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The early clinical phenotype of Fabry disease: A study on 35 European children and adolescents


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Unlabelled: Fabry disease (FD) is a debilitating progressive multisystem X-linked lysosomal storage disorder. It was generally believed that the disease affects only adult males. Through systematic pedigree analysis, we identified 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 observed. 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 frequently affected at an early age, not much differently than males. They should be carefully examined because most carriers are symptomatic. Conclusion: Fabry disease usually becomes clinically manifest in childhood. Renal involvement can begin in adolescence. The diagnosis 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 replacement therapy has shown promising effectiveness in adults. Considering its widespread therapeutic and potential preventive benefits, enzyme replacement therapy should be initiated at an early stage, prior to the onset of irreversible complications.
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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
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
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
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
), 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].
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
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.
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,
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
Sex Age
and/or low
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
10 9 M 15 + + + + +
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
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
Decreased GALA activity
Decreased creatinine clearance
caused by deposition of Gb
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
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
[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-
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
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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... In vitro models have been generated for genetic pain syndromes using iPSC-derived sensory neurons [15][16][17]44 and have helped to unravel disease pathophysiology 15,44,45 and identify novel targets for treatment. 16,17 In Fabry research, generation of sensory neurons retaining cellular disease phenotype using patient biomaterial was not successful so far, 46 Pain in Fabry disease is one of the very early symptoms starting in childhood 51 and is mostly episodic and triggerable. 4,52 Using our in vitro disease model, we show that heat, a typical trigger of Fabry pain, leads to increased Ca 2+ levels in Fabry neurons, pointing to higher neuronal activity (Fig. 6B). ...
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Acral burning pain triggered by fever, thermal hyposensitivity, and skin denervation are hallmarks of small fibre neuropathy in Fabry disease, a life-threatening X-linked lysosomal storage disorder. Variants in the gene encoding alpha-galactosidase A may lead to impaired enzyme activity with cellular accumulation of globotriaosylceramide (Gb3). To study the underlying pathomechanism of Fabry-associated small fibre neuropathy, we generated a neuronal in vitro disease model using patient-derived induced pluripotent stem cells from three Fabry patients and one healthy control. We further generated an isogenic control line via CRISPR/Cas9 gene editing. We subjected iPSC to targeted peripheral neuronal differentiation and observed intra-lysosomal Gb3 accumulations in somas and neurites of Fabry sensory neurons using super-resolution microscopy. At functional level, patch-clamp analysis revealed a hyperpolarizing shift of voltage-gated sodium channel steady-state inactivation kinetics in Fabry cell lines as compared to the healthy control. Moreover, we demonstrate a drastic increase in Fabry sensory neuron Ca ²⁺ levels at 39°C mimicking clinical fever (p < 0.001). This pathophysiological phenotype was accompanied by thinning of neurite calibres in sensory neurons obtained from Fabry patients compared to healthy control cells (p < 0.001). Linear-Nonlinear cascade models fit to spiking responses revealed that Fabry cell lines exhibit altered single neuron encoding properties relative to control. We further observed jam of mitochondrial trafficking at sphingolipid accumulations within Fabry sensory neurites utilizing a click-chemistry approach together with mitochondrial dysmorphism compared to healthy control cells. We pioneer insights into the cellular mechanisms contributing to pain, thermal hyposensitivity, and denervation in Fabry small fibre neuropathy, and pave the way for further mechanistic in vitro studies in Fabry disease and the development of novel treatment approaches.
... Bu intrasitoplazmik birikintiler, Fabry hastalığında terleme yeteneğinin azalmasından sorumlu olabilir [93]. Yapılan bir çalışma Fabry hastası çocuklarda erkeklerin %50'sinde ve kadınların %25'inde terlemenin veya ısı intoleransının azaldığını göstermiştir [94], [95] Psoriatik hastalarda ekrin ter salgılama kapasitesi azalır. Bunun başlıca nedeni ter bezlerinin keratin tarafından mekanik olarak tıkanmasıdır ve bu tıkanıklığın giderilmesi daha yüksek terleme oranları sağlar. ...
