounced hepatomegaly and nephromegaly. Biochemical
manifestations include hypoglycemia, hyperlipidemia, hyper-
triglyceridemia, hyperlactatemia, and hyperuricemia. Patients
with type Ib also have neutropenia and impaired neutrophil
function, resulting in recurrent bacterial infections and oral
and intestinal mucosa ulceration. Neutropenia may also be
observed in a subset of GSD Ia patients.6 Patients with GSD I do
not have skeletal myopathy or increased creatine kinase levels,
which are characteristic of GSD type IIIa.
GSD I is an autosomal recessive, pan-ethnic disorder with
genetic mutations identied in Caucasians, Ashkenazi Jews,
Hispanics, and Asians.7–15 e overall incidence of the disease
is ~1/100,000. e disease prevalence is relatively high in the
Ashkenazi Jewish population (prevalence 1/20,000). ere
are many known pathogenic mutations in both G6PC and
SLC37A4 genes. However, some ethnic group–specic common
mutations account for ~ 90% of known disease alleles.7,12,16,17
Depending on the specic ethnic group, these common muta-
tions can account for 100% of disease alleles.
Clinical history
e diagnosis is based on the clinical presentation, specic con-
stellation of biochemical abnormalities, molecular genetic test-
ing, and/or enzymology in liver biopsy tissue.18 Symptomatic
hypoglycemia may appear soon aer birth; however, most
patients are asymptomatic as long as they receive frequent feed-
ings that contain sucient glucose to prevent hypoglycemia.
Symptoms of hypoglycemia typically appear only when the
interval between feedings increases, such as when the infant
starts to sleep through the night or when an intercurrent illness
disrupts normal patterns of feeding. Very rarely, hypoglycemia
may be mild, causing a delay in the diagnosis until adulthood
when liver adenomas and hyperuricemia are detected.19
Patients may present with hyperpnea due to lactic acidosis,
which may simulate that occurring in pneumonia. e condi-
tion may not be recognized until the infant is several months
old with an enlarged liver and protuberant abdomen noted
on a routine physical examination. Ultrasound imaging of the
liver is similar in GSD I, GSD III, and several other liver stor-
age disorders. However, the presence of nephromegaly and the
characteristic biochemical abnormalities seen in GSD I pro-
vide clues to the diagnosis.21
Untreated patients typically appear short for age, with a
round face and full cheeks, giving them a cushingoid appear-
ance. ey have failure to thrive and delayed motor develop-
ment. Cognitive development is usually normal unless the
patient has cerebral damage from recurrent hypoglycemic epi-
sodes. During infancy, the BG concentration may decrease to
<40 mg/dl (2.2 mmol/l) within 3–4 hours of a feeding. Longer
intervals between feedings cause more severe hypoglycemia
accompanied by lactic acidemia and metabolic acidosis.
Long-term complications are common and are beginning to
be more recognized and understood. In most individuals with
GSD I, hepatomegaly decreases with age; however, develop-
ment of liver adenomas is common with increasing age, and
some individuals develop hepatocellular carcinoma (HCC).22–
26 GSD I has been associated with a bleeding diathesis due to
impaired platelet function27 and/or a von Willebrand–like
platelet defect.28 Anemia is also noted, especially in patients
with hepatic adenomas.29 Vitamin D deciency is increasingly
recognized in these patients.30–35 Individuals with GSD I have
decreased bone mass and are at increased risk for osteoporo-
sis and fractures.36 Proximal renal tubular dysfunction is com-
mon in inadequately treated patients, and patients with poorly
controlled conditions may develop renal glomerular dysfunc-
tion that can progress to renal failure and require a renal trans-
plant.37–40 Liver transplant (LT) or a combined liver and kidney
transplant is needed in some cases.41–43 Menorrhagia appears to
be a problem in females of reproductive age with GSD I.44,45
GENETICS in MEDICINE
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GSD I guideline | KISHNANI et al ACMG StAndArdS And GuidelineS
Polycystic ovaries have been documented in females with
GSD I aer 4 years of age, but fertility is not thought to be
reduced.46–48 Pulmonary hypertension has also been reported
in patients.49,50 e serum of untreated patients is oen cloudy
or milky with very high triglyceride concentrations and mod-
erately increased levels of phospholipids, total lipoprotein cho-
lesterol, and low-density lipoprotein cholesterol; by contrast,
the concentration of high-density lipoprotein cholesterol is low.
Early atherosclerosis with risk for ischemic stroke is a poten-
tial long-term concern.51 Acute pancreatitis may occur in some
patients with severe hyperlipidemia, especially in individuals
with severe persistent hypertriglyceridemia (>1,000 mg/dl).18
Patients with GSD Ib, and on occasion those with Ia, are at
increased risk for Crohn disease–like enterocolitis.52
e circulating concentration of free fatty acids is markedly
increased, whereas blood β-hydroxybutyrate levels are only
mildly or moderately increased relative to the corresponding
free fatty acid levels.53,54
Eruptive xanthomata may appear on the extensor surfaces of
the extremities and on the buttocks.55 ese ndings are becom-
ing less common with increased awareness and earlier diagnosis.
A bleeding tendency manifested as recurrent epistaxis in
childhood followed later in life by easy bruising and/or oozing
aer dental or other surgeries, as well as menorrhagia in men-
struating females is caused by impaired platelet function and/
or an acquired von Willebrand–like disease.45 Reduced plate-
let adhesiveness, abnormal platelet aggregation, and impaired
release of adenosine diphosphate in response to collagen and
epinephrine have been observed. e platelet defects are sec-
ondary to the systemic metabolic abnormalities and may be
corrected by improving control of the metabolic state.18,27,56,57
Although hypoglycemia becomes less severe with increas-
ing age, inadequate therapy causes pronounced impairment
of physical growth, delayed onset of puberty, and many long-
term sequelae of the disease. However, normal growth can
occur, provided that patients maintain good metabolic control
at an early age.58
A majority of patients with GSD I have nephromegaly that
is readily demonstrable by ultrasonography.37,59 Proximal tubu-
lar dysfunction (glucosuria, phosphaturia, hypokalemia, and
a generalized aminoaciduria) may be observed in untreated
or inadequately treated patients. e proximal tubular dys-
function is reversible with improved metabolic control of the
disease.37,60 Some patients have a distal renal tubular acidica-
tion defect associated with hypocitraturia and hypercalciuria,
predisposing them to nephrocalcinosis and renal calculi.40,61
Increased urinary albumin excretion (microalbuminuria) due
to hyperltration may occur in adolescents and young adults
with GSD I, similar to what is seen in diabetic patients.
Severe renal injury with proteinuria, hypertension, and
decreased creatinine clearance due to focal segmental glomeru-
losclerosis and interstitial brosis, ultimately leading to end-
stage renal disease, may also be seen in young adults.62 Patients
with persistently elevated blood lactate, serum lipids, and uric
acid levels appear more at risk for nephropathy.58,63
Patients with GSD Ib have similar clinical and biochemi-
cal abnormalities in addition to neutropenia (persistent or
cyclic)—the severity of which varies from mild to complete
agranulocytosis—associated with recurrent bacterial infec-
tions.64 Children with GSD Ib are prone to oral complications,
including recurrent mucosal ulceration, gingivitis, and rap-
idly progressive periodontal disease. ey frequently develop
inammatory bowel disease (Crohn disease–like enterocolitis)
and may have an increased prevalence of thyroid autoimmunity
and hypothyroidism.65
METHODS/PROCESS
Consensus development panel
A national group of experts in clinical and laboratory diagnosis,
treatment and management (cardiovascular, gastrointestinal/
nutrition, hepatic, reproductive, neuromuscular), and genetic
aspects of GSD I was assembled to review the evidence base and
develop management guidelines. Aer a meeting during which
published material and personal experience were reviewed
by the panel, experts in the various areas reviewed the litera-
ture in these areas and draed the guidelines. e participants
provided conict of interest statements and their conicts are
stated in the Acknowledgments section. All members of the
panel reviewed and approved the nal guidelines. Consensus
was dened as agreement among all members of the panel. For
the most part, the evidence and resulting recommendations are
considered expert opinion because additional levels of evidence
were not available in the literature. Penultimate dras of these
guidelines were shared with an external review group consisting
of Yuan-Tsong Chen, Philippe Labrune, Areeg El-Gharbawy,
and Kathy Ross. e working group considered their sugges-
tions and changes were made as considered appropriate.
Target audience
is guideline is directed at a wide range of care providers.
Although care is commonly provided by metabolic disease
specialists/biochemical geneticists, gastroenterologists, and
endocrinologists in conjunction with a clinical nutritionist
(dietician), it is important that primary-care providers and
other specialists who oen are involved in the care of individu-
als with GSD I also be able to recognize the condition and pro-
vide appropriate care for these patients.
DIAGNOSTIC CONFIRMATION
Differential diagnosis
e diagnosis in a classic case of GSD I is usually straightfor-
ward. e principal dierential diagnosis includes other forms
of GSD associated with hepatomegaly and hypoglycemia, espe-
cially GSD type III and Fanconi–Bickel syndrome, a glucose
transporter 2 transporter defect classied as GSD XI, which is
not involved in the glycogen metabolism pathway (Tab l e 1 ),
and, possibly, GSD VI and IX. GSD I and III have several fea-
tures in common, including hepatomegaly, hypoglycemia, and
hyperlipidemia. However, some key dierences between GSD
I and GSD III help to dierentiate these two disorders. Patients
GENETICS in MEDICINE
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KISHNANI et al | GSD I guideline
ACMG StAndArdS And GuidelineS
with GSD I typically present earlier (in the rst few months of
life) with severe fasting hypoglycemia within 3–4 hours aer
feeding. Hypoglycemia is usually not as severe in patients with
GSD III because gluconeogenesis is intact and the peripheral
branches of the glycogen molecule can be mobilized by the
action of hepatic phosphorylase. Nonetheless, for reasons that
are not well understood, some patients with GSD III have an
early clinical onset and experience severe hypoglycemia aer a
brief period without feeding.66
Blood lactate levels increase rapidly in GSD I as BG con-
centrations decrease to levels that normally trigger a counter-
regulatory response (<70 mg/dl or 4 mmol/l) and are markedly
increased when BG levels decrease to <40–50 mg/dl or 2.2–2.8
mmol/l). Blood β-hydroxybutyrate levels increase only mod-
estly in GSD I,53,54 in contrast to marked hyperketonemia with
fasting hypoglycemia characteristic of GSD 0, III, VI, and IX.54
Other biochemical characteristics that help to distinguish
between these disorders are elevated uric acid and lactate levels
in GSD I, whereas these are typically normal in GSD III. At the
time of diagnosis, serum concentration of hepatic transaminase
(aspartate aminotransferase and alanine aminotransferase) are
increased in GSD I and oen return to normal or near-normal
levels with appropriate treatment. By contrast, serum aspartate
aminotransferase and alanine aminotransferase levels are typi-
cally higher in GSD III, VI, and IX, and increased levels tend
to persist despite treatment. Although elevated transaminase
levels and hepatomegaly are common to many primary liver
diseases and other metabolic disorders, hypoglycemia is dis-
tinctly uncommon until the development of end-stage liver
disease for most disorders, except GSDs67,68 and disorders of
fructose metabolism. An increase in creatine phosphokinase
is also oen noted in GSD IIIa due to involvement of skeletal
and cardiac muscle; however, a normal creatine phosphokinase
concentration does not rule out muscle involvement. Whereas
patients with GSD VI and GSD IX are usually reported to
be relatively mildly aected, some patients are more severely
aected and closely resemble patients with GSD III.
Hypoglycemia and ketosis are not typical features of GSD IV.
In this disorder, liver dysfunction that progresses to liver cir-
rhosis is a typical clinical feature. Hypoglycemia is a late nding
and is typically only observed in the setting of liver failure. In
GSD IV, abnormally structured glycogen resembling plant-like
bers (amylopectin) accumulates in the liver.
Fructose-1,6-bisphosphatase deciency,69–71 a disorder of glu-
coneogenesis, and Fanconi–Bickel syndrome (GSD XI)72–75 both
have some features that may be confused with GSD I (Tab l e 1 ).
Because of severe hepatomegaly, lysosomal storage disorders
such as Gaucher disease and Niemann–Pick type B disease may
initially be confused with GSD I. In both these storage diseases,
however, there is striking splenomegaly, which is an important
distinguishing feature, and hypoglycemia does not occur.68
Clinical and laboratory evaluation
GSD I most commonly presents as hypoglycemia and/or hep-
atomegaly in infants.76 A blood sample drawn at the time of
hypoglycemia (“critical sample”) is useful in evaluating the
various metabolic and endocrine causes of hypoglycemia. e
presence of hepatomegaly with hypoglycemia should prompt
a workup that includes measurement of BG, lactate, uric acid,
hepatic prole including liver function tests, cholesterol, triglyc-
erides, basic chemistry panel, creatine kinase, complete blood
cell count with manual dierential white cell count, plasma total
and free carnitine, acylcarnitine prole, plasma amino acids,
β-hydroxybutyrate, urinalysis, urinary Hex4, and urine organic
acids. It should be noted that the pattern of increased low-density
lipoprotein cholesterol, decreased high-density lipoprotein cho-
lesterol, and increased triglycerides seen in GSD I is similar to
the lipid prole observed in patients with hyperlipidemia type II.
In the absence of signicant hepatomegaly, blood measurement
of lactate, uric acid, triglycerides, and cholesterol, in addition to
insulin, growth hormone, and cortisol levels, is recommended
to rule out GSD I in patients with hypoglycemia. Neonates and
children with GSD I who have mild hepatomegaly may be mis-
takenly diagnosed and treated for growth hormone deciency.
In addition, when working up newborns or young infants for
hypoglycemia, results of newborn screening (when available)
should be checked because fatty acid oxidation disorders and
galactosemia (included in standard newborn screening panels)
must be considered in the dierential diagnosis. Patients with
GSD I have signicant lactic acidosis during episodes of hypo-
glycemia with values that may be variable but that are usually
10 mmol/l or more. If there is a concern about blood lactate
levels due to use of a tourniquet to obtain the blood sample,
then examination of the basic metabolic panel will provide sup-
portive evidence of a high anion gap metabolic acidosis due to
lactic acidosis. e combination of hypoglycemia, lactic acido-
sis, hypercholesterolemia, hypertriglyceridemia, and hyperuri-
cemia is strongly suggestive of the diagnosis of GSD Ia.
e presence of neutropenia is suggestive of GSD Ib; how-
ever, it is prudent to remember that neutrophil counts may be
normal during the rst 2 years of life.
e clinical and laboratory evaluation should be sucient to
suggest the correct diagnosis, which can be conrmed by non-
invasive molecular genetic testing either by targeted mutation
analysis based on the patient’s ethnic background or by com-
prehensive gene sequencing.
DIAGNOSTIC TESTING
Laboratory
Initial laboratory ndings that are consistent with GSD I include
hypoglycemia, lactic acidosis, hyperuricemia, hypercholesterol-
emia, hypertriglyceridemia, and, in GSD type Ib, abnormalities
in neutrophils. In addition, some patients may have been evalu-
ated for other causes of hypoglycemia with glucagon stimula-
tion. A glucagon stimulation test may lead to worsening of the
metabolic acidosis in GSD I and therefore is not recommended
to make the diagnosis of GSD I. If it is performed, very close
monitoring is required due to the risk of acute acidosis and
decompensation. In GSD I there will be a signicant increase
in blood lactate but little or no increase in BG concentration.
