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ORIGINAL PAPER
The early clinical phenotype of Fabry disease:
a study on 35 European children and adolescents
Received: 31 January 2003 / Revised: 22 July 2003 / Accepted: 21 August 2003 / Published online: 20 September 2003
Springer-Verlag 2003
Abstract Fabry disease (FD) is a debilitating progressive
multisystem X-linked lysosomal storage disorder. It was
generally believed that the disease affects only adult
males. Throu gh systematic pedigree analysis, we identi-
fied 35 paediatric FD patients (age 1 to 21 years, mean
12.6 years) in 25 families. Predominant signs in this
cohort were: acroparesthesia, hypohidrosis, and cornea
verticillata. Neurological and psychological changes,
such as tinnitus, recurrent vertigo, headache, diminished
level of activity, fatigue, and depression were often ob-
served. Angiokeratoma and gastrointestinal symptoms
were frequent. Some patients also showed cardiac
abnormalities. Six children and adolescents (three males
and three females) over 14 years of age had renal
involvement (all with proteinuria, one male had a
decreased creatinine clearance of 62 ml/min). No males,
but three females (1.5, 4 and 9 years of age), were free of
signs and symptoms. Males (n=15, age 1 to 21 years,
mean 12.4 years) and females (n=20, age 1.5 to 20 years,
mean 12.7 years) showed comparable disease severity.
However, the clinical courses demonstrated a wide intra-
and interfamilial variability and tended to be more
heterogeneous in the girls. Female patients are fre-
quently affected at an early age, not much differently
than males. They should be carefully examined because
most carriers are symptomatic. Conclusion: Fabry dis-
ease usually becomes clinically manifest in childhood.
Renal involvement can begin in adolescence. The diag-
nosis is made following a high level of suspicion or
systematic pedigree analysis. It is crucial for paediatric
Fabry disease patients to have early access to optimal
supportive symptomatic management. Enzyme replace-
ment therapy has shown promising effectiveness in
adults. Considering its widespread therapeutic and po-
tential preventive benefits, enzyme replacement therapy
should be initiated at an early stage, prior to the onset of
irreversible complications.
Keywords Adolescence Æ Child Æ Fabry disease Æ
Females Æ Genetics
Abbreviations FD Fabry disease Æ GALA
a-galactosidase A Æ Gb
3
globotriaosylceramide
Introduction
Fabry disease (FD; OMIM 301500) is an X chromo-
somal linked inherited lysosomal storage disorder, due
to partial or complete deficiency of ceramidetrihexosi-
dase, commonly referred to as a-galactosidase A
(GALA) [3]. This results in progressive storage of
Eur J Pediatr (2003) 162: 767–772
DOI 10.1007/s00431-003-1299-3
Markus Ries Æ Uma Ramaswami Æ Rossella Parini
Bengt Lindblad Æ Catharina Whybra Æ Ingrid Willers
Andreas Gal Æ Michael Beck
M. Ries (&) Æ C. Whybra Æ M. Beck
Centre for Lysosomal Storage Disorders,
Children’s Hospital, Johannes Gutenberg-University,
55101 Mainz, Germany
E-mail: mr380t@nih.gov
Tel.: +1-301-4961465
Fax: +1-301-4969480
U. Ramaswami
Department of Paediatric Endocrinology Diabetes
and Metabolism, Addenbrooke’s Hospital,
CB2 2QQ Cambridge, UK
R. Parini
Paediatric Centre for Clinical Genetics,
Department of Paediatrics,
Istituti Clinici di Perfezionamento,
20122 Milano, Italy
B. Lindblad
Go
¨
teborg Paediatric Growth Research Centre,
The Queen Silvia Children’s Hospital, Institute for the Health
of Women and Children, Go
¨
teborg University,
416 85 Go
¨
teborg, Sweden
I. Willers Æ A. Gal
Institute of Human Genetics,
University Hospital Eppendorf, 22529 Hamburg, Germany
Present address: M. Ries
Room 3D03, Developmental and Metabolic Neurology Branch,
National Institute of Neurological Disorders and Stroke,
