Pediatric Fabry disease

University of Hamburg, Hamburg, Hamburg, Germany
PEDIATRICS (Impact Factor: 5.3). 03/2005; 115(3):e344-55. DOI: 10.1542/peds.2004-1678
Source: PubMed

ABSTRACT Fabry disease is an underdiagnosed, treatable, X-linked, multisystem disorder.
To test the hypothesis that quality of life and sweating are decreased among pediatric patients with Fabry disease, compared with control subjects, and to provide quantitative natural history data and novel clinical end points for therapeutic trials.
Prospective, cross-sectional, observational study.
Referral to the National Institutes of Health.
Twenty-five male children with Fabry disease (mean age: 12.3 +/- 3.5 years) and 21 age-matched control subjects.
Quality of life (measured with the Child Health Questionnaire) and sweating (assessed with the quantitative sudomotor axon reflex test).
Quality of life scores for pediatric patients <10 years of age with Fabry disease, compared with published normative values, were 55 +/- 17 vs 83 +/- 19 for bodily pain and 62 +/- 19 vs 80 +/- 13 for mental health. Bodily pain scores for patients > or =10 years of age were 54 +/- 22 vs 74 +/- 23. Sweat volume in the Fabry disease group was 0.41 +/- 0.46 microL/mm2, compared with 0.65 +/- 0.44 microL/mm2 in the control group. Renal function, urinary protein excretion, and cardiac function and structure were normal for the majority of patients. The 3 patients with residual alpha-galactosidase A activity > or =1.5% of normal values were free of cornea verticillata and had normal serum and urinary globotriaosylceramide levels. All other children had glycolipid levels comparable to those of adult patients with Fabry disease. Acroparesthesia and cardiac abnormalities were generally present before anhidrosis and proteinuria. Mapping of the missense mutations on the crystallographic structure of alpha-galactosidase A revealed that the mutations were partially surface-exposed and distal to the active site among individuals with residual enzyme activity. Mutations associated with left ventricular hypertrophy (defined as left ventricular mass index of >51 g/m2.7) were localized near the catalytic site of the enzyme.
Despite the absence of major organ dysfunction, Fabry disease demonstrates significant morbidity already in childhood. We have identified important, potentially correctable or preventable, outcome measures for future therapeutic trials. Prevention of complications involving major organs should be the goal for long-term specific therapy.