GENETICS in MEDICINE
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GSD I guideline | KISHNANI et al ACMG StAndArdS And GuidelineS
Biochemical analysis of liver sample. Hepatomegaly oen
leads gastroenterologists to perform a biopsy of the liver to
dierentiate among the diverse etiologies of hepatomegaly. It
should be emphasized that biopsies are not necessary when
GSD is suspected, because gene sequencing is now available
for individual disorders as well as panels of relevant genes.
Biopsies should lead to a denitive diagnosis in most cases but
are critically dependent on correct processing of the tissue.
Tissues should be processed for light microscopy and electron
microscopy and also should be snap-frozen (~15 mg) in the
operating room in liquid nitrogen for biochemical analysis.
Usually 30–40 mg of tissue or four cores of liver tissue are
required for all the studies necessary to make a denitive
diagnosis. In the United States, reliable enzymatic analysis is
available on frozen liver biopsy samples.
Liver histology can help dierentiate GSD I from other
hepatic forms of GSD. Histopathological ndings of the liver
in GSD I include distention of the liver cells by glycogen and
fat and the nding that glycogen is uniformly distributed.77 e
amount of glycogen accumulation may be normal or only mod-
estly increased. Lipid vacuoles are large and numerous.77 By
contrast, in most patients with GSD III, the liver biopsy dem-
onstrates a vacuolar accumulation of non–membrane bound
glycogen primarily located in the cytoplasm. Lipid vacuoles are
far less numerous in GSD III than in GSD I. e presence of
brosis, ranging from minimal periportal brosis to micronod-
ular cirrhosis, occurs in GSD III, GSD VI, and GSD IX but not
in GSD I.18,77,78 Periportal brosis is a very early nding in GSD
III. In both GSD I and GSD III, the stored material is within the
cytoplasm, periodic acid schi positive, and diastase sensitive.
In GSD I, the total glycogen content is much lower than in
GSD III, GSD IV, GSD VI, and GSD IX. Clinical assays mea-
sure overall G6Pase enzyme activity in liver tissue samples (see
description above). Normal G6Pase enzyme activity level in
liver is 3.50 ± 0.8 µmol/min/g tissue. In most individuals with
GSD Ia, the G6Pase enzyme activity is less than 10% of nor-
mal. However, in rare aected individuals with milder clinical
manifestations, the G6Pase enzyme activity can be higher (>1.0
Table 1 Differential diagnosis of GSD I
Disorder Similarity with GSD I Distinguishing features
GSD type 0 (glycogen
synthase deficiency)
Fasting hypoglycemia Absence of hepatomegaly; postprandial hyperglycemia,
hyperalaninemia and hyperlactatemia; fasting ketosis
GSD III (glycogen debrancher
enzyme deficiency)
Hepatomegaly, fasting hypoglycemia, ↑ AST
and ALT,a hyperlipidemia
Hypoglycemia is usually less severe, but the patient may have more
severe ketosis and absence of hyperlactatemia and hyperuricemia;
↑ AST, ALT usually higher (may be >500 U/l); cardiac and skeletal
muscle involvement with ↑ CK concentrations in GSD IIIa; normal
blood lactate and uric acid
GSD IV (branching enzyme
deficiency)
Hepatomegaly, ↑ AST and ALT,a prolonged
PT and low albumin in advanced stage of
disease
Lack of hypoglycemia until end-stage liver disease; PT commonly
prolonged in GSD IV; increased GGT
GSD VI (hepatic
phosphorylase deficiency)
Hepatomegaly, fasting hypoglycemia, ↑ AST
and ALT,a hyperlipidemia
Hypoglycemia usually occurs only during fasting and is associated
with hyperketosis; GSD VI can be less severe, however, in some
patients there is significant hypoglycemia; blood lactate is normal
but there can be postprandial elevations.
GSD IX (hepatic form of
phosphorylase kinase
deficiency)
Hepatomegaly, fasting hypoglycemia, ↑ AST
and ALT,a hyperlipidemia; some rare patients
have a proximal renal tubular dysfunction
(X-linked form)
Hypoglycemia is typically less severe, usually occurs only during
fasting, and is associated with hyperketosis; blood lactate is normal;
but there can be postprandial elevations metabolic acidosis is rare;
some patients develop liver fibrosis which can progress to cirrhosis
in rarer cases
GSD XI (Fanconi–Bickel
syndrome due to GLUT 2
deficiency)
Hepatomegaly, fasting hypoglycemia and
ketosis, ↑ AST and ALT,a Fanconi-like renal
tubular dysfunction (glucosuria, proteinuria,
phosphaturia, generalized aminoaciduria)
Postprandial hyperglycemia; gastrointestinal symptoms (chronic
diarrhea from carbohydrate malabsorption); hypophosphatemic
rickets; significant short stature
Disorders of gluconeogenesis
(e.g., fructose-1,6-
bisphosphatase deficiency)
Hepatomegaly, fasting hypoglycemia and
hyperlacticacidemia, ↑ uric acid, AST, and ALT
Hypoglycemia after more prolonged (e.g., overnight) fasting or
during intercurrent illness with reduced carbohydrate intake
Primary liver disease (e.g.,
α-1-antitrypsin, hepatitis)
Hepatomegaly, ↑ AST and ALTaLack of fasting hypoglycemia and hyperlacticacidemia
Other storage (metabolic)
diseases (Niemann–Pick B
disease, Gaucher disease)
Hepatomegaly and splenomegaly, growth
failure, hyperlipidemia
Lack of fasting hypoglycemia, significant splenomegaly; storage
cells characteristic of the disease, other features such as bone and
pulmonary involvement
Hereditary fructose
intolerance
Hepatomegaly, ↑ AST and ALTaGastrointestinal symptoms, long-term liver and kidney damage,
prolonged PT, hypoalbuminemia, elevation of bilirubin, and proximal
tubular dysfunction; hypoglycemia provoked by fructose intake;
improvement of symptoms with fructose restriction
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; GGT, gamma-glutamyl transpeptidase; GLUT 2, glucose transporter 2; GSD, glycogen
storage disease; PT, prothrombin time.
aIn GSD I, increased AST and ALT is usually most pronounced in the untreated or inadequately treated state and tends to normalize with appropriate treatment.
GENETICS in MEDICINE
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KISHNANI et al | GSD I guideline
ACMG StAndArdS And GuidelineS
and <2.7 µmol/min/g tissue). G6P translocase activity in vitro
is dicult to measure in frozen liver biopsy specimens; fresh
(unfrozen) liver biopsy tissue is needed to assay enzyme activity
accurately. As a result, most clinical diagnostic laboratories do
not oer enzyme activity testing for GSD Ib.
Molecular genetic testing. Noninvasive molecular genetic
testing through full gene sequencing of the G6PC (GSD Ia)
and SLC37A4 (GSD Ib) genes can be used for conrming
the diagnosis.79 Mutations in the G6PC gene are responsible
for ~80% of GSD I cases, and mutations in SLC37A4 gene
are responsible for ~20% of GSD I cases. Although full gene
sequencing for both of these genes is available for clinical
testing, targeted mutation analysis can be helpful in some
ethnic groups. Testing for specic common mutations can
identify up to 100% of aected individuals, depending on the
ethnic group.7,12,16,17
Some examples of the common mutations seen in GSD Ia are
listed in Tab le 2 .
Some common mutations seen in GSD Ib are listed in Tab l e 3 .
Sequence analysis. Although sequence analysis of G6PC can
detect up to 100% of aected individuals in some homogeneous
populations,14 in mixed populations (e.g., in the United States)
the detection rate can be lower (~94%), as indicated by some
individuals with clinically and enzymatically conrmed GSD Ia
for whom only one mutation can be detected. It is possible that
these individuals carry large deletion mutations of one or more
exons, introns, or the whole gene that are unlikely to be detected
by current sequencing methods. Mutations in the promoter
region will also be missed by standard sequence analysis.
Similarly, full gene sequence analysis of SLC37A detects
mutations in up to 100% of aected individuals in some homo-
geneous populations,7,12,79–81 but in mixed populations the
detection frequency could be lower because both mutations
may not be detected in some individuals even though the clini-
cal phenotype is consistent with GSD Ib.
Pathologic allelic variants. At present, 86 disease-causing
mutations have been reported in the G6PC gene (GSD
Ia) and 82 disease-causing mutations have been reported
in the SLC37A4 gene (GSD Ib). e reported mutations
are scattered throughout these genes. Some additional,
but as yet unreported, mutations have been identied
through clinical testing of known patients from various
ethnic groups. e mutations identied include missense
and nonsense mutations, small deletions and insertions
resulting in frameshis, splice-site mutations, and rare gene
rearrangements.7,12,17,79,80,82
Deletion/duplication analysis. Large multiexon deletion/
duplications in the G6PC and SLC37A4 genes cannot be
detected by sequence analysis. Although the exact frequency
of exonic or multiexonic deletions is not known, very few
such mutations have been reported in either of these genes83
(unpublished clinical laboratory observations). A variety
of methods, including quantitative PCR, long-range PCR,
multiplex ligation-dependent probe amplication, and targeted
array (gene/segment-specic), may be used for deletion/
duplication analysis. Comparative genomic hybridization
analysis that detects deletions/duplications across the genome
may also include these genes/segments.
Testing strategy for GSD I
Mutation analysis is the rst choice for diagnosis if GSD I is
suspected (B ox 1). Complete G6PC sequencing is usually per-
formed rst, unless neutropenia is present. If snap-frozen liver
biopsy tissue is available to conrm the diagnosis, it can be ana-
lyzed for G6Pase enzymatic activity. Decient enzyme activity
conrms the diagnosis of GSD Ia.
Table 2 Common mutations seen in GSD Ia
cDNA changeaOld cDNA nomenclaturebAmino acid changeaEthnicity References
c.247C>T C326T p.Arg83Cys Caucasian (32%), Jewish (96%) 4,8,9,12,15
c.248G>A G327A p.Arg83His Chinese (38%) 9,12,202
c.378_379dupTA 459insTA p.Tyr128Thrfs*3 Hispanic (50%) 4,12,13
c.648G>T G727T p.Leu216Leu; creates new splice site Japanese (85–88%), Chinese (36–40%) 9–12
c.1039C>T 1118C>T p.Gln347* Caucasian (21%) 7,9,12,14
cDNA, complementary DNA; GSD, glycogen storage disease.
aNomenclature based on the recommendation of the Human Genome Variation Society (http://www.hgvs.org). bEarly reports of mutations in G6PC designated the
transcription start site as +1 (ref. 4).
Table 3 Common mutations seen in GSD Ib
cDNA changeaOld nomenclaturebAmino acid changeaEthnicity References
c.352T>C 512T>C p.Trp118Arg Japanese (37–50%) 9,12,80,81,203
c.1015G>T 1184G>T p.Gly339Cys Mixed Caucasian (19–21%), German (29%) 9,12,204
c.1042_1043delCT 1211delCT p.Leu348Valfs*53 Mixed Caucasian (27–31%), German 32% 7,9,12,79,114
cDNA, complementary DNA; GSD, glycogen storage disease.
aNomenclature based on the recommendation of the Human Genome Variation Society (http://www.hgvs.org). bEarly reports of mutations in G6PC designated the
transcription start site as +1 (ref. 205).
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OVERVIEW OF MANAGEMENT
GSD I is a multisystem disorder that is best managed by a mul-
tidisciplinary team led by a physician with expertise in man-
aging this disorder; this physician—who may be a metabolic
disease specialist/biochemical geneticist, endocrinologist, or
hepatologist—coordinates the patient’s care together with a
metabolic dietician. Other specialists required to manage spe-
cic manifestations of the disease include a nephrologist, a
hepatologist, a hematologist, a genetic counselor, and a cardi-
ologist. Transplant specialists are consulted when indications
for liver and/or kidney disease arise.
All specialists involved in the care of an individual with GSD
I should have an understanding of the disease, its protean man-
ifestations, and its unique challenges, including the psycho-
logical and emotional impacts of this disease on patients and
families.84
GASTROINTESTINAL/NUTRITIONAL ASPECTS
e defect of G6Pase and translocase greatly impacts the nutri-
tion status of those with GSD I. Nutrition therapy for GSD Ia
and GSD Ib is the same, but those with GSD Ib may require
further dietary intervention related to the consequences of neu-
tropenia such as Crohn disease–like enterocolitis.
Infants and young children
Hypoglycemia—the primary concern in infants and young chil-
dren with GSD I—permeates all aspects of their diet and lifestyle
(although in rare cases older children or adults with GSD I may
present without hypoglycemia) (see Box 2). It is critical that the
initial nutrition assessment be broad, not only evaluating the
child’s intake but also documenting sleep patterns, signs and
symptoms of hypoglycemia, the timing of feedings, BG records,
gastrointestinal disturbances, and vitamin/mineral supplemen-
tation. Children who are fed frequently from birth may not
exhibit obvious signs of hypoglycemia until they sleep through
the night or have an illness and fast for an extended period of
time. A child with an undiagnosed or improperly treated case
may have BG levels less than 40 mg/dl (normal: 70–100 mg/dl
or 3.9–5.6 mmol/l) even aer a short fast of 3–4 hours.85,86 Early
diagnosis reduces the risk of prolonged hypoglycemia, which,
untreated, may cause developmental and physical delay, sei-
zures with or without cerebral damage, and even death. Once a
diagnosis is made and nutrition therapy is implemented, close
BG monitoring and other laboratory parameters must con-
tinue as the child grows and nutritional needs change. Without
frequent BG monitoring, asymptomatic low BG levels result
in suboptimal control, which further inhibits normal growth,
development, and overall metabolic control. e aim should be
to keep BG ≥70 and to avoid rapid glucose uxes.
Nutrition therapy. Recurrent hypoglycemia causes lactic
acidosis, hepatomegaly, hypertriglyceridemia, hyperuricemia,
and failure to thrive in the young child. us, avoidance
of fasting is the rst line of treatment in GSD I. To prevent
hypoglycemia, small frequent feedings high in complex
carbohydrates (preferably those higher in ber) are evenly
distributed over 24 hours.
In general, the nutrient composition of the diet is 60–70%
calories from carbohydrates, 10–15% calories from protein (to
provide the daily recommended intake), and the remaining
calories from fat (<30% for children older than 2 years).84,87–89
As a result of the deciency of the G6Pase enzyme, fructose and
galactose are not metabolized to glucose-6-phosphate, which
further contributes to the biochemical abnormalities.90,91 ere
is no consensus regarding the restriction of these two sugars in
the diet, but sucrose (fructose and glucose) and lactose (galac-
tose and glucose) are oen limited or avoided.89 Limiting these
sugars reduces or completely eliminates sugar, fruit, juice, dairy,
and foods that contain these products from the diet. Careful
assessment and supplementation of micronutrients is required
to avoid nutrient deciencies.
Infants
Formulas and enteral feedings. In infancy, a soy-based, sugar-
free formula or a formula that is free of sucrose, fructose, and
lactose is fed on demand every 2–3 hours. Once the infant is
able to sleep longer than 3–4 hours at a time, several decisions
must be made to avoid hypoglycemia during the overnight fast.