Conference Paper
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Elektronik kartlar beyaz eşya sektöründe yaygın bir biçimde kullanılmaktadır. Bu kartların ürünlere bağlanabilmesi için bir çok bağlantı elemanlarına ihtiyaç duyulmaktadır. Bu bağlantı elemanlarının bir çeşidi de yaylı sabitleme ayaklarıdır. VTC elektrikli ocaklarda kullanılan elektronik kartın bir parçası olan bu yaylı sabitleme ayaklarının ocak taban sacına montajlanması elektrikli ocağın dokunmatiği için önem arz etmektedir. Bu yaylı ayaklar elektronik kartta 4 adet bulunmaktadır. Bu ayakların montajının elektrikli ocağın alt taban sacına düzgün oturtulmaması durumunda dokunmatik algılamamakta veya farklı komutları uygulamaktadır. Bu çalışmada iki farklı ayak tasarımı üzerine analiz yapılmıştır. Bunun sebebi VTC elektrikli ocakta halihazırda kullanılan sabitleme ayaklarının montajlandıktan sonra gereğinden fazla esnemesidir ayrıca elektrikli ocak üzerinde montaj tamamlandıktan sonra cam üzerinde komutların çalışmamasıdır. Bunun üzerine sabitleme ayaklarının esnemesini önlemek amacıyla ek bir tasarım iyileştirmesi yapılmış daha sonra ANSYS Structural ara yüzünde iki tasarımın da tek eksenli ve toplam yer değiştirmeleri incelenmiştir. Mevcut tasarım bu çalışmada tasarım-1 olarak adlandırılmış, tek eksenli yer değiştirmesi 0.45 mm toplam yer değiştirmesi 0.48 mm olarak bulunmuştur. Tasarım iyileştirmesi olarak önerilen ise tasarım-2 olarak adlandırılmış ve tek eksenli yer değiştirmesi 0.4 mm toplam yer değiştirmesi ise 0.42 mm olarak bulunmuştur. Mevcut sonuçlar değerlendirildiğinde yapılan iyileştirmenin fayda sağladığı, endüstriye uygulanabilir olduğu görülmüş, elektronik kartın sabitleme ayaklarının esnemesinin azaltılabileceği tespit edilmiştir.
... Another reason would be the non-specific symptomatology present at the beginning: acroparesthesias, abdominal pain, changes in intestinal transit or urinalysis (presence of proteinuria or microscopic hematuria). Therefore, in the absence of a positive family history, these changes are not associated with Fabry disease at the beginning [1,7]. ...
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Fabry disease is an X-linked lysosomal storage disease, second in prevalence after Gaucher disease. The onset of symptoms occurs in childhood or adolescence with palmo-plantar burning pains, hypo hidrosis, angiokeratomas, and corneal deposits. In the absence of diagnosis and treatment, the disease will progress to the late phase, characterized by progressive cardiac, cerebral and renal damage, and possible death. We present the case of an 11-year-old male boy who was transferred to the Pediatric Nephrology Department for palmo-plantar burning pain and end stage renal disease. Following the evaluations for the etiology of end stage renal disease we excluded the vasculitis, the neurologic diseases, extrapulmonary tuberculosis. Because of suggestive aspect at CT scan and lack of etiologic diagnosis of renal insufficiency we performed lymph node and kidney biopsy, with a surprising result for storage disease. The specific investigation confirmed the diagnosis.
... Currently there is on average a 15-year delay in the diagnosis of FD, due to the lack of awareness about the disease and non-specific symptoms [6,24]. The diagnosis is based on a thorough family history, on the evaluation of enzymatic activity of alpha-galactosidase A on leukocytes and plasma [25]; the evaluation of Gb3 levels in serum and urine [26], and on cardiac and renal biopsies [2]. ...