National Institutes of Health, 10 Center Drive,
Bethesda, MD 20892–1260 USA
glycosphingolipids including globotriaosylceramide
(Gb
3
), digalactosylceramide, blood group B, B1, and P1
glycolipids. The accumulation occurs in many types of
cell, such as dorsal root ganglia, neuro nal cells of the
autonomic nervous system, glomerular epithelial cells
(podocytes), tubular epithelial cells, mesangial cells in
the kidney, myocardial cells, valvular fibroblasts as well
as en dothelial cells, pericytes, and smooth muscle of the
vascular system. FD is a multi-system disorder, with a
wide spec trum of physical signs and symptoms pre-
dominantly affecting the nervous system, skin, heart,
kidneys and the eyes. In the first two decades, acute and
chronic neuropathic pain, hypohidrosis, angiokeratoma
and gastrointestinal symptoms significantly reduce the
quality of life. Lifespan is shortened by late complica-
tions in adulthood that include heart failure, renal fail-
ure and cerebrovascular accidents. A detailed analysis of
clinical picture of this disease in male and female adults
has recently been reported by M acDermot et al. [17, 18].
The GALA gene is localized on Xq22.1. Although het-
erozygous, females are often severely affected [27], due
but probably not limited to random X-inactivation, as it
is in few other X-linked conditions, e.g. ornithine tran-
scarbamylase defici ency, an inborn error of metabolism
in the urea cycle.
To elucidate the natural history of FD and its
implications for the paediatric population, we investi-
gated 35 patients from Mainz (n=20), Cambridge
(n=6), Milan (n=6), and Go
¨
teborg (n=3).
Patients and methods
The patients (age 1 to 21 years, mean 12.6 years) were identified by
systematic pedigree studies from 25 families, investigating subjects
at genetic risk for FD. After a comprehensive history, thorough
physical and neurological examinations were performed. Oph-
thalmological examination, ECG, cardiac ultrasound and creati-
nine clearance were done. To confirm the diagnosis, mutation
analysis was performed except for patients 9, 22, and 34. Patients 9
and 22 had decreased GALA activity, assayed in leucocytes with an
artificial 4-methylumbelliferyl-substrate [19]. Patient 34, having an
affected father, is a symptomatic obligate carrier; however, the
identification of this family’s mutation is still pending. To deter-
mine severity, patients were classified according to the previously
described Mainz Severity Score Index (MSSI) quantifying general,
neurological-psychological, cardiovascular, and renal abnormali-
ties in each patient. In this scoring system the physical signs or
symptoms are weighted according to their contribution to the
morbidity of the disease and quantified by numbers. The MSSI
scores are then divided into severity bands of mild (<20), moderate
(20–40) and severe (>40) affliction, to reflect the clinical spectrum
of FD [28].
Results
Physical signs and symptoms found in our patients are
listed in detail in Table 1 and Fig. 1.
In the group of mal e patients (n=15, age between 1
and 21 years, mean 12.4 years), 93% had hypohidrosis.
Cream-coloured, whorl-shaped corneal opacities, also
known as cornea verticillata, were found in 73%. Ac-
roparaesthesias, often triggered by changes of the envi-
ronmental or body temperature as well as by emotional
stress, were present in 67%. Neurological and psyc ho-
logical findings, such as headache, tinnitus, recurrent
vertigo, diminished level of activity, fatigue, or depres-
sion could be identified in 67%. Of males, 53% had
angiokeratoma. Gastrointestinal symptoms, including
diarrhoea, recurrent nausea or vomiting were reported
by 40%. Cardiac abnormalities, such as cardiomyopa-
thy, or mitral valve prolapse, could be detected in 13%.
