[show abstract][hide abstract] ABSTRACT: Guanidinoacetate methyltransferase (GAMT) deficiency is a good candidate disorder for newborn screening because early treatment appears to improve outcomes. We report elevation of guanidinoacetate in archived newborn dried blood spots for 3 cases (2 families) of GAMT deficiency compared with an unaffected carrier and controls. We also report a new case of a patient treated from birth with normal developmental outcome at the age of 42months.
Molecular Genetics and Metabolism 03/2013; · 2.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: Enzyme replacement therapy (ERT) for Pompe disease using recombinant acid alpha-glucosidase (rhGAA) has resulted in increased survival although the clinical response is variable. Cross-reactive immunological material (CRIM)-negative status has been recognized as a poor prognostic factor. CRIM-negative patients make no GAA protein and develop sustained high antibody titers to ERT that render the treatment ineffective. Antibody titers are generally low for the majority of CRIM-positive patients and there is typically a better clinical outcome. Because immunomodulation has been found to be most effective in CRIM-negative patients prior to, or shortly after, initiation of ERT, knowledge of CRIM status is important before ERT is begun. We have analyzed 243 patients with infantile Pompe disease using a Western blot method for determining CRIM status and using cultured skin fibroblasts. Sixty-one out of 243 (25.1%) patients tested from various ethnic backgrounds were found to be CRIM-negative. We then correlated the CRIM results with GAA gene mutations where available (52 CRIM-negative and 88 CRIM-positive patients). We found that, in most cases, CRIM status can be predicted from GAA mutations, potentially circumventing the need for invasive skin biopsy and time wasted in culturing cells in the future. Continued studies in this area will help to increase the power of GAA gene mutations in predicting CRIM status as well as possibly identifying CRIM-positive patients who are at risk for developing high antibody titers.
American Journal of Medical Genetics Part C Seminars in Medical Genetics 02/2012; 160(1):40-9. · 4.44 Impact Factor
[show abstract][hide abstract] ABSTRACT: We found that the missense mutation p.Pro1205Leu in the PHKA2 gene is a common cause of hepatic phosphorylase-kinase deficiency in Dutch patients, suggesting a founder-effect. Most patients presented with isolated growth delay and diarrhea, prior to the occurrence of hepatomegaly, delaying diagnosis. Tetraglucoside excretion correlated with disease severity and was used to follow compliance. The clinical presentation and therapeutic requirements in the same mutation carriers were variable, and PhK deficiency necessitated tube-feeding in some children.
Molecular Genetics and Metabolism 08/2011; 104(4):691-4. · 2.83 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pompe disease (glycogen storage disease type II, acid maltase deficiency) is caused by deficiency of lysosomal acid α-glucosidase (GAA). A few late-onset patients have been reported with skin fibroblast GAA activity levels of <2%.
We measured GAA activity in skin fibroblasts from 101 patients with late-onset Pompe disease. Whenever possible, we performed Western blot analysis and correlated the results with GAA activity and GAA gene mutations.
Thirteen patients (13%) had skin fibroblast GAA activity of <1% of normal. Although there was wide genetic heterogeneity, none of these patients carried the common late-onset mutation c.-32-13T > G. We performed Western blot on 11 patients with <1% GAA activity. All produced GAA protein that was at lower levels and/or was abnormally processed.
There is no common mutation associated with <1% GAA activity in late-onset Pompe disease patients. Most patients produce unprocessed forms of GAA protein compared with patients with higher GAA activity.
[show abstract][hide abstract] ABSTRACT: Glycogen Storage Disease Type III (limit dextrinosis; Cori or Forbes disease) is an autosomal recessive disorder of glycogen metabolism caused by deficient activity of glycogen debranching enzyme in liver and muscle (Glycogen Storage Disease Type IIIa) or liver only (Glycogen Storage Disease Type IIIb). These two clinically distinct phenotypes are caused by mutations in the same gene (amylo-1,6-glucosidase or AGL). Although most patients with Glycogen Storage Disease Type III have private mutations, common mutations have been identified in some populations, and two specific mutations in exon 3, c.18_19delGA (p.Gln6HisfsX20) and c.16C>T (p.Gln6X), are associated with the Glycogen Storage Disease Type IIIb phenotype.
To further examine the heterogeneity found in Glycogen Storage Disease Type III patients, we have sequenced the AGL gene in 34 patients with a clinically and/or biochemically confirmed diagnosis of Glycogen Storage Disease Type III.
We have identified 38 different mutations (25 novel and 13 previously reported) and have compiled a list of all mutations previously reported in the literature.
We conclude that Glycogen Storage Disease Type III is a highly heterogeneous disorder usually requiring full gene sequencing to identify both pathogenic mutations. The finding of at least one of the two exon 3 mutations in all of the Glycogen Storage Disease Type IIIb patients tested allows for diagnosis of this subtype without the need for a muscle biopsy.