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Background Fabry disease (FD) is a rare X-linked, lysosomal storage disorder caused by mutations in the alpha-galactosidase gene and characterized by neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and ocular manifestations. The aim of this study is to characterize morphological, functional and autophagy-lysosome pathway alterations of the ocular surface in FD patients. Methods Eleven subjects with a diagnosis of FD and fifteen healthy control subjects were examined. All patients underwent ocular surface slit lamp examination, corneal aesthesiometry and in vivo confocal laser-scanning microscopy (CCM). Conjunctival impression cytology was performed in six FD patients and six controls, to assess for expression of two markers of the autophagy-lysosome pathway: the microtubule-associated protein light chain 3 (LC3) and lysosome-associated membrane protein 2 (LAMP2). Results Cornea verticillata and increased conjunctival vessel tortuosity were detected respectively in 67% and 33% of patients with FD. Compared with healthy subjects, patients affected by FD showed a significant reduction in corneal nerve fiber length, density and nerve branching on CCM and a significantly increased expression of LC3 on conjunctival impression cytology ( p < 0.001). No changes were observed in the conjunctival expression of LAMP2 between the two groups. Conclusions This study shows that FD is associated with ocular surface alterations including corneal and conjunctival morphology, innervation and vascularization changes. Our data demonstrate an increased expression of LC3 protein in patients with FD, suggesting that alteration of the autophagy-lysosome pathway may play a role in the occurrence of ocular manifestations.
Fabry disease (FD) and hereditary transthyretin amyloidosis (ATTR amyloidosis) are conditions that cause adult hypertrophic cardiomyopathy in addition to the involvement of other organs. In childhood, the diagnosis of FD is a challenge due to its varied presentation. The diagnosis of ATTR amyloidosis is not common in pediatrics. Both conditions have a genetic origin, so a family history is essential. This chapter aims to describe the clinical and genetic diagnosis of the two diseases in children and adolescents.
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Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is α-galactosidase A (α-Gal A), which is due to a mutation in the GLA gene on the X chromosome. The enzyme deficiency leads to a continuous deposition of neutral glycosphingolipids (globotriaosylceramide) in the lysosomes of numerous tissues and organs, including endothelial cells, smooth muscle cells, corneal epithelial cells, renal glomeruli and tubules, cardiac muscle and ganglion cells of the nervous system. This condition leads to progressive organ failure and premature death. The increasing understanding of FD, and LSD in general, has led in recent years to the introduction of enzyme replacement therapy (ERT), which aims to slow, if not halt, the progression of the metabolic disorder. In this review, we provide an overview of the main features of FD, focusing on its molecular mechanism and the role of biomarkers.
Fabry disease newborn screening (NBS) has been ongoing in Oregon for over 41 months by first‐tier enzyme quantitation and second‐tier DNA testing. During that period the majority of abnormal referrals received (34/60) were for the presence of the controversial c.427G > A (p.Ala143Thr) aka A143T and the majority of non‐A143T referrals were for other variants of uncertain significance (17/60) resulting in at least 32 infants with an inconclusive case outcome even after clinical evaluation and/or diagnostic testing. To date there has been no significant family history or onset of symptoms in individuals with an inconclusive outcome. Based on our experience, we have developed a framework for approaching A143T and other variants of uncertain clinical significance in an attempt to balance sensitivity with the unnecessary medicalization of healthy infants.
Background Fabry disease (FD) is an inherited lysosomal storage disorder, leading to multisystemic manifestations and causing significant morbidity and mortality. Objective The aim of this narrative review is to present the current and novel therapeutic strategies in FD, including symptomatic and specific treatment options. Methods A systematic literature search was conducted to identify relevant studies, including completed and ongoing randomized-controlled clinical trials (RCTs), prospective or retrospective cohort studies, case series and case reports that provided clinical data regarding FD treatment. Results A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity. During the last two decades, FD-specific treatments, including two enzyme-replacement-therapies (agalsidase alfa and agalsidase beta) and chaperone treatment with migalastat have been approved for use and allowed for symptoms’ stabilization or even disease burden reduction. More therapeutic agents are currently under investigation. Substrate reduction therapies, including lucerastat and venglustat, have shown promising results in RCTs and may be used either as monotherapy or as complementary therapy to established enzyme-replacement-therapies. More stable enzyme-replacement-therapy molecules that are associated with less adverse events and lower likelihood of neutralizing antibodies formation have also been developed. Ex-vivo and in-vivo gene therapy is being tested in animal models and pilot human clinical trials, with preliminary results showing a favorable safety and efficacy profile.