One option is to continue to wake the infant every 3–4 hours
to monitor BG and oer feedings. Another option is to use
overnight gastric feedings (OGFs). Due to the life-threatening
risks of severe hypoglycemia causing seizures, permanent brain
damage, and even death in GSD I, it is recommended that the
parents (and/or child, when older) be trained in inserting a
nasogastric (NG) tube or that a G-tube be surgically placed so
that there is always access to treat for hypoglycemia, especially
Box 1 Laboratory diagnostic testing recommendations
• Blood/plasma hypoglycemia, lactic acidosis, hypercholesterol-
emia, hypertriglyceridemia, and hyperuricemia are consistent
with GSD type I.
• Neutropenia suggests GSD Ib; however, neutropenia can be seen
in GSD Ia also. Neutrophil counts may be normal in GSD Ib dur-
ing the first years of life.
• Diagnosis should be confirmed by full gene sequencing of the
G6PC (GSD Ia) and SLC37A4 (GSD Ib) genes.
• If liver biopsy is performed, histology typically shows fat and
glycogen in hepatocytes without fibrosis. Glycogen content is
mildly increased as compared with that seen in other liver GSDs
(especially GSD III and GSD IX). Diagnosis is often made by mea-
suring G6Pase enzyme activity on a piece of snap-frozen liver
biopsy tissue; however, G6Pase enzyme activity on a piece of
snap-frozen liver biopsy tissue will not detect GSD Ib.
• Targeted mutation analysis is useful for prenatal diagnosis and
carrier testing for patients with known private family mutations
and may be useful when knowledge of common mutations for
specific ethnic groups is available.
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during times of illness or refusal to eat. For patients with
GSD Ib and neutropenia, a G-tube may not be a good option
because of the risk for recurrent infections at the surgical site.
If a child has neutropenia, a G-tube should be placed only if
granulocyte colony-stimulating factor (G-CSF) (Neupogen)
is being administered. e formula may be oered every 4
hours by mouth and/or by tube, or the formula may be infused
continually at a rate to provide adequate glucose to maintain
the BG level at more than 70 mg/dl or 4 mmol/l. Formulas for
the OGF may be the same infant formula the child uses during
the day (should be sucrose free, fructose free, and lactose free)
or it may be an elemental formula that has a higher percentage
of carbohydrates. Infusing glucose may be an option in some
cases. Feeding regimens are determined case by case. In general,
the rate of the continuous tube feeding is calculated to provide a
glucose infusion rate of 8–10 mg glucose/kg/min during infancy
and 4–8 mg glucose/kg/min in older children.92–94 Adjustments
of the rate of the tube feeding are made based on BG monitoring
so that optimal control is achieved. When the tube feeding is
completed each morning, there will still be high circulating
insulin levels. us, it is important to feed the infant immediately
aer discontinuing tube feedings to avoid a rapid decrease in
glucose (it may be benecial to feed rst and wait 30 min before
disconnecting glucose). OGFs are not without fault or risks.
ere have been reports of pump failures and occluded or
disconnected tubing preventing the formula from being infused
and leading to hypoglycemia, seizures, and even death.95 Safety
precautions such as bed-wetting devices (to detect formula
spilling onto the bed), infusion pump alarms, safety adapters,
connectors, and tape for tubing should be advised.
Introducing solid food. Solid food is introduced along the
normal time line between 4 and 6 months of age. Infant cereals
are followed by vegetables and then by meat. Fruits, juice, and
other sucrose-containing, fructose-containing, and lactose-
containing foods are limited or omitted. Spoon-feeding,
drinking from a cup, and the introduction of table foods should
follow the normal feeding progression in order to prevent long-
term feeding disorders. Any delays in this progression should
be addressed immediately (see later section on feeding issues).
The young child
Restricting fruit, juice, and dairy foods impacts two entire food
groups and renders the diet inadequate. In GSD I, a complete
multivitamin with minerals is essential. If a sugar-free soy-
based milk that is fortied with calcium and vitamin D is not
included, then calcium with vitamin D supplements are also
essential. Without appropriate supplements, these children are
at risk for a variety of nutritional deciencies.96 In a recent study,
61.5% of those with GSD I who were tested for 25-OH-vitamin
D levels had insucient levels (<30 ng/ml). ese levels were
low despite the subject’s reports of taking their prescribed sup-
plements.87 Osteoporosis is a known long-term consequence
of GSD I. Although the cause may be multifactorial, optimal
nutrition at a young age can only help prevent or delay some of
the long-term consequences of the disease. erefore, the focus
of the diet (Tab l e 4 ) must go beyond simply preventing and
treating hypoglycemia.97
Cornstarch. Raw cornstarch (CS) has been used for the treatment
of hypoglycemia in GSD I since the early 1980s.98 ere is no
consensus regarding the age at which CS therapy should be
initiated, but a trial is oen introduced between 6 months and
1 year of age. Amylase is needed for the digestion of CS; this
enzyme may or may not be fully present until 2 years of age.
Starting with a small dose of raw, uncooked CS and gradually
increasing the dose to the goal may help improve tolerance.
Side eects of CS may include gas, bloating, and diarrhea, but in
some cases the symptoms may subside aer 2 weeks of therapy.86
ose with GSD Ib oen have worse gastrointestinal issues
and may be diagnosed with a Crohn disease–like colitis.99,100
In some cases, pancrelipase (lipase, protease, and amylase) has
been used in conjunction with CS therapy to reduce the side
eects, but routine usage is not recommended.98 CS is digested
slowly, providing a steady release of glucose, which allows more
stable glucose levels over a longer period of time as compared
with other sources of carbohydrates.98,101
General guidelines for dosing CS include 1.6 g of CS per kilo-
gram of body weight (ideal body weight) every 3–4 hours for
young children, and 1.7–2.5 g CS/kg every 4–5 hours (some-
times 6 hours) for older children, adolescents, and adults. Some
adults may eventually only require one dose of CS at bedtime
to maintain their BG at more than 70 mg/dl or 4 mmol/l and to
maintain their lactates at less than 2 mmol/l through the night.98
Given these variations in how oen dosing should occur in
order to maximize metabolic control including BG, cholesterol,
triglycerides, and liver enzymes, and given a limited evidence
base related to CS dosing and metabolic control, it is important
for adolescents and adults to continue to check BG and lactate
levels regardless of how stable they feel personally.
Argo (Summit, IL; http://www.argostarch.com) brand CS,
by patient report, is the preferred brand in the United States in
terms of both taste and sustainability. Other brands should be
used with caution, and randomly switching between brands is
not recommended. A modied CS, Glycosade, is available in
Europe and the United States for overnight treatment.97 Because
data are limited with regard to long-term use of Glycosade,
the new therapy should be used only with close monitoring of
markers of metabolic control. As with any changes to CS brand
or dose, changes should be made under the supervision of the
metabolic team with frequent BG monitoring.
CS can be mixed in sucrose-free, fructose-free, lactose-free
infant formula, sugar-free soy milk, sugar-free drinks, and/or
water. In previous studies, mixing CS with lemonade or hot
water or taking high doses of vitamin C resulted in a sharp
increase in BG levels, followed by a rapid decline. It was specu-
lated that the heating process and the ascorbic acid disrupted
the starch granules, rendering the CS less eective.98,101 Patients
with low citrate who are prescribed Bicitra have become hypo-
glycemic when mixing their Bicitra with their CS beverage. e
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mechanism is likely similar to that described above for lemon-
ade. Until further studies are available to investigate this mech-
anism, patients should not mix Bicitra with their CS drink.
Ideally, the CS dose should be weighed on a gram scale.
When a scale is not available, the dose may be translated into
tablespoons. One level tablespoon of CS weighs approxi-
mately 8 g. e dilution is approximately 1 g of CS to 2–3 ml
of uid. e amount of uid can be adjusted based on prefer-
ence or tolerance.101 Similar dilutions of 3 g CS to 10 ml uid
have also been suggested.89 If gastrointestinal disturbances
occur, increasing the liquid may be benecial. As with the
OGF, CS therapy also has its limitations. Missed CS doses
because of failure of alarm clocks or sleeping through an
alarm can lead to hypoglycemia, seizure, and even death.95
e use of battery-operated alarm clocks, setting two alarm
clocks, and keeping the alarm clock out of reach to avoid
rolling over and turning it o should be advised. Parents may
need to alternate nightly duties to avoid sleep deprivation
that can lead to lapses.
BG monitoring
BG monitoring is essential for well-controlled GSD. Frequent
BG monitoring is needed to establish the initial diet prescrip-
tion and then should occur randomly to avoid asymptomatic
hypoglycemia. BG testing should be documented before each
clinic visit so that diet, CS intake, and OGFs can be adjusted. A
detailed record noting the time, the BG level, and all foods, CS,
and beverages consumed should be provided to the clinic dieti-
tian. e BG levels should be checked before meals, before CS
intake, and/or before and aer exercise for 2–3 days before the
clinic visit. When the CS dose is changed, BG levels should be
checked aer 4 hours and then at 1-hour intervals to establish
Table 4 Foods allowed and foods not allowed in GSD I
Food group Foods allowed Foods not allowed
Dairy Limit to one serving per day: Ice cream
1 cup low-fat milk (ideally soy or almond milk)
1 cup low-fat sugar-free yogurt Sweetened yogurt with milk
1.5 oz. hard cheese Sweetened milk
Cereals Dry and cooked cereal with no added sugar Cereals with fruit or sugar added
Breads White, wheat, or rye breads Raisin bread
Crackers, matzo Muffins
English muffins Sweet rolls
Dinner rolls, biscuits Pies
Pita bread Cakes
Sweet breads
Waffles and pancakes made with sugar
Starches Brown and white rice Any starches with sugar added
Pasta Sweet potatoes
Popcorn
Tortillas
White potatoes
Vegetables All nonstarchy vegetables including asparagus, cabbage, spinach,
squash, onions, green beans, turnips, greens
Any with added sugar, milk, cheese
Corn, peas, and carrots have more sugar than the others
Fruit Lemons and limes All other fresh, canned, dried, and dried fruits
Avocados Tomatoes
Meat Lean poultry, beef, pork, fish Organ meats
Fatty and processed meats
Legumes/nuts All beans and nuts Any beans, nuts, or seeds with sugar added
Soups Broth soups made with allowed meats, starches, and vegetables Creamed soups
Fats Canola and olive oil Trans fatty acids
Corn, safflower, canola, and soybean oil–based condiments Saturated fats
Reduced-fat condiments
Sweets Sugar substitutes, sucralose All other sugars, sweets, syrups, high-fructose corn syrup,
honey, molasses, sorbitol, and cane sugar, juice, and syrups
Dextrose
100% Corn syrup, rice syrup
Sugar-free Jell-O and pudding
Candies made with dextrose
GSD, glycogen storage disease.
Data from ref. 87.
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the duration of eectiveness (how long the dose of CS will
maintain the BG level >70 mg/dl). Other changes to routines,
school schedules, activities, or those at the onset of illness also
require close BG monitoring.
Lactate meter. e use of a portable lactate meter (LactatePro)
has been studied and used for the GSD population by at least
one group in the United States and in Europe. e lactate meter
may be a good supplement to glucose monitoring, especially
during times of illness to help prevent acute deterioration, to
avoid hospitalization, or to alert the parent that is time to go to
the emergency room. e lactate meter has been found more
useful in GSD Ia as compared with GSD Ib in one study.102
Continuous blood glucose monitoring system. Another tool
that is oen considered for monitoring and managing BG
control in GSD is the continuous glucose monitoring system.103
is tool has been used in the diabetic population for more
than a decade and, more recently, has been studied in the
GSD population. e concern is that the meter may not be as
good at detecting low glucose levels, and 20% of hypoglycemia
occurrences were missed in one study. However, this may change
with the development of new meters. e use of continuous
glucose monitoring systems in the home environment under
real-life circumstances may provide more realistic data and may
show trends more clearly than in measurements made in the
hospital setting. e system may also help detect asymptomatic
hypoglycemia.
Treating hypoglycemia
BG levels should be maintained at more than 70 mg/dl. If the
BG level is less than 60 mg/dl, then hypoglycemia should be
treated. Signs of low glucose may include lethargy, muscle
weakness, nausea, irritability, or a sense of lightheadedness or
sweating. However, in many instances, patients with GSD I do
not experience low glucose symptoms until BG levels become
very low (<60 mg/dl).
Treatment for hypoglycemia is twofold. First, the low BG must
be rescued with a quick-acting source of glucose. en, a snack
or CS is given in order to sustain normal BG. Treatment agents
include commercially prepared glucose polymers or over-the-
counter diabetic glucose tablets and gels. e amount of glucose
given is determined based on the glucose delivery rate desired.
All people with GSD I should wear a medical alert bracelet
because prompt and appropriate treatment is critical in GSD I.
Continual episodes of hypoglycemia indicate an underly-
ing problem. It may be time to adjust the CS dose or schedule.
ere may be an intercurrent illness or there may be a compli-
ance fa ctor.
Overtreatment
Parents fearing the known consequences of hypoglycemia may
overcompensate by overtreating and overfeeding their child.
Parents should be cautioned against overtreatment at each
clinic visit, especially if an increased weight trend is noted.
Other complications of overfeeding, including increased gly-
cogen storage, over time can lead to hyperinsulinemia and
insulin resistance.97 Excess CS or taking CS too close to meal
time reduces the appetite at meal time, limiting the intake
of nutritious foods, and can result in nutrient deciencies.96
Overtreatment can also lead to worsening lactic acidosis.
Increased gastrointestinal disturbances may also result from
excess CS. Scheduling CS and balancing meals can be dicult
and the metabolic dietitian should work closely with the family
early on to avoid the development of feeding issues.
Feeding issues
With most chronic illnesses that involve dietary treatment, it
may be dicult for the family to achieve an appropriate balance.
Children may be delayed making the transition from formula to
baby food and from baby food to table food. ey may be delayed
in weaning from the bottle to a cup. e child may be too full from
formula and CS and refuse to take solid foods. e metabolic
dietitian will need to address these issues by periodically assessing
the diet and adjusting the meal and snack schedules, CS doses,
meal times, and OGFs. ere is a ne balance between maintain-
ing as much normalcy as possible while meeting the goals of the
GSD diet, maintaining normal BG levels, and meeting the child’s
individual nutrient needs for normal growth and development. If
a child continues to show signs of diculty with feeding, the child
should be referred to a speech or occupational therapist for a full
feeding evaluation. In some cases, if psychosocial issues are appar-
ent, the family may be referred to the clinical social worker or the
child may need a full psychological evaluation.104
Growth
It is important to track the height, weight, weight/height ratio,
body mass index, and head circumference in patients with GSD
I. Changes in growth trends may reect poor metabolic control.
If revisions to the diet, CS, and OGFs do not improve growth, a
referral to an endocrinologist may be indicated.
In the older child who has a delayed bone age, the length needs
to be corrected accordingly on the growth chart. Otherwise, the
child may be misdiagnosed with poor growth.
Diet and pregnancy
Successful pregnancies in both GSD Ia and GSD Ib have been
reported in the literature.48,105–108 Planning ahead of time in
accordance with the metabolic team to optimize nutrition,
including supplements and tight metabolic control before con-
ception, is recommended. Close BG monitoring is required
so that diet and CS dosing and frequency can be adjusted. CS
requirements typically increase during pregnancy. e meta-
bolic team and a high-risk obstetrics group should coordinate
care together. e admission should be planned in advance so
an i.v. glucose infusion can be initiated before delivery to main-
tain normal BG levels. Good metabolic control also decreases
the bleeding complications that could occur at the time of
labor and delivery if poor metabolic control is a factor (see
Hematology section).