Genetics in medicine: official journal of the American College of Medical Genetics 07/2010; 12(7):424-30. · 3.92 Impact Factor
[show abstract][hide abstract] ABSTRACT: Glycogen storage disease type IV (GSD IV; Andersen disease) is caused by a deficiency of glycogen branching enzyme (GBE), leading to excessive deposition of structurally abnormal, amylopectin-like glycogen in affected tissues. The accumulated glycogen lacks multiple branch points and thus has longer outer branches and poor solubility, causing irreversible tissue and organ damage. Although classic GSD IV presents with early onset of hepatosplenomegaly with progressive liver cirrhosis, GSD IV exhibits extensive clinical heterogeneity with respect to age at onset and variability in pattern and extent of organ and tissue involvement. With the advent of cloning and determination of the genomic structure of the human GBE gene (GBE1), molecular analysis and characterization of underlying disease-causing mutations is now possible. A variety of disease-causing mutations have been identified in the GBE1 gene in GSD IV patients, many of whom presented with diverse clinical phenotypes. Detailed biochemical and genetic analyses of three unrelated patients suspected to have GSD IV are presented here. Two novel missense mutations (p.Met495Thr and p.Pro552Leu) and a novel 1-bp deletion mutation (c.1999delA) were identified. A variety of mutations in GBE1 have been previously reported, including missense and nonsense mutations, nucleotide deletions and insertions, and donor and acceptor splice-site mutations. Mutation analysis is useful in confirming the diagnosis of GSD IV-especially when higher residual GBE enzyme activity levels are seen and enzyme analysis is not definitive-and allows for further determination of potential genotype/phenotype correlations in this disease.
Journal of Inherited Metabolic Disease 01/2010; · 4.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pompe disease (acid maltase deficiency; glycogen storage disease type II) is caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Our clinical laboratory began to offer a fluorometric dried blood spot (DBS)-based GAA activity assay for Pompe disease in 2006 after the FDA approved GAA enzyme replacement therapy in April of that year. The purpose of this study was to examine the experience of our clinical laboratory in using this assay. Over a 2-year period, we received samples for the DBS GAA assay from 891 patients referred for possible Pompe disease, of whom 111 (12.5%) patients across the disease spectrum who had results in the affected range. The majority of the patients were referred by neurologists and geneticists. When available, we correlated the results obtained through DBS GAA activity assay with the results from a second DBS, or a second tissue (cultured skin fibroblasts or muscle biopsy). In our experience, the DBS GAA activity assay provides a robust, rapid, and reliable first tier test for screening patients suspected of having Pompe disease.
[show abstract][hide abstract] ABSTRACT: Glycogen storage disease type I (GSDI) is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. Some untreated neonates present with severe hypoglycemia; more commonly, untreated infants present at age three to four months with hepatomegaly, lactic acidosis, hyperuricemia, hyperlipidemia, and/or hypoglycemic seizures. Affected children typically have doll-like faces with fat cheeks, relatively thin extremities, short stature, and protuberant abdomen. Xanthoma and diarrhea may be present. Impaired platelet function can lead to a bleeding tendency with frequent epistaxis. Untreated GSDIb is associated with impaired neutrophil and monocyte function as well as chronic neutropenia after the first few years of life, all of which result in recurrent bacterial infections and oral and intestinal mucosal ulcers. Long-term complications of untreated GSDI include growth retardation and resulting short stature, osteoporosis, delayed puberty, gout, renal disease, pulmonary hypertension, hepatic adenomas with potential for malignant transformation, polycystic ovaries, pancreatitis, and changes in brain function. Normal growth and puberty may be expected in treated children. Many affected individuals live into adulthood.
The diagnosis of GSDI is based on clinical presentation, abnormal blood/plasma concentrations of glucose, lactate, uric acid, triglycerides, and lipids, and molecular genetic testing. Mutations in G6PC (GSDIa) are responsible for 80% of GSD1 and mutations in SLC37A4 (GSDIb) are responsible for 20% of GSD1. Molecular testing is clinically available for both genes.
Treatment of manifestations: Medical nutrition therapy to maintain normal glucose concentrations, prevent hypoglycemia, and provide optimal nutrition for growth and development. Allopurinol to prevent gout when dietary therapy fails to completely normalize blood uric acid concentration; lipid-lowering medications when lipid levels are elevated despite good metabolic control; citrate supplementation to help prevent development of urinary calculi or ameliorate nephrocalcinosis; angiotensin-converting enzyme (ACE) inhibitors to treat microalbuminuria; kidney transplantation for end-stage renal disease; surgery or other interventions such as percutaneous ethanol injections and radiofrequency ablation for hepatic adenomas; liver transplantation for patients refractory to medical treatment or with hepatocellular carcinoma; and treatment with human granulocyte colony-stimulating factor (G-CSF) for recurrent infections in GSDIb. Prevention of secondary complications: Improve hyperuricemia and hyperlipidemia and maintain normal renal function to prevent development of renal disease. Surveillance: Annual ultrasound examination of the kidneys and liver after the first decade of life; liver ultrasound examinations every three to six months if hepatic adenoma is detected. Agents/circumstances to avoid: Diet should be low in fructose and sucrose; galactose and lactose intake should be limited to one serving per day. Testing of relatives at risk: Molecular genetic testing (if the family-specific mutations are known) and/or evaluation by a metabolic physician soon after birth (if the family-specific mutations are not known) allows for early diagnosis and treatment of sibs at risk for GSDI.
GSD1 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible by molecular genetic testing if both disease-causing alleles of an affected family member have been identified.