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Inherited renal diseases represent 20% of the causes of end-stage renal diseases. Fabry disease, an X-linked lysosomal storage disorder, results from α-galactosidase A deficient or absent activity followed by globotriaosylceramide (Gb3) accumulation and multiorgan involvement. In Fabry disease, kidney involvement starts early, during intrauterine life by the Gb3 deposition. Even if chronic kidney disease (CKD) is discovered later in adult life in Fabry disease patients, a decline in glomerular filtration rate (GFR) can occur during adolescence. The first clinical sign of kidney involvement is represented by albuminuria. So, early and close monitoring of kidneys function is required: albuminuria and proteinuria, urinary albumin-to-creatinine ratio, serum creatinine, or cystatin C to estimate GFR, while urinary sediment with phase-contrast microscopy under polarized light may be useful in those cases where leucocyte α-Gal A activity and GLA genotyping are not available. Children with Fabry disease and kidney involvement should receive enzyme replacement therapy and nephroprotective drugs (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) to prevent or slow the progressive loss of kidney functions. Early diagnosis of Fabry disease is important as enzyme replacement therapy reduces symptoms, improves clinical features and biochemical markers, and the quality of life. More importantly, early treatment could slow or stop progressive organ damage in later life.
A 21-year-old man developed clinical angiokeratoma corporis diffusum at about the age of 4 years. The initial diagnosis was based on typical skin and histological findings. Recent enzyme studies on this patient have revealed a severely reduced α-L-fucosidase activity but a normal α-galactosidase activity; earlier reports have associated angiokeratoma corporis diffusum with decreased α-galactosidase activity. These findings suggest that cutaneous angiokeratoma corporis diffusum can occur with at least two different enzyme abnormalities. Electron micrographs have shown abnormal storage vacuoles in endothelial cells, histiocytes, fibroblasts, and within keratinocytes.
Fabry's disease, lysosomal alpha-galactosidase A deficiency, results from the progressive accumulation of globotriaosylceramide and related glycosphingolipids. Affected patients have microvascular disease of the kidneys, heart, and brain. We evaluated the safety and effectiveness of recombinant alpha-galactosidase A in a multicenter, randomized, placebo-controlled, double-blind study of 58 patients who were treated every 2 weeks for 20 weeks. Thereafter, all patients received recombinant alpha-galactosidase A in an open-label extension study. The primary efficacy end point was the percentage of patients in whom renal microvascular endothelial deposits of globotriaosylceramide were cleared (reduced to normal or near-normal levels). We also evaluated the histologic clearance of microvascular endothelial deposits of globotriaosylceramide in the endomyocardium and skin, as well as changes in the level of pain and the quality of life. In the double-blind study, 20 of the 29 patients in the recombinant alpha-galactosidase A group (69 percent) had no microvascular endothelial deposits of globotriaosylceramide after 20 weeks, as compared with none of the 29 patients in the placebo group (P<0.001). Patients in the recombinant alpha-galactosidase A group also had decreased microvascular endothelial deposits of globotriaosylceramide in the skin (P<0.001) and heart (P<0.001). Plasma levels of globotriaosylceramide were directly correlated with clearance of the microvascular deposits. After six months of open-label therapy, all patients in the former placebo group and 98 percent of patients in the former recombinant alpha-galactosidase A group who had biopsies had clearance of microvascular endothelial deposits of globotriaosylceramide. The incidence of most treatment-related adverse events was similar in the two groups, with the exception of mild-to-moderate infusion reactions (i.e., rigors and fever), which were more common in the recombinant alpha-galactosidase A group. IgG seroconversion occurred in 88 percent of patients who received recombinant alpha-galactosidase A. Recombinant alpha-galactosidase A replacement therapy cleared microvascular endothelial deposits of globotriaosylceramide from the kidneys, heart, and skin in patients with Fabry's disease, reversing the pathogenesis of the chief clinical manifestations of this disease.