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Long-term complications and nutrition implications
It is important to review vitamin/mineral compliance annu-
ally. ose with GSD I are at an increased risk for osteoporosis.
Good metabolic control, including adequate nutrients through-
out the life span, may help prevent or delay bone loss. DEXA
scans and 25-OH vitamin D are included as part of the standard
screening for GSD I.
Gout is another long-term complication of GSD I. Again, diet
adherence and good metabolic control from the onset may pre-
vent the high levels of uric acid that can cause gout. For those
with a tendency toward gout attacks, a low-purine diet is pre-
scribed in addition to allopurinol. e side eects of allopurinol
should be monitored, including hypersensitivity syndrome and
Stevens–Johnson syndrome.
Other dietary considerations
Elevated triglycerides and cholesterol above the normal ranges
may persist in some patients with GSD I, despite appropriate
dietary treatment. Although eects of hyperlipidemia in GSD I
have been studied for decades, there is no consensus regarding
the long-term complications or the best treatment for hyperlip-
idemia in this disorder. Both dietary and pharmacological treat-
ments have been studied, including brates, statins, niacin, and
sh oil.109,110 e eect of medium-chain triglycerides on lowering
cholesterol and triglycerides is currently being studied.111,112 e
use of vitamin E and its eectiveness in reducing the frequency of
infection and improving neutropenia has been reported.113
In conclusion, dietary therapy for the treatment of GSD I has
improved the long-term outcomes for patients, but, unfortu-
nately, many complications remain. Further studies of dietary
practices and alternative dietary treatments are needed to pro-
vide consensus for evidence-based guidelines.
LIVER ISSUES
Hepatic manifestations
Hepatomegaly in GSD I attributable to fat and glycogen depo-
sition is universal, resulting in a marked steatotic and enlarged
liver.114–116 Hepatomegaly is more pronounced in the younger
child, resulting in abdominal protrusion; however, with age, the
liver size tends to decrease. Given that the stored glycogen is
normal in structure, liver enzymes are typically normal in GSD
I. An elevation of liver enzymes may sometimes be noted early
in the disease course, typically around the time of diagnosis.
Hepatocellular adenoma (HCA), HCC, hepatoblastoma, focal
fatty inltration, focal fatty sparing, focal nodular hyperplasia,
and peliosis hepatis are some of the liver lesions noted in GSD Ia
patients. Of these lesions, HCAs are the most common and typi-
cally appear in the second or third decade of life; reported fre-
quencies range from 16 to 75%.115,117 However, there are patients
who have HCAs at an older age, leading to a diagnosis of GSD I.19
Adenoma characterization
e prevalence of HCAs increases with age in GSD I.
Historically, 70–80% of patients older than 25 years have at least
one lesion. Progression in size and/or number of HCAs occurs
in 50% of patients.33 e mean age of adenoma presentation is
14.8 years, but HCAs have been reported in younger patients.
Adenomas noted in patients with GSD I are dierent than those
that are noted in the general population. GSD Ia patients seem
to present with greater numbers of HCAs that are more likely
to be in a bilobar distribution than those in the general popu-
lation. Furthermore, unlike in the general population, there is
no gender predisposition in GSD I. One study noted that of 66
HCAs detected by magnetic resonance imaging in 14 patients,
44 lesions were found in 5 patients, with a mean of 5 lesions
per GSD I patient.118 e general population usually has single,
large, encapsulated HCAs, commonly caused by the use of oral
contraceptive pills.24 In GSD I patients, HCAs are thought to be
the result of inadequate metabolic control. A recent study dem-
onstrated decreased adenoma formation in the setting of good
metabolic control, and regression of adenomas has occurred
Box 2 Gastrointestinal/nutrition recommendations
• A metabolic dietitian is an important member of the team. If not
available, one should be consulted.
• Maintaining blood glucose levels ≥70 mg/dl is important to
achieve good metabolic control. Levels should be kept consis-
tent to avoid hypoglycemia and fluctuations in the blood glucose
levels.
• In infants and children:
°Avoid fasting for more than 3–4 hours.
°Offer small, frequent feedings; avoid or limit sucrose, fructose,
and galactose (a soy formula such as Prosobee may be used
overnight).
°Access via NG or G-tube placement is recommended for
emergencies and/or for OGFs; caution with surgical G-tube
placement should be taken in GSD Ib.
°Monitor blood glucose before feeds.
°Raw, uncooked cornstarch may be introduced between 6 and
12 months of age.
°Continuous gastric feedings may be used overnight.
• In adolescents and adults:
°Avoid fasting for more than 5–6 hours with the use of raw,
uncooked cornstarch and/or OGFs; it is important to not
change the brand of cornstarch. If changed, then monitoring
of BG levels after the change is necessary.
°Plan for small, frequent meals (nutrient distribution: 60–70%
carbohydrates, 10–15% protein, <30% fat); avoid or limit su-
crose, fructose, and galactose.
°Regular blood glucose monitoring is needed, especially during
periods of growth.
• Multivitamins, calcium, and vitamin D are necessary because of
the restricted nature of the diet.
• Both overtreatment and undertreatment are harmful. Overtreat-
ment can result in insulin resistance.
• Good glucose control improves several of the metabolic
sequelae of GSD I.
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in some patients aer outstanding metabolic control was
achieved.118 It should be remembered that factors other than
metabolic control can play a role in the development of ade-
nomas (see next section). As discussed in the Gynecological/
Obstetric Care section, estrogen-based contraceptives should
be avoided when possible.
Hepatocellular carcinoma
Because patients with GSD I live longer, new long-term com-
plications are being recognized. HCC has been noted in several
patients with GSD I.
ere are several challenges concerning the diagnosis of
HCC in GSD I. e cause for HCC is unclear, but there appears
to be an adenoma-to-HCC transformation, rather than HCC
arising in normal liver tissue. Because of the abundance of ade-
nomas, biopsy is not an option. ere is no eective biomarker
because α-fetoprotein and carcinoembryonic antigen levels are
oen normal even in the setting of HCC. No good imaging tool
separates HCA from HCC.
Until recently, the genetic makeup of the adenomas from
patients with GSD I was not known. However, Kishnani et al.120
recently published the ndings of chromosomal and genetic
alterations in 10 cases of HCA associated with GSD type I using
a sensitive genome-wide high-density single-nucleotide poly-
morphism analysis and mutation analysis of two target genes,
HNF1A and CTNNB1. Chromosomal aberrations were identi-
ed in 60% of the HCAs from GSD Ia adenomas, with the most
signicant chromosomal aberration on chromosome 6, show-
ing a simultaneous gain of 6p and loss of 6q. Although loss of 6q
without gain of 6p was identied in two (non-GSD I HCA) gen-
eral population HCAs in this study, and simultaneous gain of
6p and loss of 6q has been reported in two general population
HCAs in a previous report,121 the signicance of loss of 6q for
HCA development in the general population was inconclusive
because the aberration was just one of multiple chromosomal
aberrations in these cases. By contrast, the fact that chromo-
some 6 alterations was the major nding, with minimal changes
in other chromosomes in three GSD Ia HCAs, strongly suggests
that loss of 6q and/or gain of 6p may be an early event in the
liver tumorigenesis in GSD I. It is speculated that GSD I HCA
with simultaneous gain of 6p and loss of 6q could confer high
risk for malignant transformation, implicating genes on chro-
mosome 6 in the transformation of HCA to HCC. Patients with
these high-risk aberrations may be good candidates for LT until
we have a better understanding of the pathogenesis and other
therapeutic targets. ese ndings also suggest that good meta-
bolic control alone may be insucient to prevent the develop-
ment of HCA in some patients with GSD I.
Clinical monitoring
In the general population, HCAs regress in some patients aer the
cessation of oral contraceptives. In GSD I, there is some evidence
that metabolic control may be a modier of adenoma formation
and progression,118 but there are cases in which adenomas occur
despite good metabolic control. Whereas most investigators
agree that HCAs in GSD Ia patients should be observed for signs
of malignancy, the management of concerning lesions is not
established. Liver imaging is routinely performed in individu-
als with GSD I. In children (<18 years), liver ultrasounds can be
performed every 12–24 months. With increasing age, computed
tomography or magnetic resonance imaging scanning using i.v.
contrast should be considered to look for evidence of increas-
ing lesion size, poorly dened margins, or spontaneous hemor-
rhage.24,33,84,122 e use of i.v. contrast to minimize the number
of missed lesions is recommended. Laboratory testing should
include serum transaminases, creatinine, international normal-
ized ratio (prothrombin time/partial thromboplastin time), albu-
min, and bilirubin tests every 6 months to yearly to monitor the
extent of hepatic damage and to delineate if there is progression
of liver disease, especially in the setting of LT. It is also known
that α-fetoprotein and carcinoembryonic antigen levels do not
predict the presence of HCAs or malignant transformation24,117
in patients with GSD I (see next section).
Initially, the management of liver adenomas in the GSD I pop-
ulation should be conservative (Box 3). An approach of watchful
waiting may be used. ere are reports of the use of percutane-
ous ethanol injection as the initial treatment of enlarging liver
adenomas.123 However, if there are concerns of malignant trans-
formation or the possibility of life-threatening hemorrhage, ade-
noma resection is recognized as a therapeutic option. Resection
of HCAs suspected of being malignant is an eective intermedi-
ate step in the prevention of HCC in GSD Ia patients. As such,
adenoma resection may be used as the initial management of
lesions suspicious for malignancy in GSD I. A study by Reddy
et al.23 is the largest single-center study of adenoma resection in
GSD Ia patients and the only study comparing clinical outcomes
between GSD Ia patients and the general population. In this study
it was noted that GSD Ia patients present with a greater burden of
adenomatous disease and shorter progression-free survival aer
resection than the general population. is experience of HCA
resection in GSD Ia patients demonstrates that partial hepatec-
tomy is feasible in these patients and is an eective intermediate
step in the prevention of HCC until denitive treatment such as a
LT. Because of the low numbers, the true risks of partial hepatec-
tomy particular to this population have not been explored.
Indications for LT
Liver replacement is the ultimate therapy for hepatic metabolic
disease. It should be considered for patients with multifocal,
growing lesions that do not regress with improved dietary regi-
mens and who do not have evidence of distant metastatic disease.
e rst reported LT for GSD I was performed in 1982
(ref124). Since then, more than 100 children and adults with
GSD Ia have undergone liver transplantation in North America
with a 1-, 5-, and 10-year survival rate of 82%, 76%, and 64%,
respectively.125 Aer liver transplantation, all GSD I patients have
achieved resolution of their metabolic derangement, including
correction of hypoglycemia, lactic acidosis, hyperuricemia, and
hyperlipidemia.126 Other benets of transplantation include lib-
eralization of the diet and reduction in the risk of malignancy.42
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However, there are several obstacles to LT in GSD Ia patients.
ese include uncertainties regarding timing of transplanta-
tion, limited organ availability, prospects of worsening renal
function with immunosuppression, and fears of poor patient
compliance with immunosuppressive medication given a his-
tory of faulty adherence to a strict dietary regimen.33,63,122,127 In
the United States, and increasingly in other countries, prior-
ity for LT is governed by the individual’s “model for end-stage
liver disease” (MELD) score. is score is calculated using a
logarithmic assessment of three objective and reproducible
variables, namely total serum bilirubin and creatinine concen-
trations, and the international normalized ratio. e score may
range from as low as 6 to a high of 40. In contrast to the Child’s
score, which formed the basis of assessment of disease sever-
ity, and therefore organ allocation until 2002, the MELD score
represents a continuous assessment of liver disease severity.127
e primary function of the MELD score is to estimate an indi-
vidual’s mortality risk from liver disease and its complications
during the next 90 days: the higher the score, the greater the risk
of death. A MELD score of 15–17 is signicant in that this is the
point at which the mortality risk associated with liver disease and
its complications is equivalent to the 1-year mortality associated
with complications arising from LT.128 Since the inception of the
MELD score as the basis for deceased donor organ allocation,
patients with HCC have been granted additional priority.
In GSD I, because the hepatic abnormalities are the result of
a single-gene, cell-autonomous defect, there is no possibility
of recurrence of primary liver disease within the transplanted
allogra.
e most common indication for liver transplantation in
GSD I has been hepatic adenomatous disease for removal
of potentially premalignant lesions. Other indications have
included growth failure and poor metabolic control.22,42
Optimal metabolic control appears to normalize growth and
minimize the risk of hepatic adenomas, and surgical resection
is recommended over transplantation when solitary lesions are
present.23,118 us, in light of the modest mortality risk associ-
ated with transplantation, the high rate of complications, and
improved prognosis with medical management, routine trans-
plantation is not recommended. Transplantation should be
reserved for patients who have not had success with medical
management, have a history of recurrent adenomas despite
liver resection, have a rapid increase in the size and number of
liver adenomas, and are at high risk for liver cancer.
Although the survival rate aer transplantation has improved
over the past 20 years, complications in the postoperative
course remain. Chronic renal failure is a well-documented
complication of liver transplantation in GSD Ia,129 and some
patients with GSD Ia have progressed to renal failure within a
few years of transplantation.22,126 Of note, nephropathy occurs
even in GSD type Ia patients without overt evidence of renal
disease at the time of liver transplantation.130 e use of nephro-
toxic transplant medications has been proposed as one contrib-
uting factor. Alternatively, a primary GSD-related nephrotoxic
eect may be present because of the untreated condition in the
kidney. Postoperative pulmonary hypertension has also been
documented in a small number of patients aer transplantation.
Although hypoglycemia similarly abates when liver trans-
plantation is performed in GSD Ib, the neutropenia, neutro-
phil dysfunction, and Crohn disease–like inammatory bowel
disease are variably aected by liver transplantation. G-CSF is
still oen needed to treat the neutropenia associated with GSD
Ib despite normalization of the metabolic prole aer liver
transplantation because neutropenia is primarily attributable
to an intrinsic defect in the neutrophils of GSD Ib patients and
is not corrected by LT.126,131 Posttransplant immunomodulation
may also increase neutropenia risk in GSD Ib patients aer
Box 3 Hepatic and hepatic transplant recommendations
• There should be monitoring for the development of liver ad-
enomas via liver imaging especially after the onset of puberty.
• Adenomas are often multiple. In some situations, there is regres-
sion of adenomas noted with good metabolic control. Other ge-
netic factors can play a role in hepatic adenoma development.
There is a risk for adenoma to HCC transformation, especially
when there is a rapid increase in size or number of adenomas.
In the setting of adenomas, routine laboratory testing to include
hepatic profile (serum glutamic oxalacetic transaminase, serum
glutamic pyruvic transaminase, albumin, bilirubin) should be per-
formed every 6 months. In the setting of consideration of an
LT, laboratory testing that includes serum creatinine and interna-
tional normalized ratio (prothrombin time/partial thromboplastin
time) tests, in addition to hepatic profile, should be performed
every 6 months.
• α-Fetoprotein and chorionic embryonic antigen levels are often
normal, even in the setting of HCC, and do not predict hepato-
cellular adenoma to malignancy transformation.
• Abdominal ultrasound is reasonable in the pediatric population.
Abdominal imaging should be performed at baseline and then
every 12–24 months.
• Abdominal computed tomography/magnetic resonance imaging
with contrast should be performed in older patients or patients
within the pediatric age group once adenomas are detected on
ultrasound and are to be repeated every 6–12 months or earlier
based on laboratory and clinical findings.