Renal complicati ons of the disease, i.e. proteinuria, were
already present in 13% of the male patients. Patient 10
had, in addition, a decreased creatinine clearance of
62 ml/min. The MSSI (Fig. 2) ranged from 6 to 27
(mean 11.9). No boy was free of physi cal signs and
symptoms.
The females (n=20) were between 1.5 and 20 years
(mean 12.7 years) old of whom 70% had cornea verti-
cillata and 65% reported acroparaesthesias. Angioker-
atoma were found in 30%. Hypohidrosis was present in
25% of the female patients. Comparable to the group of
male patients, although less frequent, a wide range of
neurological/psychological findings, such as diminished
level of activity, fatigue, tinnitus, recurre nt vertigo,
headache, or depression was documented in 25% of the
females. Gastrointestinal problems consisting of
abdominal pain and constipation were reported by 20%.
The overall prevalence of cardiac abnormalities was
20%. We found a short PR interval, mitral valve
regurgitation, and septum enlargement; one patient had
a partial atrioventricular septal defect. Of the fem ale
patients, 15% had renal invo lvement manifesting with
proteinuria. The MSSI (Fig. 2) ranged from 0 to 17
(mean 6.5). Three girls (1.5, 4 and 9 years of age) did not
have a clinical man ifestation of the disease.
Discussion
It was generally believed that FD clinically affects only
adult males. The present study, on the contrary, dem-
onstrates that FD is a burdensome condition already in
childhood, not only for males but also for females.
Diagnostic delay is frequent, probably due both to the
rarity of the disease and to the fact that the first com-
plaints of the disease are only subjective symptoms dif-
ficult to understand and evaluate.
Acroparaesthesia is agonising pain of burning and
tingling character, often associated with a deep ache,
predominantly seen in the palms and soles of the feet and
radiating proximally. It can be continuously present or
consist of episodic attacks, aggravated by body or envi-
ronmental temperature changes, illness or physical as well
as emotional stress. Rest, temperature changes, or medi-
cation may alleviate it. This pain can be severe, especially
in boys, and often makes them cry. In 23/35 patients it was
the first reported symptom with onset as early as 3 years of
age in boys and 6 years of age in girls. The presumed
explanation for this nerve pain is a structural damage,
768
Table 1 Synopsis of findings in 35 European paediatric FD patients (a,b, v, d, ,u, c,g, and i denotes siblings, parentheses denote cousins, ND not done)
Patient Family
number
Sex Age
(years)
Acroparaes-
thesia
Hypohi-
drosis
Cornea
verticillata
Angiokera-
toma
Gastro-
intestinal
problems
Cardiac
abnorma-
lities
Proteinuria
and/or low
creatinine
clearance
Neurological/
psychological
findings
MSSI Genotype
1 a 1 M 1 – – – – + – – – 8 A143T
2 a 1 M 2.5 – + – – – – – + 8 A143T
3(b) 2 M 5 + + + – – – – + 6 R301X
4 3 M 6 – + + – + – – + 14 R49S
5 v 4 M 11 + + + – – – – – 9 W236C
6 d 5 M 12 + + + + + – – + 11 124-125delAT
7 6 M 12 + + + – – – – + 11 R227X
8 7 M 13 – + + + – – – + 10 I317N
9 8 M 14 + + + + – – – 13 ND
a
10 9 M 15 + + + + – – +
b
– 20 A288D
11 u 10 M 17 + + – + – – – – 8 IVS6-1g<a
12 11 M 18 – + + – – – – + 6 C52S
13 12 M 18 + + – + + + – + 17 L129P
14 13 M 21 + + + + + + – + 11 R342X
15 u 10 M 21 + + + + + – + + 27 IVS6-1g<a
16 c 14 F 1.5 – – ND – – – – – 0 W209X
17 c 14 F 4 – – ND – – – – – 0 W209X
18 (v) 4 F 6 + + + – – – – – 7 W236C
19 g 15 F 8 – – + – – – – – 1 P265L
20 v 4 F 9 – – – – – – – – 0 W236C
21 16 F 9 + – + + – – – – 9 A350P
22 17 F 11 + – + – – – – – 6 ND
a
23 18 F 12 – – + – – – – + 2 P409A
24 19 F 14 – – + – – – – – 4 R220X
25 7 F 14 + + – + – – – – 6 I317N
26 g 15 F 14 + – + + – – + – 9 P265L
