Fabry's disease E75.2

Authors: Prof. Dr. med. Peter Altmeyer, Alexandros Zarotis

All authors of this article

Last updated on: 29.10.2020

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Synonym(s)

Anderson-Fabry disease; angiokeratoma corporis diffusum; angiokeratoma universale; Ceramide trihexosidase deficiency; Ceramide trihexosidose; Fabry disease; Fabry M.; M. Fabry; Ruiter-Pompen-Weyers syndrome; Thesaurismosis hereditaria lipoidica

History
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Anderson, 1898; Fabry, 1898

Definition
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X-linked, rare lysosomal storage disease (see lysosome below) with deficiency of lysosomally localized alpha-galactosidase A, with neurological, nephrological cardiac and dermatological (small papular angiomas in about 70% of patients) symptoms.

Occurrence/Epidemiology
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Incidence: 1/3.100 live births

Etiopathogenesis
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X-linked recessive mutation of the alpha-galactosidase A gene (alpha GAL), which is mapped on gene locus Xq22 The consequence is a deficiency of alpha-galactosidase A and leads to an accumulation of glycosphingolipids, preferably globotriaosylceramides and galabiosylceramides, in the vascular endothelia, but also in other cells.

Manifestation
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First symptoms in childhood and adolescence (especially acroparesthesia, angiokeratomas, lid edema or vasospasms), internal organ involvement clinically noticeable only in adulthood. In the case of cardiac or renal variants, isolated involvement of the heart or kidney, often not before the age of 45 (late onset).

Localization
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Umbilical region (leading symptom), gluten, scrotum, trunk, rarely extremities. Rare is an involvement of the oral mucosa and the conjunctiva.

Clinical features
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  • In the first years of life (usually beginning in schoolchildren), diffuse pain symptoms and paresthesias of the extremities, angiokeratomas and hypohidrosis are the main clinical manifestations.
  • Integument (70% of patients): Multiple, symmetrically distributed, 1-3 mm large, purple-red to black-blue, only partially hyperkeratotic papules. The manifestation may be very discreet or absent. Clusters of capillaries of the nail fold as a possible precursor of an angiokeratoma. Hypo- or anhidrosis, therefore temperature increase during physical exertion; increased sensitivity to sudden temperature changes.
  • In the further course, superficial symptoms of vascular involvement, e.g. heart failure due to cardiovascular changes(hypertrophic cardiomyopathy), progressive renal failure, nephrogenic hypertension and cerebral insults.
  • Eye involvement: vertebral, subepithelial, yellow-brown corneal clouding lines (Cornea verticillata in 80% of cases), retinal vessel aneurysms, ampullae of the conjunctival veins.
  • Neurological symptoms: paresthesias, temperature-dependent pain crises of the extremities (acroparesthesias) which decrease from the 30th LJ, headaches, pareses, cerebral hemorrhages.

Laboratory
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Determination of globotriaosylceramide (Gb3) in blood (norm: < 2.3ug/l) and urine.

Complementary: Determination of the α-galactosidase A activity in leukocytes, serum, tear fluid.

In hemicygotes no or significantly reduced enzyme activity; in heterozygous women possibly no or slight reduction of enzyme activity - nevertheless, clinical symptoms cannot be excluded!

Note: Women represent a genetic mosaic: in one part of the body cells the functional X chromosome is switched on, in another part it is switched off. Women also fall ill, but later with much less severe symptoms.

Note: There are also polymorphisms without disease value.

Histology
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Acanthotic, partially hyperkeratotic epidermis. Subepidermal capillary ectasia, often enclosed by the long drawn-out reteleastern ridges. Detection of lipids in vessel walls and hair follicle muscles (Sudan black or Sudan red, intensive PAS reaction) Electron microscopy: Intracytoplasmic, osmophilic inclusion bodies in endothelial cells.