• Percutaneous ethanol injections, radiofrequency ablation, and
partial liver resection are treatment options for liver adenomas
(especially if an increase in size, number, or bleeding is noted).
Ahigh suspicion of HCC is needed because no reliable biomark-
er is currently available for HCA-to-HCC transformation. A sud-
den increase in size or number, or an increase in vascularity of
adenomas, is concerning for HCC transformation.
• Monitoring of the patient’s MELD score is critical because it is
used to assess the extent of liver disease and for ranking for LT.
The latter should be performed at centers with experience in
ranking GSD I severity.
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transplantation.132 us, a lot of caution needs to be exercised
when deciding on LT as a treatment option for GSD.
NEPHROLOGY
Renal manifestations of GSD I appear early in childhood and
oen go undetected without specic diagnostic evaluation.
Glycogen deposition occurs in the kidneys, which typically are
large on renal imaging; however, nephromegaly is not sucient
to be readily detected on physical examination. As a result of
both the metabolic perturbations that arise and the glycogen
accumulation with GSD I, there can be not only proximal and
distal renal tubular dysfunction but also progressive glomerular
injury that can result in functional renal impairment and even
end-stage renal disease requiring renal replacement therapy.
Specic interventions aimed at ameliorating or trying to pre-
vent the progression of these renal consequences of GSD I are
best commenced early aer their presentation to have the best
opportunity to alter the course of renal injury.
Proximal and distal tubular dysfunction
e proximal tubule is the site of a great deal of energy expen-
diture and G6Pase activity is normally highest. With proxi-
mal tubular dysfunction, wasting of bicarbonate, phosphate,
glucose, and amino acids can be seen. In GSD I, proximal
tubular dysfunction has been ascribed to glycogen accumula-
tion in proximal tubular cells or inability to produce glucose
for metabolic needs. In children with poorly controlled GSD
I, there tends to be more documentation of aminoaciduria
and phosphaturia because these children have such low serum
glucose and bicarbonate levels that little tubular reabsorption
is required. e other proximal tubular defects improve with
eective therapy such as the provision of CS and, as a result,
tend not to be seen in most patients receiving treatment to
maintain glucose levels.37
Along the proximal tubule, there is also sodium-linked reab-
sorption of calcium and the organic acids such as citrate that
can freely cross the glomerular ltration barrier. Up to 90%
of ltered citrate is usually reabsorbed, although citrate reab-
sorption does tend to decrease during adulthood, likely due to
changes in the maximal transport capacity of aging nephrons.
e citrate that remains in the urine plays an important role
in enhancing the ionic strength of the urine, essentially che-
lating urinary calcium and helping to prevent its precipitation
and the development of nephrolithiasis or nephrocalcinosis. As
a result, individuals with low urinary citrate levels are more pre-
disposed to urinary tract calcications, and such urinary tract
calcications can increase the chances of urinary tract infection
or mediate renal parenchymal damage with loss of renal func-
tional reserve.
In normal individuals, urinary citrate excretion exceeds 5 mg/
kg/day or 300 to 400 mg/g urinary creatinine in spot samples
of urine. With GSD I, instead of the usual increasing urinary
excretion of citrate with ongoing maturity, there is an actual
decrease in citrate excretion that accelerates during adoles-
cence and early adulthood.40 Although citraturia is inuenced
by acid–base homeostatic mechanisms, with increasing urinary
citrate excretion seen in systemic alkalosis and decreasing uri-
nary citrate excretion seen in systemic acidosis, metabolic con-
trol alone is not responsible for the changes in citrate excretion
in GSD I because, even in metabolically well controlled GSD
I with normal acid–base status or compensated mild meta-
bolic acidosis without systemic pH change, there is widespread
hypocitraturia.40 ere has also been speculation that, over
time, GSD I patients develop an incomplete distal renal tubular
acidosis that may also contribute to the low urinary citrate lev-
els and hypercalciuria.62
Glycogen deposition in the proximal tubule does reduce
proximal tubular calcium reabsorption and is the likely mech-
anism for altered urinary calcium levels in GSD I. Normally,
urinary calcium excretion is less than 4 mg/kg/day or less than
0.2 mg/mg when a random urinary calcium to creatinine ratio
is obtained. Hypercalciuria is widespread in prepubertal chil-
dren with GSD I, and the likelihood for nephrolithiasis and
nephrocalcinosis increases with ongoing signicant elevation
in urinary calcium levels.60,61 e combination of hypercalciuria
and hypocitraturia enhances the likelihood for urinary calcium
precipitation and readily accounts for the high rates of urinary
tract calcications seen in GSD I.
Therapeutic strategies for renal tubular dysfunction
Oral citrate supplementation will augment citrate excretion,
favorably altering the urinary milieu to decrease the chances of
urinary calcium precipitation and, as a result, is likely very ben-
ecial in GSD I patients with low urinary citrate levels (Box 4).
With citrate supplementation, the aim is to achieve at least
300 mg/g creatinine on spot urine ratios. In individuals with nor-
mal renal function, potassium citrate is preferred over sodium
citrate because higher sodium intake is linked to greater urinary
calcium excretion. It also can result in systemic hypertension. In
young children, liquid potassium citrate preparations are gener-
ally well tolerated at an initial dose of 1 mEq/kg/day divided into
three doses, with dose augmentation directed by urinary citrate
excretion. In older children and adults, potassium citrate tablets
at a dose of 10 mEq three times per day can also be commenced
and the dose adjusted as needed. Because the eects of citrate
supplementation wane over time, multiple daily doses spread
over the waking hours are preferred to maximize the propor-
tion of the day with improved urinary citrate levels. Citrate use
should be monitored because it can cause hypertension and life-
threatening hyperkalemia in the setting of renal impairment.
Patients should also be monitored for sodium levels.
With hypercalciuria, thiazide diuretics can also be provided
as a way to enhance renal reabsorption of ltered calcium and
decrease urinary calcium excretion. Especially in GSD I indi-
viduals with known urinary tract calcication and ongoing
hypercalciuria, thiazide diuretic therapy can be considered.
Chlorothiazide is used in young children who require liq-
uid preparations; tablets of hydrochlorothiazide are recom-
mended for older children and adults. e ecacy of therapy
can be gauged by interval urinary calcium-to-creatinine ratios.
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GSD I guideline | KISHNANI et al ACMG StAndArdS And GuidelineS
is ability to decrease urinary calcium excretion is unique to
thiazide diuretics, unlike other classes of diuretics that tend to
increase urinary calcium excretion.
Other nonspecic measures to reduce urinary calcium depo-
sition, such as optimizing hydration, maintaining a no-added
salt diet, or supplementing magnesium intake, can also be con-
sidered on an individual basis as well.
Glomerular injury
GSD I mediates hemodynamic and structural changes in the
kidney that can lead to the development of glomerular injury.
e exact mechanisms by which these changes occur are not
well understood, but activation of the renin–angiotensin sys-
tem, prolonged oxidative stress, and probrotic cytokines such
as transforming growth factor-β have all been implicated, as
well as alterations in renal tubular epithelial cell energy stores
related to G6Pase defects.133–136 ese renal changes occur
early, and many children with GSD I will have evidence of
glomerular hyperltration or elevation in the glomerular l-
tration rate (GFR) to more than 140 ml/min/1.73 m2 within a
few years of life.137
ese changes in GFR may not be readily detected because
they result in serum creatinine levels that are oen reported
as normal. Many clinicians are less familiar with the concept
of GFR and the use of certain validated formulas such as the
Bedside Schwartz Equation, which allows the GFR to be esti-
mated in children using the serum creatinine value and the
child’s height, or the Modication of Diet in Renal Disease
Study Equation, which uses serum creatinine, age, gender,
and ethnicity to estimate the GFR in adults.138,139 ese equa-
tions have been validated against nuclear medicine isotope
GFR assessments and are logistically easier and less costly
than the gold standard GFR studies or less accurate older
methods of assessing GFR such as timed urinary creatinine
clearance studies.
With hyperltration, enhanced glomerular blood ow and
intraglomerular pressure occur.140 Over time, these factors
seem to accelerate the normal rate of glomerular obsolescence.
As glomeruli become obsolete, brosis replaces surface area
that previously allowed ltration. Histologically, this injury
appears as focal and segmental sclerosis, with a subset of glom-
eruli demonstrating limited scarring.60 As this process contin-
ues, scarring progresses and encompasses entire glomeruli with
resulting loss of viability of the tubular segments and areas of
interstitial brosis of those nephrons. As more and more glom-
eruli are lost to scarring, the overall GFR decreases and there is
then an accelerated rate of obsolescence in these remnant glom-
eruli, creating even more stimuli for further glomerular injury.
Generally, because there is early glomerular scarring, there
is the development of microalbuminuria, with urinary albu-
min-to-creatinine ratios exceeding 30 µg albumin/mg creati-
nine. Over time, microalbuminuria has a tendency to progress
to frank proteinuria with urinary protein-to-creatinine ratios
exceeding 0.2 mg protein/mg creatinine. Chronic proteinuria is
thought to exacerbate glomerular injury through induction of
chemokines and inammatory pathways. In GSD I, the devel-
opment of pathologic proteinuria may be inevitable. In a large
European cohort, by age 25 years, more than 50% of patients
had frank proteinuria, with the remainder all demonstrating
microalbuminuria.33
In GSD I, this initial period of hyperltration that leads to
microalbuminuria and frank proteinuria does seem to then
progress to widespread glomerular scarring and eventual renal
dysfunction. Most renal biopsy samples from GSD I patients
with frank proteinuria or any decrease in GFR demonstrate
focal and segmental sclerosis as the histologic change that pre-
cedes the loss of renal function and progression to end-stage
renal disease.60,135,137
Attenuating hyperfiltration injury
ere have been some data to suggest that metabolic control in
GSD I may aect the progression of renal injury. In one study, a
signicantly smaller proportion of patients with optimal meta-
bolic control of their serum glucose, triglyceride, and uric acid
concentrations and urine lactate/creatinine ratios had micro-
albuminuria or proteinuria than patients with poor control.135
Once proteinuria has occurred and there is established renal
injury in GSD I, it becomes less clear if metabolic control alone
alters the loss of GFR over time, underscoring the importance
of using other forms of treatment that may delay the process.
For many years, angiotensin blockade has been used to blunt
proteinuria and slow loss of GFR in patients with renal diseases
such as diabetes mellitus, in which there is similar hyperltra-
tion injury.141 ere are also data showing that GSD I patients
treated with angiotensin blockade show improvement in their
degree of glomerular hyperltration and can demonstrate
restored normal rates of GFR for some time.142 Angiotensin
blockade also seems to slow the tempo of GFR loss once it has
started to occur.135 Use of either an angiotensin-converting
enzyme (ACE) inhibitor or an angiotensin receptor blocker
(ARB) medication by itself can be ecacious. In cases in which
there is a need for further angiotensin blockade, use of both an
ACE and an ARB can prove synergistic to reduce proteinuria,
with no increased rate of hyperkalemia or drug-related renal
insuciency.143
Although not yet tested in any systematic fashion in GSD I,
the role of initiating angiotensin blockade with the early onset
of persistent microalbuminuria seems to be a potential strat-
egy to try to slow the factors that cause accelerated glomeru-
lar obsolescence and that ultimately lead to microalbuminuria,
proteinuria, and renal insuciency.142 Because these agents
tend to be well tolerated, and because many GSD I patients will
ultimately receive angiotensin blockade later in their disease
course, there seems to be limited risk in considering such an
approach as a way to try to alter the natural course of GSD-
associated nephropathy.
Routine evaluation and management
Typical measures to maintain GSD metabolic control are
benecial to general renal health because they help prevent
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ACMG StAndArdS And GuidelineS
acidosis and limit hyperuricemia and hyperlipidemia. Chronic
acidosis can predispose to higher urinary calcium excretion and
decreased urinary citrate, both problems that already exist in
GSD I. Hyperuricemia and hyperlipidemia by themselves have
both been implicated in causing or accelerating renal injury.
In patients receiving eective dietary therapy for their GSD I,
it is unlikely that there will be diuse proximal tubular dysfunc-
tion. ere should be periodic assessment of serum electrolytes,
calcium, and phosphate as well as interval measurement of
blood urea nitrogen and creatinine levels.
GFR should be estimated from the serum creatinine using
a validated formula such as the Bedside Schwartz Equation in
children or the Modication of Diet in Renal Disease Equation
for adults. Hyperltration is present if estimated GFR exceeds
140 ml/min/1.73 m2, and angiotensin blockade should be con-
sidered and potential risks/benets should be discussed with
the patient and family given the natural course of hyperltra-
tion accelerating glomerular obsolescence.
In the event that a patient has not yet begun follow-up with
a nephrologist and there is a decrease in estimated GFR to less
than 60 ml/min/1.73 m2, referral should be made to help coor-
dinate aspects of necessary care that will arise due to advanc-
ing chronic kidney disease and further decrease in GFR.
Screening urinalysis should be performed at intervals on all
GSD I patients. e presence of hematuria determined by dip-
stick should lead to assessment of urinary calcium excretion
and ultrasound imaging of the urinary tract for calcications.
Even in the absence of hematuria, renal ultrasound should be
performed at intervals to assess kidney size and to assess for
evolving nephrocalcinosis or nephrolithiasis. Especially for
purposes of screening or for routine follow-up, ultrasound is
preferred to other imaging techniques.
Despite good metabolic control, hypocitraturia and hypercal-
ciuria may be common in GSD I and, as a result, urine should
be assessed at regular intervals for calcium and citrate excretion
even if urinalysis is benign. Spot samples are adequate and easier
and quicker to collect than are those of timed urine collection.
With hypocitraturia, citrate supplementation should be con-
sidered, especially if there is concomitant hypercalciuria or a
history of nephrolithiasis or nephrocalcinosis. With hypercal-
ciuria, there needs to be ongoing good hydration and consid-
eration of thiazide therapy to reduce urinary calcium levels,
especially in individuals with known or recurrent urinary tract
calcications.
Urine should also be assessed for microalbuminuria and
proteinuria. With a negative screening urinalysis for proteins,
urine albuminuria should be quantied by spot albumin-to-
creatinine ratio. Dipstick-positive proteinuria should be quan-
tied by urinary protein-to-creatinine ratio. Positive results
should be conrmed using a rst morning void sample to rule
out any orthostatic component.
Persistent microalbuminuria or frank proteinuria warrants
initiation of angiotensin blockade despite patients being nor-
motensive. Medications should be adjusted to try to blunt
the proteinuria to levels that are normal or as near normal as
possible as tolerated without causing postural hypotension or
hyperkalemia. Attempts should be made to maintain angioten-
sin blockade chronically, and medication sequelae should be
treated in some fashion so that the angiotensin blockade can be
maintained or a dierent type of angiotensin blockade (ACE vs.
ARB) should be attempted.
Because chronic hypertension accelerates renal injury, blood
pressure should be maintained in a normal range for adults
and at less than the 90th percentile for age, gender, and height
for children. If antihypertensive therapy needs to be started,
angiotensin blockade with ACE or ARB should be considered
as rst-line therapy if not already instituted for other rea-
sons. Loop diuretics should be avoided because of the risk of
hypercalciuria.
With renal insuciency, there is decreased production of
erythropoietin (EPO) by the kidney and anemia may develop.