27 i 20 F 14 + – + – – – + – 15 34del24
28 21 F 15 – – + + + – – + 3 R220X
29 i 20 F 15 + – + + – + – – 7 34del24
30 22 F 16 + + + – + – – + 17 DQ358
31 23 F 17 + + + + + + + + 17 1072delGAG
32 (b) 2 F 17 + + – – + + – + 8 R301X
33 24 F 19 + – + – – + – – 7 591delG
34 25 F 19 + – + – – – – – 8 ND
35 d 5 F 20 + – – – – – – – 3 124-125delAT
a
Decreased GALA activity
b
Decreased creatinine clearance
769
caused by deposition of Gb
3
in nerve axons and dorsal
root ganglia, to which long unmyelinated fibres are pri-
marily susceptible [4]. An alternative explanation is that
exposure to cold induces local vasoconstriction and small-
fibre mal-p erfusion due to accumulation of stor age
material in cutaneous vessels and vasa vasorum [9]. Lu-
ciano et al. [16] found a length-dependent dysfunction of
a-delta and c-fibres resulting in greater impairment of cold
than warm sensation. Of the 28 adult patients in that
study, 6 had median nerve entrapment at the wrist [16].
However, significantly decreased cold an d warm sensa-
tion on physical examination is primarily a phenomenon
associated with adults. It is usually normal in paediatric
patients. Other possible causes of neuropathic pain in-
clude molecular mechanisms resulting in accumulation of
sodium channels in injured nerves, pathological sym-
patho-afferent coupling, disinhibition of nocioception,
and central or peripheral nocioceptive sensitisation.
Identification of the specific mechanism of neuropathic
pain in each patient would be advantageous for a more
precise selection of analgesic therapy [2]. Anticonvulsants,
for example carbamazepine [14], pheny toin [15], neuro-
tropin combined with carbamazepine [10], and gabapen-
tin [24] have been used for treatment of the chronic
neuropathic pain associated with FD.
A wide spectrum of other neurological and psycho-
logical findings could be documented in most of the
males and females. The range of these symptoms was
wide, producing diminished level of activity, fatigue,
tinnitus, recurrent vertigo, headache and depression.
Hypohidrosis, due to the accumulation of Gb
3
in the
eccrine sweat glands and their associated blood vessels
Fig. 1 Comparison of clinical
findings in males (solid bars)
and females (shaded bars). For
range of physical signs and
symptoms (asterisks), please
refer to the text
Fig. 2 Disease severity in males
(squares) and females (circles)
as a function of age. Open
symbols represent patients
without renal involvement and
solid symbols those with renal
involvement
770
[13], is very common in boys and was also observed to a
lesser degree in female patients. In many of our patients
it interfered with normal physical exercise mainly in the
summer. As body temperature changes are a triggering
factor, the inability to cool the body during exercise may
even increase neuropathic pain.
Angiokeratoma (Fig. 3), appearing as small, raised,
dark-red spots, were not always present. Although not
specific for FD, it can be idiopathic or associated with
other diseases [7, 8, 12, 20, 26]. It is the only objective
sign that may present early and usually allows prompt
diagnosis. In the absence of angiokeratoma, early clini-
cal diagnosis is often difficult to establish.
Gastrointestinal symptoms are quite frequent, pre-
senting with diarrhoea, constipation, recurrent nausea
or vomiting and abdomina l pain. These symptoms often
lead to hospitalisation and are sometimes mistaken for
chronic inflammatory bowel disease. Mala bsorption can
be caused by storage deposition in the small intestine,
while diarrhoea and altered intestinal motility may be
due to lipid accumulation in intestinal autonomic nerve
ganglia [21]. Argoff et al. [1] described improvement in
gastrointestinal emptying with oral metoclopropamide.