Differential diagnosis
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Other types of angiokeratomas, e.g. Angiokeratoma Mibelli, Angiokeratoma circumscriptum scrotalis (no birefringent lipids), other sphingolipidoses, senile angiomas, Teleangiectasia hereditaria haemorrhagica.

Therapy
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Enzyme replacement therapy: Agalsidase alpha (Replagal) 0.1 mg/kg bw over 40 minutes or Agalsidase beta (Fabrazyme) 1 mg/kg bw over 2-4 hours at regular (usually 14-day) intervals. Both preparations often cause at least a stagnation of the course of the disease, decrease of acroparaesthesia and improvement of the quality of life. Indications of improvement of heart and kidney insufficiency. Furthermore, symptomatic treatment of cardiovascular, pulmonary and muscular disorders.

Progression/forecast
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Untreated infaust. Lethal outcome between 30 and 50 years of age due to cardio- and renovascular complications (uremia or vascular insults). Under therapy probably significant improvement of the prognosis. With late-onset variants normal life expectancy.

Note(s)
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Diagnosis often only in adulthood with progression of the clinical symptoms. In case of suspected disease interdisciplinary approach with molecular genetic analysis, histology, bone marrow biopsy, urine sediment (Maltese crosses: polarization microscopic birefringent ceramide crystals). Eye examination with slit lamp: subepithelial deposited glycosphingolipids.

Capillary microscopy: tufts of some capillaries in 2 to 5 loops and their elongation. Medium plexus visibility (plexus score 2 according to Maricq). Pathological capillaroscopy may be an indication of a systemic vascular change which may occur without lipid deposition in the endothelial cells. The changes are similar to those in systemic collagenosis.

Prenatal diagnosis: chorionic villus sampling in 10th-12th weeks or amnioscentesis in 15th-18th weeks.

Literature
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  1. Anderson W (1898) A case of angio-keratoma. Brit J Derm 10: 113-117
  2. Bengtsson BA et al (2003) Enzyme replacement in Anderson-Fabry disease. Lancet 361: 352
  3. Desnick RJ et al (2003) Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 138: 338-346
  4. Fabry J (1898) A contribution to the knowledge of Purpura haemorrhagica nodularis (Purpura papulosa haemorrhagica Hebrae). Arch Derm Syphil (Berlin) 43: 187-200
  5. Frank J et al (1996) Angiokeratoma corporis diffusum universale (Fabry's disease). Dermatologist 47: 776-779
  6. Frustaci A et al (2001) Improvement in cardiac function in the cardiac variant of Fabry's disease with galactose-infusion therapy. N Engl J Med 345: 25-32
  7. Gahl WA (2001) New therapies for Fabry's disease. N Engl J Med 345: 55-57
  8. Gerbig A et al (1997) Capillary microscopy in angiokeratoma corporis diffusum. Dermatologist 48: 505.
  9. Laxmisha C et al (2003) Cutaneous variant of angiokeratoma corporis diffusum. Dermatol Online J 9:13
  10. Koch N et al (2015) Erythematous papules in a 26-year-old patient. Dermatologist 66: 868-880
  11. Mehta A (2009) Enzyme replacement therapy with agalsidase alfa in patients with Fabry`s disease. Lancet 374: 1986-1996
  12. Mohrenschlager M et al (2001) Skin manifestations of Fabry disease. JAMA 286: 1315
  13. Pastores GM, Thadhani R (2001) Enzyme-replacement therapy for Anderson-Fabry disease. Lancet 358: 601-603
  14. Peters FP et al (2001) Anderson-Fabry's disease: alpha-galactosidase deficiency. Lancet 357: 138-140
  15. Pieroni M et al (2003) Early detection of Fabry cardiomyopathy by tissue Doppler imaging. Circulation 107: 1978-1984
  16. Waldek S et al (2003) PR interval and the response to enzyme-replacement therapy for Fabry's disease. N Engl J Med 348: 1186-1187

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Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

Authors

Last updated on: 29.10.2020