Patients with GFRs less than 50 ml/min/1.73 m2 are particularly
prone to development of anemia attributable to chronic kidney
disease. Concomitant clinical factors in GSD patients such as
chronic metabolic acidosis, iron deciency, and bleeding dia-
thesis may potentiate or exacerbate this anemia. In children
and adolescents with chronic kidney disease, anemia is linked
to impairments in cognitive and developmental gains as well
as increased hospitalization rates. Accordingly, when hemoglo-
bin decreases to less than 10 g/dl, EPO therapy is initiated and
titrated to maintain levels between 10 and 12 g/dl. With adults,
there are fewer data to support a specic hemoglobin level under
which EPO should be started. As a result, EPO therapy is ini-
tiated if there is any evolving symptomatic anemia to prevent
the need for blood transfusion. Adults using EPO should avoid
hemoglobin levels higher than 12 g/dl because these levels may
increase the risk for cardiovascular events. Because iron de-
ciency anemia is common in GSD I, it is prudent to screen both
children and adults with chronic renal failure for iron deciency
anemia and replace iron as needed before starting EPO therapy.
Long-term exposure to nephrotoxic medications should also
be avoided. is includes use of nonsteroidal anti-inamma-
tory drugs such as ibuprofen and is especially important if there
is any reduction in GFR or if patients have a bleeding diathesis.
With cases of advanced chronic kidney disease and a GFR that
declines to less than 15 ml/min/1.73 m2, renal replacement therapy
with dialysis or transplantation needs to be considered. Metabolic
derangements from ongoing chronic renal insuciency may
exacerbate some of the issues that arise from GSD, making renal
transplantation a more attractive therapy. In this case the option of
both liver and kidney transplant may be considered.
HEMATOLOGIC ASPECTS
Hematologic aspects in GSD I include risk for anemia, bleeding
diathesis, and neutropenia in GSD Ib.
Anemia in type Ia
Anemia is a signicant long-term morbidity in individuals with
GSD I. In 1994, Talente et al.114 reported that 81% of patients
with GSD Ia had anemia in adulthood.
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e report was based on an observational study of 32 sub-
jects. Anemia in the pediatric population was recognized in
2002 (ref. 84), and a prevalence ranging from 17 to 60% was
found across dierent age groups in patients with GSD Ia.
e cause of anemia in GSD I is multifactorial—the restricted
nature of the diet, chronic lactic acidosis, renal involvement,
bleeding diathesis, chronic nature of the illness, suboptimal
metabolic control,40 hepatic adenomas,29 and irritable bowel
disease in GSD Ib are all contributing factors. In one study it
was noted that patients with hemoglobin concentrations 2 SDs
below the mean for their age had higher mean daily lactate
concentrations as compared with the nonanemic population
(3.2 vs. 1.9 mmol/l). An association between severe anemia
and large hepatic adenomas was identied as well.29
Many patients with GSD I have iron deciency anemia. In
some, it is an iron refractory anemia attributable to aberrant
expression of hepcidin.29 Hepcidin is a small peptide hormone
produced in the liver. It is secreted in the bloodstream and is
the key regulator of iron in the body, controlling iron absorption
across the enterocyte, as well as macrophage recycling of iron. In
the presence of hepatic adenomas, there are increased hepcidin
levels. e inability of hepcidin to be downregulated in the set-
ting of anemia causes abnormal iron absorption and iron de-
ciency. Intravenous iron infusions can partially overcome the
resistance to iron therapy, but, because of an inhibition of mac-
rophage recycling of iron, a good response is typically not seen.
e restricted nature of the diet, with a focus on maintain-
ing normoglycemia, oen results in nutritional deciencies
(see Nutrition section) including poor intake of iron, vita-
min B12, and folic acid. Progression of kidney disease is
another risk factor for anemia, and some patients require
supplementation with EPO to maintain hemoglobin levels.
Anemia in type Ib
e causes of anemia in GSD Ib are similar to those of anemia
in GSD Ia, as was noted in ve subjects studied by Talente et
al.114 in 1994. Numerous case reports documented the pres-
ence of anemia in this population, but studies of the patho-
physiology of this complication were lacking. Interleukin
6—a marker of inammation known to upregulate hepcidin
expression, which is increased during inammatory bowel
disease exacerbations—is the likely cause of low hemoglobin
concentrations and another cause for the anemia observed in
patients with GSD Ib.
A larger study involving 202 subjects with GSD I at two
large GSD centers has shed more light on the causes of
anemia in GSD I.144 In this study it was noted that in the
GSD Ia population, the prevalence of anemia increases with
age. Mild anemia is common in the pediatric population
because of iron deciency and dietary restrictions. As pre-
viously stated, overall, pediatric patients with anemia have
worse metabolic control, but the anemia is responsive to
improved therapy and iron supplementation. By contrast,
anemia in adulthood is associated with hepatic adenoma
formation, particularly in people with more severe anemia.
More than 85% of patients with hematocrit values less than
30% have large hepatic adenomas exceeding 5 cm in diam-
eter. e nding that all subjects who had resection of the
dominant hepatic adenoma experienced resolution of their
anemia supports the proposed pathophysiology of hepcidin-
induced anemia.
Of the patients with GSD Ib (n = 39), anemia was present in
72%. In contrast to the GSD Ia population, there was no associ-
ation between anemia and metabolic control or hepatic adeno-
mas in either children or adults with GSD Ib; however, a strong
association with systemic inammation was documented.
Severe anemia was much more common in the patients with
GSD Ib, and those with hematocrit values less than 30% were
found to have active GSD enterocolitis. e enterocolitis in
GSD Ib histologically resembles inammatory bowel disease/
Crohn disease with transmural inammatory changes and
granuloma formation.100
Bleeding diathesis
In GSD I, a coagulation defect attributed to acquired platelet
dysfunction with prolonged bleeding times, decreased platelet
adhesiveness, and abnormal aggregation has been described
(Box 5). Some patients with GSD I have features suggestive
of a von Willebrand disease–like defect with reduced von
Willebrand factor antigen and/or dysfunctional von Willebrand
factor. Bleeding manifestations include epistaxis, easy bruis-
ing, menorrhagia,45 and excessive bleeding during surgical
procedures. Although dietary intervention can ameliorate the
Box 4 Nephrology recommendations
• Diagnostic studies should be performed at routine visits to fol-
low renal manifestations of GSD I, including
°Renal ultrasound to assess kidney size and growth, nephroli-
thiasis, or nephrocalcinosis;
°Urinalysis for hematuria and proteinuria;
°Quantification by spot samples of urinary microalbumin/cre-
atine excretion, citrate, and calcium/creatine excretion;
°Measurement of serum electrolytes, calcium, and phosphate;
blood urea nitrogen and serum creatinine with calculation of
estimated GFR.
• Consider initiating an ACE inhibitor or ARB with evidence of
hyperfiltration (sustained estimated GFR >140 ml/min/1.73 m2).
• Initiate an ACE inhibitor or ARB for persistent microalbuminuria
(>30 μg albumin /mg creatinine).
• Initiate an ACE inhibitor or ARB for frank proteinuria (>0.2 mg
protein/mg creatinine).
• Initiate citrate supplementation for hypocitraturia, use of potas-
sium citrate in patients with good renal function, accompanied
by careful monitoring of electrolytes. Use extreme caution in the
setting of renal failure.
• Consider a thiazide diuretic for hypercalciuria.
• Maintain normal blood pressure for age.
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bleeding diathesis, the exact etiology of the bleeding diathesis
remains unclear. More than one study, with limited numbers of
patients, showed that infusions of glucose and total parenteral
nutrition corrected the bleeding time and in vitro platelet func-
tion in patients with GSD I, suggesting that coagulation defects
were secondary to metabolic abnormalities.27,56,57
Standard management of patients with platelet dysfunction/
von Willebrand disease include antibrinolytics and deam-
ino-8--arginine vasopressin, which acts by stimulating fac-
tor VIII from endothelial cells and improving von Willebrand
factor activity and the platelet release reaction. ese agents
could be utilized in patients with GSD I when clinically indi-
cated, but use of deamino-8--arginine vasopressin in GSD
I must be performed with caution because of the risk of
uid overload and hyponatremia in the setting of i.v. glucose
administration.145,146
In addition, the use of a brinolytic inhibitor, such as
ε-aminocaproic acid (Amicar), can be used as an adjunctive
medication if there is mucosal-associated bleeding. For oral
hemorrhage, Amicar can be given as a solution to “swish for
30 seconds and spit” at a dose of 1.25 g four times daily. For
more severe mucosal-associated bleeding, an i.v. bolus of 4 g
in 250 ml of D5W/NS infused over 1 hour followed by a drip
of 1 g/h (50 ml/h) for 8 hours or until bleeding is controlled is
needed. If the i.v. form is not available and the patient can take
oral medications, 5 g may be given in the rst hour, followed
by 1 g/h orally for 8 h or until hemorrhage is controlled. e
use of Amicar is contraindicated in individuals with dissemi-
nated intravascular coagulation and if activated prothrombin
complex concentrate (FEIBA) has been used. Caution must be
taken to ensure that there is no genitourinary tract bleeding,
because inhibition of brinolysis can lead to an obstructive
ne p hropat hy.
Neutropenia, neutrophil dysfunction, and enterocolitis in
GSD Ib
Neutropenia and recurrent infections are common manifesta-
tions of GSD Ib. In a European survey of 57 patients with GSD
Ib, 49 patients (86%) had severe neutropenia with an abso-
lute neutrophil count (ANC) less than 0.5 × 109/l (ref. 147).
Neutropenia persists throughout childhood with little change
in the neutrophil levels.147 However, some children with GSD
Ib, who develop neutropenia later in life, have normal neutro-
phil counts early in life. It is unclear if neutrophil function is
normal in this setting. Adult patients also have severe neutro-
penia and recurrent infections.148 Patients are prone to develop-
ment of gingivitis, mouth ulcers, upper respiratory infections,
deep abscesses, and enterocolitis. e patterns of infections
vary from patient to patient, but there is no clear genotype–
phenotype relationship.114
Neutropenia and the susceptibility to infections are now
attributed to specic abnormalities in neutrophil production
and function.149 Glucose is critical for the neutrophil’s meta-
bolic burst, which occurs with the ingestion of microorgan-
isms. Mutations in glucose 6-phosphate transporter (G6PT)
cause apoptosis of developing neutrophils, ineective neutro-
phil production, and neutropenia.150 e mature cells that sur-
vive to enter the blood have a reduced metabolic burst when
they ingest particles or microorganisms. Monocyte functions
are also abnormal, probably contributing to the formation of
granulomas and chronic inammatory responses.151
It is also important to note that some patients with GSD Ia
have also been known to develop neutropenia. Individuals
with GSD Ia who are homozygous for the mutation
p.Gly188Arg were reported to have a GSD Ib–like phenotype
with neutropenia.6
Neutropenia treatment
G-CSF has been used for treating neutropenia and preventing
infections in patients with GSD Ib since 1989 (refs. 152,153).
is cytokine stimulates and accelerates neutrophil produc-
tion by the bone marrow, releases neutrophils from the bone
marrow, prolongs the survival of the cells, and enhances their
metabolic burst. Administration of G-CSF increases blood
neutrophil counts to normal or above normal levels, usually
within a few hours. In a review of 18 European patients given
either glycosylated or nonglycosylated G-CSF (median age: 8
years; treated for up to 7 years), there was a positive clinical
response both in the severity of infections and in the manifes-
tations of inammatory bowel disease in all patients.147 One
patient had relapses in bowel disease while taking G-CSF, but
the others did not. Almost all reports on GSD Ib indicate that
G-CSF increases blood neutrophil levels, decreases the occur-
rence of fevers and infections, and improves enterocolitis.154,155
e cytokine granulocyte macrophage colony–stimulating fac-
tor has also been used on a short-term basis, but it is not as well
tolerated on a long-term basis as G-CSF. e Severe Chronic
Neutropenia International Registry (a National Institutes of
Health/National Institute of Allergy and Infectious Diseases–
sponsored registry based at the University of Washington,
Seattle, WA) maintains records for 37 patients with GSD Ib (23
adults (16 female, 7 male) and 14 children (9 female, 5 male);
age 4.1–39.5 years; DC Dale et al., unpublished data). Before
G-CSF treatment, median ANC for this group was 0.44 × 109/l.
Treatment can be performed daily, on alternate days, or on a
Monday–Wednesday–Friday schedule with similar benets
(DC Dale, personal communication), but some children require
daily therapy to avoid infections. In the United States, the dose
used is generally low, approximately 2 g/kg/day. G-CSF should
be administered subcutaneously starting at 1.0 g/kg/day given
daily or every other day. e G-CSF dose should be increased in
a stepwise manner at approximately 2-week intervals until the
target ANC of more than 500 to up to 1.0 × 109/l is reached. e
ANC for these patients is not pushed to higher levels because
G-CSF appears to increase the spleen size in GSD Ib patients.
is dose then should be maintained, adjusting for subsequent
increases in the patient’s weight with growth and development.
Blood count should be monitored several times per year. Bone
marrow examinations are not recommended, unless there is
an unexpected change in the patient’s other blood counts. e
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lowest eective G-CSF dose should be used to avoid spleno-
megaly, hypersplenism, hepatomegaly, and bone pain.
With use of G-CSF, occurrences of infections were greatly
reduced and inammatory bowel disease also improved in
most, but not all, patients. In more than 470 patient-years of
observations, the Severe Chronic Neutropenia International
Registry has recorded three deaths in GSD Ib patients, (sepsis,
1; aer liver and hematopoietic transplant, 1; hepatomegaly
and neutropenia, 1).
Side eects of treatment with G-CSF in the GSD Ib popu-
lation were reported by the European Study on Glycogen
Storage Disease Type I.147 e most serious complication was
splenomegaly. is complication did regress with reduced
treatment. ere are known cases in which the splenomegaly
did not improve with reduction of the dose and splenectomy
was required. Increase in spleen size and the need to reduce
G-CSF dose can usually be determined by physical examina-
tion and conrmed by ultrasound when necessary. In addi-
tion, this group reported two patients that have been on G-CSF
and developed acute myelogenous leukemia. Based on avail-
able data, the risk of acute myelogenous leukemia is very low.
However, all patients should be observed, with serial blood
counts monitored approximately quarterly for development of
loss of response to G-CSF, presence of myeloblasts in the blood,
evidence of hypersplenism, new patterns of bone pain, or any
other changes that might suggest a change in hematological dis-
ease or development of a myeloid malignancy.
CARDIOVASCULAR ASPECTS
In contrast to the hypertrophic cardiomyopathy of GSD II
(Pompe disease) or GSD III, the heart itself is not primarily
aected by GSD I. e most common cardiovascular abnormal-
ity in patients with GSD I is systemic hypertension (Box 6 ).84
It usually occurs in the context of renal disease and does not
develop until the second decade of life or later, with the median
age of onset 17 years.84 e diagnosis, monitoring, and treat-
ment of systemic hypertension is similar to that of essential
hypertension in children. is is reviewed in the Nephrology
section of this article. Hypertension and hyperlipidemia are
both independent risk factors for the development of athero-
sclerosis later in life; thus, it is pertinent to question whether
individuals with GSD I are at increased risk for and/or earlier
risk for development of atherosclerosis as adults. ere are con-
icting data about this question, and two small series examining
clinical surrogates of early atherosclerosis found no evidence to
suggest early atherosclerosis.119,156 Nonetheless, there are a few
case reports of patients with early coronary artery disease.114 It
is likely that early atherosclerosis is a rare complication of GSD
I and management should aim to maintain normal blood pres-
sure, renal function, and lipid levels to prevent its occurrence.