Neuropathische Schmerzen treten dann auf, wenn das Nervensystem selbst geschädigt ist. In der gängigen Klassifikation werden neuropathische Schmerzen noch nach deren Ätiologie eingeteilt. Durch die Forschung der letzten Jahre gelang es jedoch, die wichtigsten molekularen Mechanismen neuropathischer Schmerzen aufzuklären. Es hat sich dabei gezeigt, dass diese Mechanismen prinzipiell unabhängig von der Ätiologie der Nervenschädigung sind. Die wichtigsten Mechanismen sind die Akkumulation von spannungsabhängigen Na⁺-Kanälen im verletzten Nerv, die pathologische Kopplung zwischen sympathischen und nozizeptiven Axonen, die Disinhibition der Schmerzempfindung auf Rückenmarksebene, die zentrale (spinale) und die periphere nozizeptive Sensibilisierung. Gegen jeden einzelnen Mechanismus gibt es bereits heute therapeutische Optionen. Das Ziel einer erfolgreichen Schmerztherapie muss also sein, individuelle Schmerzmechanismen und nicht ätiologische Krankheitsentitäten zu bekämpfen. Die Aufgaben der klinischen Forschung in den nächsten Jahren liegen darin, dazu die nötigen Instrumentarien zu liefern. Nur so wird jeder Patient mit neuropathischen Schmerzen die für ihn effiziente Therapie bekommen können.
A 19 year old male affected with Fabry's disease suffered from severe nervous manifestations. Despite very peculiar pains of the extremities, the diagnosis has been missed for a long time and was painted out at this age because of sharp reconstitution of the family history. Fabry's disease was confirmed by discovering typical corneal lesion, a low leucocyte (W.B.C.) alpha-galactosidase activity and foam cells in renal glomerular epithelium. The importance of an early diagnosis is obvious in this case: 10 Instead of degrading narcotic therapy, Carbamazepin brought forward normal social and school living. 20 Familial investigations show up that all the siblings were affected (three boys including the propositus)--several symptoms were found in the heterozygous conductor mother. Despite the rarety of Fabry's disease, the authors emphasize the easiness of diagnosis on simple clinical and biochemical grounds. The authors insist on the symptomatic and therapeutic action of Carbamazepin or Diphenytoin in order to prevent painfull symptoms which often appear during initial course of the disease.
We describe a patient with adult-onset neuronal storage disease characterized by myoclonus, cerebellar ataxia, convulsive seizures, cherry-red spots, skeletal dysplasia, mild gargoyle features, inguinal hernia, and angiokeratoma. Cytoplasmic inclusions consistent with lysosomal storage disease were demonstrated in neurons of the autonomic nervous system. Accumulation of GM3 and GM2 gangliosides was found in sympathetic ganglia but a catabolic disturbance of these gangliosides was ruled out by normal levels of GM3 ganglioside sialidase and N-acetyl-β-hexosaminidase A activities. β-Galactosidase activity was decreased in leukocytes and fibroblasts, but not in serum. GM1 gangliosidosis was ruled out by lipid analyses, and mucopolysaccharidosis by normal excretion of mucopolysaccharide in urine. Sialyl oligosaccharides were increased in urine and α-neuraminidase was deficient in fibroblasts. This disorder is considered to be an inherited metabolic disorder of sialyl glycoproteins and oligosaccharides due to deficiency of an α-neuraminidase.
Neurotropin, an extract from the inflamed skin of vaccinia virus-inoculated rabbits, was effective in the relief of sharp or burning pain induced by pyrexia, hot weather, bathing, or exercise in 2 siblings with Fabry disease. Neither neurotropin nor carbamazepine mono-therapy relieved the episodic colicky pain in 1 patient; however, therapy with both drugs eliminated the pain completely. This result suggests that the mechanisms underlying the analgesic actions of both drugs may be complementary in ameliorating the pain of Fabry disease, even though the mechanism underlying the pain has not been clearly elucidated.
A 46-year-old Japanese woman had disseminated angiokeratoma, confirmed by electron microscopy which showed numerous cytoplasmic vacuoles in cells of the kidney and skin. Enzyme activities against synthetic and natural substrates in leucocytes and fibroblasts were normal. Her urine contained a large amount of sialylglycoaminoacids, with predominant excretion of an O-glycoside-linked glycoaminoacid.
Eight patients with clinically and biochemically diagnosed Fabry's disease and chronic acroparesthesias were treated with diphenylhydantoin, aspirin or multivitamins in a double blind crossover controlled study. Plasma diphenylhydantoin concentrations of more than 4 mcg per milliliter were effective in eliminating the pain associated with Fabry's disease.