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Available from: Markus Ries, Aug 13, 2014
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    • "Most patients with Fabry disease have a complete loss of GALA enzyme activity, but some individuals maintain residual enzyme function. The presence of residual enzyme is associated with a milder form of disease as shown before for pain, kidney involvement or as an overall effect in the pediatric population (Altarescu et al., 2001b;Branton et al., 2002;Ries et al., 2005). "
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    ABSTRACT: Fabry disease, OMIM 301500, is a progressive multisystem storage disorder due to the deficiency of alpha-galactosidase A (GALA). Neurological and vascular manifestations of this disorder with regard to hearing loss have not been analysed quantitatively in large cohorts. We conducted a retrospective cross sectional analysis of hearing loss in 109 male and female patients with Fabry disease who were referred to and seen at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA on natural history and enzyme replacement study protocols. There were 85 males aged 6-58 years (mean 31 years, SD 13) and 24 females aged 22-72 years (mean 42 years, SD 12). All patients underwent a comprehensive audiological evaluation. In addition, cerebral white matter lesions, peripheral neuropathy, and kidney function were quantitatively assessed. HL(95), defined as a hearing threshold above the 95th percentile for age and gender matched normal controls, was present in 56% [95% CI (42.2-67.2)] of the males. Prevalence of HL(95) was lower in the group of patients with residual GALA enzyme activity compared with those without detectable activity (33% versus 63%) HL(95) was present in the low-, mid- and high-frequency ranges for all ages. Male patients with HL(95) had a higher microvascular cerebral white matter lesion load [1.4, interquartile range (IQR) 0-30.1 +/- versus 0, IQR 0-0], more pronounced cold perception deficit [19.4 +/- 5.5 versus 13.5 +/- 5.5 of just noticeable difference (JND) units] and lower kidney function [creatinine: 1.6 +/- 1.2 versus 0.77 +/- 0.2 mg/dl; blood urea nitrogen (BUN): 20.1 +/- 14.1 versus 10.3 +/- 3.28 mg/dl] than those without HL(95) (P < 0.001). Of the females, 38% had HL(95). There was no significant association with cold perception deficit, creatinine or BUN in the females. Word recognition and acoustic reflexes analyses suggested a predominant cochlear involvement. We conclude that hearing loss involving all frequency regions significantly contributes to morbidity in patients with Fabry disease. Our quantitative analysis suggests a correlation of neuropathic and vascular damage with hearing loss in the males. Residual GALA activity appears to have a protective effect against hearing loss.
    Brain 01/2007; 130(Pt 1):143-50. DOI:10.1093/brain/awl310 · 10.23 Impact Factor
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    ABSTRACT: Aim of Investigation: The neurological manifestations of Fabry’s disease, a rare, X-linked, multisystem disorder caused by alpha-galactosidase A deficiency and globotriosylceramide (Gb3) accumulation, include both peripheral and central nervous system symptoms. Here we evaluated a prospectively recruited cohort of patients with Fabry’s disease for pain, small nerve fiber function, and skin innervation. Methods: 66 patients (31 male and 35 female) were enrolled,31 patients were on ERT. All patients underwent quantitative sensory testing (QST), electrophysiological examination, and extra- and transcranial Doppler sonography. For pain and mood assessment standardized questionnaires were used. Skin biopsies were performed at the left distal leg in 38 patients for intraepidermal nerve fiber density (IENFD) assessment. Results: Age at examination did not differ significantly between women (40.2+/-16.2 years) and men (38.9+/-13.8; n.s.). 29/31 male and 19/35 female patients complained of acroparesthesias or neuropathic pain. QST abnormalities indicative of small fiber impairment were found in 26/31 male and 28/35 female patients. Electrophysiological examination of large fibers and autonomic fibers revealed pathological findings in 11/31 male and 3/35 female patients. All patients had normal Doppler sonography results. Indicators for depression were present in 14/31 male and 10/35 female patients. 20/31 male and 18/35 female patients had a skin biopsy, the IENFD was significantly reduced in male (2.0+/-2.8 fibers/mm) compared with female patients (6.7 +/- 4.4 fibers/mm). In 10 patients free from neurological symptoms, QST and IENFD abnormalities were still detected. Follow up examination after one year in 12 patients under ERT (2.1+/-1.7 years) showed improvement in some symptoms and in QST and neurophysiology in six patients with normal renal function. 20/35 female patients older than 40 y had concomitant diseases, while none of the 18 younger female patients did. The corresponding radio in male patients was 5/19 (>=40y) and 2/13 (<40y) respectively. Conclusions: Neuropathic pain and sensory deficits of the distal extremities are common in patients with Fabry’s disease. QST and IENFD analysis are important for early diagnosis of nerve involvement in Fabry’s disease. Small fiber function may improve under ERT in patients without severe renal impairment.
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    ABSTRACT: M E D I Z I N L ysosomen sind membranumhüllte Organellen, enthalten circa 50 bis 60 saure Hydrolasen und stellen eine Art zellulären Verdauungstrakt dar. Fehlt ei-nes dieser Enzyme, bricht der lysosomale Stoffwechsel ab, und es akkumulieren entsprechende Metabolite. Krankheiten, die auf einem Mangel lysosomaler Enzy-me beruhen, werden als lysosomale Speicherkrankhei-ten bezeichnet. Da sich Lysosomen in den meisten Zel-len des Körpers befinden, manifestieren sich die Spei-cherkrankheiten multisystemisch. Eine dieser Speicherkrankheiten ist der M. Fabry, der auf einem Mangel an alpha-Galaktosidase A beruht und X-chromosomal vererbt wird (e1). Folge des Enzym-mangels ist die Akkumulation des Sphingolipids Globo-triaosylceramid (Gb3). Der M. Fabry gilt immer noch als seltene Erkrankung. Untersuchungen von Risikogrup-pen sowie prospektive Erhebungen aus dem Neugebore-nenscreening legen jedoch eine deutlich höhere Präva-lenz nahe als bisher angenommen (Tabelle 1). Die Grün-de für die erheblichen Schwankungen in den Prävalenz-zahlen sind vielschichtig. So ist der klinische Verlauf des M. Fabry uneinheitlich und insbesondere bei Frauen sehr variabel. Das Spektrum möglicher Differenzialdiagno-sen ist breit und kann viele medizinische Subdisziplinen betreffen (Tabelle 2). Entsprechend hoch ist das Risiko für eine verspätete oder falsche Diagnose. Die Zeit zwi-schen Auftreten der ersten Symptome und der korrekten Diagnose ist mit circa 13 Jahren für Männer und 17 Jah-ren für Frauen entsprechend lang (e7). Die vorliegende Arbeit möchte die klinische Vielfalt des M. Fabry aufzeigen und die Aufmerksamkeit auf dieses noch immer unterdiagnostizierte und zu wenig berücksichtigte Krankheitsbild lenken. Es wird ein Dia-gnosealgorithmus vorgestellt und abschließend ein Überblick über die Therapieoptionen gegeben. Zu diesem Zweck wurde eine selektive Literaturana-lyse durchgeführt, die insbesondere neue Arbeiten berücksichtigte, die Ergebnisse größerer Patientengrup-pen beschreiben oder vollkommen neue Aspekte bezüg-lich Pathophysiologie, Klinik oder Therapie erfassen. Klinik Eine orientierende Übersicht über das Spektrum mögli-cher Beschwerden wird im Kasten präsentiert. Haut Die klassischen Angiokeratome (Abbildung) findet man im Kindesalter nur bei etwa 30 % der unter 16-Jährigen. Im Erwachsenenalter werden die stecknadelkopf-großen, meist vereinzelt stehenden, rötlich-bräunlichen Effloreszenzen (2) jedoch bereits bei zwei Drittel aller ZUSAMMENFASSUNG Hintergrund: Untersuchungen aus dem Neugeborenen-screening und von Risikogruppen legen für den M. Fabry eine wesentlich höhere Prävalenz nahe als angenommen. Die vielfältige Symptomatik eröffnet ein breites Spektrum an Differenzialdiagnosen und bedingt eine verzögerte Dia-gnose.
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