One of the most ominous, yet rare, potential complications
of GSD I is the occurrence of pulmonary arterial hypertension
(PAH). PAH may coexist with numerous systemic illnesses such
as rheumatologic diseases, portal hypertension, infections (such
as HIV), and exposure to toxins (anorexigens). PAH is also
known to be a complication of several other conditions, such
as hypoxic lung disease, thromboembolic disease, pulmonary
venous hypertension secondary to le-sided heart disease, and
congenital heart disease with le-to-right shunting through the
lungs. Finally, it may occur in isolation as primary PAH. To date,
nine GSD I patients with PAH have been reported.49,50,157–163 Of
these, ve had concomitant conditions that were also associated
with the development of PAH, including three patients with por-
tocaval shunts, one patient with an atrial septal defect, and one
patient with hereditary hemorrhagic telangiectasia.33,49,84,157–159,161
It has been suggested that abnormal handling of serotonin might
be one event in a multistep process leading to PAH in GSD I
patients. is suggests that the GSD I patient with a coexisting
condition that may also predispose a patient to development of
PAH is at the highest risk for this complication. In all the cases of
GSD I with PAH described in the literature, the diagnosis of PAH
was not made until it was quite advanced, and in seven of nine
patients PAH led to their deaths.33,49,84,157–161 ere is one recent
case report of a patient with signicant PAH with systemic right-
ventricular pressure who responded well to medical management
with prostacyclin and sildenal (Viagra) to reduce the pulmo-
nary artery pressure.162 Historically, there have been few eective
Box 5 Hematology recommendations
• Evaluation for anemia should include nutritional causes, adenomas,
enterocolitis, menorrhagia in females, and occult blood loss. Evalu-
ations should include complete blood cell count with manual differ-
ential, serum, total iron-binding capacity, and reticulocyte counts.
°In GSD Ia, if anemia is severe, evaluation for hepatic adeno-
mas should be performed.
°In GSD Ib, if anemia is severe, evaluation for GSD enterocolitis
should be performed.
• If iron deficiency anemia is documented, iron supplementation
(oral or i.v.) as needed and optimization of metabolic control are
recommended. Consider iron refractory anemia if iron levels do
not improve.
• Neutropenic patients with GSD Ib should be treated with G-CSF,
particularly if there is already a history and pattern of fever, infec-
tions, or enterocolitis.
°The lowest effective G-CSF dose should be used to avoid
worsening of splenomegaly, hypersplenism, hepatomegaly,
and bone pain. G-CSF should be administered subcutane-
ously starting at 0.5–1.0 µg per kilogram per day given daily
or every other day. The G-CSF dose should be increased step-
wise at approximately 2-week intervals until the target ANC
of more than 500 to up to 1.0 × 109/l is reached. This dose
then should be maintained, adjusting for subsequent increas-
es in the patient’s weight with growth and development.
°Blood count with manual differential should be monitored
several times per year. Bone marrow examinations are not
recommended unless there is an unexpected change in the
patient’s other blood counts.
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long-term treatment modalities available for PAH. Recently, oral
medications for PAH, such as sildenal, have been shown to be
eective treatments. GSD I patients with this serious complica-
tion have a better chance of longer survival if PAH is diagnosed
at an earlier stage and medical treatment is initiated promptly.
Management recommendations for cardiovascular manifesta-
tions of GSD I include screening to detect systemic or pulmonary
hypertension at early stages when these conditions are most ame-
nable to treatment. Because systemic hypertension in children is
only rarely associated with clinical symptoms such as headaches
or vision changes beginning in infancy, accurate measurements
of systemic blood pressure should be obtained at all clinic visits.
Any elevated blood pressure measurements should be carefully
followed up to conrm the diagnosis of hypertension. It is impor-
tant to note that age-appropriate and gender-appropriate norms
for blood pressure should be applied when reporting it.
Good metabolic control is the best management option for
maintaining serum lipid levels as close to normal as possible,
thereby reducing the risk of acute pancreatitis and long-term
development of atherosclerosis. Management of hyperlipid-
emia with medications usually does not begin until the patient
is at least 10 years old.
Screening for pulmonary hypertension by periodic echocar-
diography with attention to estimating right-ventricular pres-
sure by tricuspid regurgitation jet is indicated because PAH
is unlikely to have clinical features that would be apparent on
physical examination or with simple testing such as electrocar-
diogram until the PAH is well advanced. Obtaining the tricus-
pid regurgitation jet by echocardiogram is the best method to
periodically screen for elevated right-side heart pressures.163
Because the reported cases of GSD I patients with PAH were
mostly children older than 10 years of age, screening by echo-
cardiography can likely be delayed until patients are 10 years of
age or older.33,84 Periodic screening echocardiograms could be
performed every 3 years or at shorter intervals if there are any
suggestive clinical symptoms. Because most of the patients with
PAH also had poor metabolic control, achieving good meta-
bolic control may prevent PAH. If PAH is detected, pursuing
eective treatment methods such as treatment with Bosentan
and Sildenal in consultation with a physician experienced in
managing PAH is recommended.
GENERAL MEDICAL CARE
All patients with GSD should have a primary-care provider
(“medical home”) specializing in pediatrics, adolescent, or
internal medicine depending on the patient’s age (Box 7). e
primary-care physician should take care of the regular physical
examinations and immunizations, as well as any intercurrent
medical problem not related to the GSD. He/she should be famil-
iar with the major manifestations of GSD I and should maintain
good communication with the patient’s specialists as needed.
Some patients/families nd it useful to have a binder in which
they can keep physician cards, insurance information, authori-
zations, school evaluations, and/or other important documents.
Routine immunizations should be scheduled as recom-
mended by the Centers for Disease Control and Prevention
(http://www.cdc.gov/vaccines/schedules/). Other available
immunizations, such as those for seasonal inuenza, hepatitis
B, and pneumococcal infections (polyvalent aer 2 years of
age), should be oered because they can prevent the hypogly-
cemia caused by the gastrointestinal manifestations associated
with the disease processes. Hepatitis C status should be moni-
tored in patients at risk.
Because patients with GSD I may receive several medications,
it is always recommended to check for potential interactions
with the physician or pharmacy when a new medication is pre-
scribed. Drugs that can potentially cause hypoglycemia should
be avoided. ese include β-blockers, quinidine, sulfonamides
(Bactrim), pentamidine, and haloperidol, as well as some over-
the-counter medications. Antidepressant agents should be used
with caution because they can aect glucose regulation (hypo-
glycemia or hyperglycemia). Insulin and insulin secretagogues
(sulfonylureas) should be used with caution.164,165 Growth hor-
mone treatment should also be avoided because it can result
in the development or an increase in the size or number of
liver adenomas, along with severe hyperlipidemia. e use of
growth hormone should clearly be limited to only those who
are proven to have a growth hormone deciency and, in this
situation, close monitoring for liver adenomas and metabolic
disturbances is critical. e use of aspirin, nonsteroidal anti-
inammatory drugs, and other medications that reduce or
aect platelet function should be avoided. Hypoglycemia risks
should be checked before starting medications.
Due consideration should be given to medications that have
a high sodium or potassium content; the latter is especially
important in the setting of renal failure.
All patients should be encouraged to participate in age-
appropriate physical activities. However, contact or competitive
sports should be avoided because of the risk of liver injury, unless
proper protection is used. Patients should avoid alcohol intake
as it may predispose them to hypoglycemia. Good hygiene and
frequent hand-washing precautions are advised, especially for
patients with neutropenia. As a general rule, patients should
avoid unnecessary contact with sick people, especially during
the winter season. Good dental hygiene and frequent monitor-
ing of dental health are advised for all patients, but it is particu-
larly important in patients with GSD Ib, who have a tendency
Box 6 Cardiovascular recommendations
• Screen systemic blood pressure to detect systemic hypertension
beginning in infancy.
• Maintain lipid levels within the normal range to prevent athero-
sclerosis and pancreatitis.
• Screen for pulmonary hypertension by periodic echocardiogra-
phy with attention to estimating right-ventricular pressure by
tricuspid regurgitation jet starting at age 10 years and repeating
every 3 years or at shorter intervals if there are suggestive clini-
cal symptoms.
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to develop chronic gingivitis. Antibiotic coverage is not needed
for routine dental cleaning, but it is indicated in the case of gin-
givitis or in case of oral infections with risk for cellulitis/sepsis
due to neutropenia.
During intercurrent illnesses, early evaluation and treat-
ment are encouraged to prevent complications, especially
when infectious processes are suspected in patients with
neutropenia. When the intercurrent illness causes decreased
dietary intake, the patient’s specialist should be contacted. In
such cases more frequent monitoring of BG and additional
doses of CS may be indicated. Patients who cannot main-
tain normal dietary intake/CS treatment or who have eme-
sis should proceed to the nearest emergency department for
evaluation and i.v. glucose treatment. e patient’s specialist
should be made aware and, ideally, should contact the emer-
gency department in advance to ensure that patient’s waiting
time in the emergency department is minimized. Some emer-
gency departments have implemented a “pathway” system for
metabolic patients to reduce the waiting time until the proper
care is started.166
All patients/families should be provided with an emergency
letter that should be carried at all times. Patients/families should
have several copies of this letter and keep them, for example,
in their wallet/purse, car glove compartment, school le, and
workplace. If possible, the emergency letter should be uploaded
into the patient’s electronic medical records for easy access. e
emergency letter should be reviewed annually and updated as
needed.
Patients should wear a medical alert identication. A variety
of types are oered by pharmacies and websites:
• Necklaces and bracelets with engraved patient name,
diagnosis, and emergency contact information.
• MedicAlert system (http://www.medicalert.org) oers a
sponsored membership program that provides bracelets
with an engraved toll-free telephone number and patient
ID number. By calling the toll-free number, the patient’s
vital information, emergency contact, and other informa-
tion can be obtained at any time, from anywhere.
• Electronic medical alert bracelets have a built-in “USB
pen-drive” containing key medical information that
can be accessed by plugging it into any computer with
a USB port.
• An ICE (in case of emergency) telephone number should
be listed in the patient’s cell phone.
Patients are advised to carry an emergency kit at all times.
e kit should include:
• Contact information;
• A copy of the emergency letter;
• Glucose meter, strips, extra battery, ashlight;
• Wa te r ;
• CS, glucose gel; and
• Cereal bar or similar source of carbohydrate.
SURGERY/ANESTHESIA
Metabolic derangement caused by fasting and infections are a
common cause of morbidity in patients with GSD I, even with
current treatments.84 In the case of surgical procedure, the met-
abolic center should be contacted in advance to provide recom-
mendations for management (Box 8).
During infections or other intercurrent illnesses, the patient’s
glucose requirement may increase. In addition, some illnesses
causing anorexia and vomiting interrupt oral or nasogastric
feedings. Patients and their parents should be educated regard-
ing the symptoms of hypoglycemia and metabolic decompen-
sation. ey should be taught to respond to minor ailments by
giving frequent oral or NG glucose-containing uids, and they
should be educated regarding the need for emergency care if
oral feeds are not tolerated.
In the case of loss of consciousness or inability to tolerate
oral or NG feedings, glucose infusion rates by age have been
published and need to be individualized based on the patient’s
needs.84 In emergency settings, i.v. glucose-containing uids
consisting of dextrose 10% with electrolytes administered at
1.5–2× the usual maintenance rate will generally increase BG
levels to the normal range and reverse catabolism. Of course,
due consideration of uid volume is given in the setting of renal
failure. Intravenous solutions containing lactate are contraindi-
cated and should be avoided.
Careful management of the patient’s glucose and electro-
lyte levels around the time of surgical procedures is needed.
Patients with GSD I cannot tolerate typical periods of fasting
before procedures. Progressive metabolic acidosis and cardiac
dysrhythmia leading to cardiac arrest during surgery have been
Box 7 General medical care recommendations
• All patients should have a primary-care provider (“medical
home”).
• Routine immunizations should be given as recommended by the
Centers for Disease Control and Prevention.
• Avoid medications that can potentially cause hypoglycemia and
check for potential drug interactions/side effects when a new
medication is prescribed.
• Patients should be encouraged to participate in age-appropriate
physical activities, but contact or competitive sports should be
avoided because of the risk of liver injury.
• Good dental hygiene and frequent monitoring of dental health
are advised.
• During intercurrent illnesses, early evaluation and treatment are
encouraged. Patients who cannot maintain normal dietary in-
take/CS treatment or who have emesis should proceed to the
nearest emergency department for evaluation and i.v. glucose
treatment.
• All patients/families should carry an emergency letter and an
emergency kit at all times (see sample).
• All patients should wear a medical alert identification.
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reported. Recommendations have been published as a guide for
perioperative management.167,168 e patient should be admit-
ted to the hospital on the day before the procedure so that a
continuous i.v. supply of glucose can be provided. e recom-
mended starting rate of 10% dextrose in 0.5 normal saline (or
age-appropriate electrolytes) is 1.25–1.5× the maintenance rate.
e i.v. uid rate should be adjusted to keep the BG higher
than 70 mg/dl. BG, electrolyte, and lactic acid levels should be
monitored. Intraoperatively, 10% dextrose solutions should be
continued with intraoperative monitoring of BG and lactic acid
levels. Although administration of dextrose-containing uids
at lower rates can result in normalization of BG, higher doses
of glucose are needed to keep the patient anabolic and prevent
lactic acidosis.169 e i.v. uids should continue until oral feed-
ing is re-established. Lactated Ringer’s should not be used as an
i.v. uid. Once the patient is taking oral feedings, the dextrose
infusion should be slowly weaned over several hours.
Prolonged bleeding aer surgery was reported in 3% of
patients with GSD I in the European Study on Glycogen Storage
Disease.33,84 Complications attributable to bleeding tendency
were reported in 23% of patients, with most being due to recur-
rent or severe epistaxis.33 e exact mechanism of the bleeding
tendency is unknown; however, defects in platelet aggregation
have been found and the bleeding time is prolonged (see sec-
tion on Hematology). It has been recommended that bleeding
time be normalized by continuous gastric drip feedings for 24 h
for 1 week before surgery; however, a more practical solution
may be continuous i.v. glucose for 24 h before surgery.33,84
GYNECOLOGICAL/OBSTETRICAL CARE
Caution should be used when prescribing hormonal birth
control; estrogen is known to contribute to development of
both benign and malignant hepatocellular tumors (Box 9).170
Given the risk of adenomas in GSD I patients, estrogen-based
contraceptives should be avoided when possible.107 Progestin-
only contraceptives do not pose the same risk and may be
considered; however, there are other challenges such as risk for
reduced bone mineral density, which needs to be monitored.171
In GSD Ib, use of an intrauterine device should be avoided.
Females with GSD I are known to have polycystic ovaries from
a young age.46 Fertility is not thought to be reduced.
Menorrhagia appears to be a problem in females of reproduc-
tive age with GSD I.44,45 Interventions have included hormonal
and nonhormonal treatments. Specic questions documenting
the occurrence of menorrhagia or irregular menstrual bleeding
should be part of the patient’s history; this area seems to be oen
overlooked because care providers are focused on other aspects
of the disease. Management of females with GSD I should
include a multidisciplinary approach including the expertise of
a gynecologist familiar with GSD I.45 is complication should
be considered when reviewing the history of female patients
with GSD I and in the management of these cases.