According to our experience, supplementation with
pancreatic enzyme preparations has resulted in
improvement of the symptoms. Some patients with
episodes of vomiting responded satisfactorily to on-
dansetrone.
Cardiac [11] and renal involvement can manifest in
childhood; hence early diagnosis and careful monitoring
is necessary. Proteinuria, i.e. albuminuria, is usually the
first indication of renal dysfunction [29]. Progressive
renal insufficiency occurs in older patients, although
significant renal involvement has previously been re-
ported in a 19-year-old female [5].
On the basis of the MSSI, 3/35 patients were unaf-
fected, 30/35 children and adolescence were mildly af-
fected (MSSI <20), with severity of symptoms in both
males and females being very similar. Two boys were
affected moderately (MS SI >20). MSSI increases with
age as the severity of symptoms worsens. In the males,
the correlation of increasing MSSI with age tended to be
more striking than in the females. This could be ex-
plained by the heterogeneity in disease severity amongst
females due to X-chr omosome inactivation and also the
later prese ntation of clinical symptoms when compared
to males. There also appeared to be significant inter- and
intrafamilial variability. Difficulties often arise in mak-
ing the diagnosis when no adult index patient is present.
This is due to the fact that many more frequent condi-
tions mimic signs and symptoms of FD [23], i.e. ‘‘growth
pain’’, rheumatological diseases, fibromyalgia, chronic
inflammatory bowel disease, and meningitis (fever, pain,
red punctuate skin lesions). Commo n symptoms in the
paediatric Fabry patient, like pain, diarrhoea, nausea,
vomiting, headache and fatigue are often misinterpreted
as non-specific. In these cases, the diagnosis may be
missed in the paediatric stage and finally be made in the
latter course of the disease when cardiac, cerebrovas-
cular, or renal complications are present.
Of the 25 families, GALA mutations were detected in
23 (92%). In our cohort, a total of 22 different muta-
tions were detected, only two apparently unrelated pa-
tients carried the same mutation (R220X in patients 24
and 28) suggesting that it is a recurrent gene defect. The
high frequency of ’private’ mutations is typical for an
X-linked trait with reduced reproductive fitness in
affected males. More than 50% of the GALA mutations
(13/22, i.e. 59%) predict a truncated protein due to an
early in frame nonsense mutation or a premature stop
codon following a DNA change with frame shift.
Clearly, some of these mutations may represent func-
tional null alleles with complete absence of the enzyme.
Nevertheless, no obvious correlation exists between the
genotype and phenotype that makes any prediction on
the clinical course of the disease difficult.
To ensure early diagnosis, a strong clinical suspicion
and systematic investigation of potentially affected fam-
ily members are essential. The high prevalence and rela-
tive specificity of cornea verticillata might suggest its
value as a screening method, for example in the context
of ophthalmological evaluations of school children or
candidates for the driving licence. The skin of the pae-
diatric pain patient needs to be evaluated for angioker-
atoma (Fig. 3) although their absence does not exclude
FD. Early diagnosis enables optimal supportive symp-
tomatic management, which, in combination with the
now available enzyme replacement therapy [6, 25] has the
potential to improve the quality of life, prevent late
complications and decrease the premature death rate. We
therefore believe that treatment with enzyme replace-
ment should be initiated at an early stage, prior to the
onset of irreversible complications. Current paediatric
enzyme replacement trials will extend the knowledge
about the potential of reversibility or prevention with this
promising therapy approach. Given the phenotypic
heterogeneity, the elaboration of therapy monitoring
Fig. 3 Angiokeratoma: diffuse and clustered (right flank of patient
15)
771
strategies may provide an indication of the quantity and
frequency of administration of the therapeutic enzyme
on an individual base. In the future, gene therapy could
be a novel therapeutic option to treat this debilitating
chronic progressive multisystemic disorder [22].
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