Pregnancy
With signicant strides in management of GSD I, patients are
surviving into adulthood and pregnancies are now becoming
common. Successful pregnancies have been documented in
women with GSD types Ia and Ib.47,48,105,106,108
Ideally, it is prudent to plan the pregnancy ahead of time
so that metabolic parameters may be monitored and nor-
malized in preparation for pregnancy. A prepregnancy con-
sultation should be conducted during which adherence to a
safe diet routine to avoid low BG, accompanied by frequent
BG monitoring, should be emphasized. Medications such
as ACE inhibitors, allopurinol, and lipid-lowering drugs
must be discontinued because they are known to cause fetal
anomalies. A baseline ultrasound of the kidneys and liver to
monitor for hepatic adenomas should be performed before
the patient becomes pregnant. Laboratory tests such as a lipid
prole, serum uric acid test, liver function test, complete
blood count, and urine protein test should be performed.
Good metabolic control will help normalize most of these
parameters if abnormal. In addition, in patients with GSD
Ib, conception at a time when inammatory bowel disease is
quiescent may make are-ups during pregnancy less likely.172
e patient may benet from a referral to a high-risk obste-
trician because care during pregnancy will require multidis-
ciplinary involvement.
Abdominal ultrasound; urine microalbumin/creatinine,
serum uric acid, cholesterol, triglyceride-level, and liver
enzyme tests; and complete blood counts should be per-
formed every 3 months. e high estrogenic state in preg-
nancy has been reported to cause an increase in adenoma
formation.173 Worsening of renal function can occur, espe-
cially if it is already compromised. Increased proteinuria may
be noted. Risk of stone formation is typically higher in GSD
Ia than in GSD Ib,40 but renal calcication was noted in two
of three pregnant patients with GSD Ib in one case series.108
Serum uric acid and serum triglycerides levels should be
monitored because elevations can occur when a patient has
poor metabolic control.
Box 8 Surgery/anesthesia recommendations
• Educate parents about symptoms of hypoglycemia and meta-
bolic decompensation.
• Enable parents to provide oral or NG glucose during minor ail-
ments.
• Parents should be provided an emergency treatment plan.
• Careful management of the patient’s glucose and electrolytes
during surgery is necessary.
• Admission 24 h before a surgical procedure allows for i.v. fluids
with D10 and metabolic control.
• Lactated Ringer’s solution should not be used because of the
risk of worsening lactic acidosis and metabolic decompensation.
• Intravenous glucose-containing fluids or nutrition (total par-
enteral nutrition when indicated) should not be discontinued
abruptly; this should be performed only after the patient is eat-
ing and maintaining blood glucose levels.
GENETICS in MEDICINE
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GSD I guideline | KISHNANI et al ACMG StAndArdS And GuidelineS
Neutropenia and Crohn disease–like enterocolitis are prob-
lems unique to GSD Ib. Low neutrophil counts can lead to infec-
tious complications. G-CSF is classied by the US Food and Drug
Administration as a pregnancy class C drug. ere are no rec-
ommendations for G-CSF use during pregnancy. ere are pub-
lished reports in the literature of normal pregnancy outcomes
aer G-CSF use.174–180 e decision to start or continue G-CSF
should be made in consultation with multiple specialists weigh-
ing the risks versus the benets. Management of Crohn disease–
like enterocolitis can be problematic in pregnancy because most
medications used for treatment are not approved for use during
pregnancy. e risk to the fetus from active enterocolitis has to
be considered in comparison with the risk from the medications
themselves during decision making regarding management.
In preparation for labor and delivery, a protocol with written
instructions must be available stressing the use of 10% dextrose
solution given intravenously during labor and delivery to pre-
vent hypoglycemia. Once the patient is in labor, close collabo-
ration between the obstetrician and the patient’s specialist is
imperative. BG levels should be monitored throughout the pro-
cess to maintain euglycemia. Transient hypoglycemia has been
observed in some neonates. Neonates have been noted to have
normal growth and development. ere is no contraindication
to breastfeeding. Increased metabolic demands will occur while
breastfeeding. It has been observed that not all mothers may be
successful at breastfeeding.
CARE COORDINATION AND SUPPORT
e Association of Glycogen Storage Disease US (http://www.
agsdus.org/) is an organization that provides information and
support to people with GSD and their families. e website
provides descriptions of the various types of GSD and a list-
serv, a mechanism for people with all forms of GSD to connect
via the Internet. e association also holds a medical confer-
ence each year for individuals with GSD and their families.
GENETIC COUNSELING, PRENATAL DIAGNOSIS,
AND SCREENING
Similar to that for other inborn errors of metabolism, genetic
counseling should be oered to all parents of children with GSD I
and to adults aected with the condition (Box 10). In counseling
families with GSD I, at least a three-generation pedigree from the
consult and/or proband should be obtained. GSD I is an autoso-
mal recessive condition. De novo mutation rates are expected to
be infrequent, and parents of an aected individual are assumed
to be carriers. e recurrence risk for parents who have had an
aected child is 25%. DNA mutation analysis is necessary for the
identication of additional family members in the extended fam-
ily who may be carriers. Several laboratories in the United States
oer DNA diagnostic and/or prenatal diagnostic testing for
GSD I (see http://www.genetests.org). Targeted mutation analy-
sis based on ethnic background is available for both the G6PC
and SLC37A4 genes. Generally, full sequence analysis is recom-
mended, starting with GSD Ia and then GSD Ib, if clinical suspi-
cion is present. Sequence analysis detects ~94% of mutations in
mixed populations. Large deletions and duplications cannot be
detected by sequence analysis. Identication of carrier status in
the general population is limited and not routinely oered; how-
ever, mutation analysis to further rene the risk of having a child
with GSD I can be oered to those at risk (e.g., the spouse of a
known carrier or spouse of an aected person).
Prenatal diagnostic testing is typically performed by muta-
tion analysis either on cultured chorionic villus samples or on
amniocytes, ideally of the probands of previously identied
mutations. When the mutations segregating in the family are
known, molecular testing is the gold standard. Prenatal genetic
diagnosis is also an option for families with GSD I if the muta-
tions have been identied.
FUTURE DIRECTIONS AND EMERGING
THERAPIES
Acute and chronic complications occur in GSD Ia despite
adherence to dietary therapy, including growth retardation,
hepatomegaly, intermittent hypoglycemia, lactic acidemia,
hyperlipidemia, gout related to hyperuricemia, proteinuria,
nephrolithiasis, and progressive nephropathy. Modied CS
shows promise for improving dietary therapy because a sin-
gle dose at bedtime prevented hypoglycemia more eectively
throughout the night in comparison with uncooked CS.86
Box 9 Gynecological/obstetrical recommendations
• Avoidance of estrogen as an oral contraceptive, because of in-
creased risk for adenoma formation, is recommended. For GSD
Ib, avoidance of an IUD because of increased infection risk is
recommended.
○ Progestin-only contraceptives may be considered. There is a risk
for reduced bone mineral density, which needs to be monitored.
• Evaluate for menorrhagia and refer as appropriate.
• Plan pregnancy so that metabolic parameters may be monitored
and normalized in preparation for pregnancy.
• Medications such as ACE inhibitors, allopurinol, and lipid-lower-
ing drugs must be discontinued during pregnancy.
• BG levels and overall metabolic control (including renal status)
should be monitored during pregnancy and labor to maintain
euglycemia.
• Pregnancies should be followed by a high-risk OB in a tertiary
setting.
Box 10 Genetic counseling/prenatal diagnosis/screening
recommendations
• Offer genetic counseling to all parents with a child with GSD I
and to all adults with GSD I.
• Determine the proband’s G6PC / SLC37A4 mutations when feasi-
ble for diagnosis and to direct further testing for family members.
• When both mutations are known, molecular testing is the pre-
ferred method for prenatal diagnosis.
GENETICS in MEDICINE
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KISHNANI et al | GSD I guideline
ACMG StAndArdS And GuidelineS
Perhaps one of the most concerning complications of GSD
I is the frequent occurrence of hepatic adenomas in adult
patients, which are accompanied by a signicant risk for malig-
nant transformation to HCC.120,121 Chromosome 6 abnormali-
ties have been demonstrated in hepatic adenomas from GSD
Ia patients.120,121 Expression of two candidate tumor suppres-
sor genes at 6q was reduced in more than 50% of these hepatic
adenomas, indicating that loss of these genes might reect an
early event in tumorigenesis in the liver. e mechanism for
tumorigenesis remains to be elucidated in GSD Ia, although it
could include chronic inammation. Intriguingly, a subclinical
abnormality of neutrophil metabolism was reported in G6Pase
(−/−) mice181; furthermore, neutrophil inltrates were demon-
strated in human GSD Ia livers accompanied by elevated inter-
leukin 8, consistent with ongoing inammation.182
Progressive nephropathy is associated with proteinuria in
adult patients.188 It has been postulated that excessive renin–
angiotensin activity could underlie hyperltration and pro-
gressive renal failure in GSD Ia.133 To test this hypothesis,
angiotensinogen was quantied and found to be elevated in kid-
neys of 2-week-old G6Pase(−/−) mice. Subsequently, increases
in transforming growth factor-β and connective tissue growth
factor were demonstrated in older G6Pase(−/−) mice, in asso-
ciation with increases by angiotensinogen expression.184 us,
the nephropathy of GSD Ia was associated with angiotensino-
gen overexpression in G6Pase(−/−) mice, even without associ-
ated proteinuria.184 e renin–angiotensin system plays a key
role in renal failure in GSD Ia and needs further study.
e overexpression of angiotensinogen suggests that sup-
pression of the renin–angiotensin system might be eective
in GSD Ia. Microalbuminuria has been eectively treated with
low doses of ACE inhibitors such as captopril and lisinopril.142
At low doses, these medications improve renal perfusion. In a
study of 95 patients with GSD I, a signicant and progressive
decrease of glomerular hyperltration was noted in patients
treated with ACE inhibitors.142 ese medications also slowed
the progression from hyperltration to microalbuminuria;
however, ACE inhibitors did not slow progression from micro-
albuminuria to frank proteinuria and renal failure.142
Hyperlipidemia in GSD Ia can be managed with lipid-lower-
ing drugs such as 3-hydroxy-3-methyl-glutaryl-CoA reductase
inhibitors and brates. e potential benet of 3-hydroxy-
3-methyl-glutaryl-CoA reductase inhibitors was emphasized
by a study that showed increased triglyceride synthesis in
GSD Ia patients compared with normal controls.185 Lowering
triglycerides could reduce the risk for pancreatitis in patients
with poor metabolic control, but no consensus regarding the
recommendation of lipid-lowering drugs has been reached.
Hyperuricemia in GSD I can improve with good metabolic
control; however, in some situations, hyperuricemia persists
and can result in gouty attacks, gouty tophi, and kidney
stones. Use of agents, such as Allopurinol and Febuxostat,
have been used to lower uric acid levels. Newer agents, such
as pegloticase, have been used in situations where the use of
other agents has failed. Colchicine has been used with success
in the acute setting of gouty attacks. At this time, there is no
consensus as when to treat hyperuricemia with medications.
e development of new therapy for GSD Ia, such as gene
therapy or cell therapy, might prevent long-term complications
that arise due to recurrent hypoglycemia and related biochemi-
cal abnormalities. Pilot studies of hepatocyte transplantation
have demonstrated persistence of donor cells, although the
long-term ecacy of this approach remains to be demon-
strated186,187 Ecacy from liver-targeted gene therapy in GSD Ia
might be expected, given the experience with human patients
aer liver transplantation. Adeno-associated virus (AAV) vec-
tors containing a human G6Pase regulatory cassette/promoter
have proven to be ecacious in animal models of GSD Ia, and
these vectors contain sequence elements that regulate G6Pase
expression appropriately.188 A small-genome, double-stranded
AAV2/8 vector containing a human G6Pase minigene dem-
onstrated high ecacy in G6pase(−/−) mice and dogs with
GSD Ia.183A single-stranded AAV vector containing a larger
human G6Pase regulatory cassette also showed high ecacy
in G6pase(−/−) mice.189 Other vectors that have been evaluated
in the G6pase(−/−) mouse model have included helper-depen-
dent adenovirus vector encoding canine G6Pase183 and a feline
immunodeciency virus vector encoding murine G6Pase.190
Although both vectors prolonged survival and prevented hypo-
glycemia in the majority of treated mice, each remains limited
by signicant concerns related to potential toxicity, and more
preclinical experiments will be needed to further evaluate the
potential of these systems for clinical translation. Furthermore,
complications of GSD Ib were incompletely reversed in experi-
ments with an AAV vector encoding G6PT, and longer-term
surviving mice developed hepatocellular carcinoma related to
inadequate correction.191
e duration of ecacy from AAV vectors has been limited,
because the AAV vector genomes remain largely episomal and
are lost aer cell division. A double-stranded AAV vector trans-
duced the liver and kidneys with higher eciency when pseu-
dotyped as AAV9 rather than the AAV8 vector used for initial
experiments; however, G6Pase expression from these vectors
gradually waned between 7 and 12 months of age.192 Another
study with a single-stranded AAV vector containing a larger
G6Pase transgene completely corrected G6Pase deciency in
the liver at 6 months, followed by 90% loss of expression by
18 months of age in G6pase(−/−) mice.193 ese studies show
that although AAV vectors confer signicantly longer expres-
sion than other common episomal gene therapy vectors (e.g.,
adenovirus or plasmid DNA vectors)194,195 expression from an
AAV vector does decrease over time. e loss of G6Pase could
be countered by readministration of an AAV vector of a new
serotype to avoid antibodies formed in response to the initial
AAV vector treatment.196,197 In addition, G6pase(−/−) mice
had decreased GH signaling, resulting in low Igf-1 and slow
growth, which was partially reversed by AAV vector admin-
istration.198 erefore, concerns regarding safety and ecacy
of gene therapy in GSD I remain to be addressed by additional
long-term preclinical experiments. ese experiments will be
GENETICS in MEDICINE
25
GSD I guideline | KISHNANI et al ACMG StAndArdS And GuidelineS
facilitated by newer animal models, including liver-specic
G6pase(−/−) mice that develop all the liver involvement of
GSD Ia, including adenomas and hepatocellular carcinoma
when fed a high-fat diet.199 Liver-specic G6pase(−/−) mice
that lack G6Pase only in the liver survive much better than
complete G6pase(−/−) mice, which will facilitate long-term
experiments to evaluate new AAV vectors in GSD Ia. Despite
these apparent limitations of gene therapy in GSD I, the devel-
opment of AAV vector–mediated gene therapy will continue
based on the success of early-stage clinical trials of gene ther-
apy in hemophilia.200,201
ACKNOWLEDGMENTS
The authors thank Areeg El-Gharbawy, Philippe Labrune, Yuan-Tsong
Chen, and Kathy Ross for their critical comments and suggestions.
They also thank Jennifer Goldstein for her help with editing this
guideline and with correcting molecular mutation data. Partial fund-
ing of this guideline was provided by an educational grant from the
Association of Glycogen Storage Disease that was restricted to use
in developing practice guidelines for glycogen storage diseases. This
study was approved by the American College of Medical Genetics
and Genomics Board of Directors on 25 March 2014.
DISCLOSURE
The authors declare no conflict of interest.
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