para>Presents in male children (as young as 9 years old) and female young adults (starting by age of 13 years)
Etiology and Pathophysiology
- X-linked inborn error of the glycosphingolipid metabolic pathway
- Deficiency of the α-galactosidase A results in the accumulation of globotriaosylceramide (Gb3) in lysosomes in multiple cell types throughout the body.
- Accumulation of Gb3 is particularly prominent in the vascular endothelium and smooth muscle cells, which can lead to vascular occlusion, ischemia, and infarction.
Genetics
- Gene defect located on the long arm of the X chromosome, Xq22
- X-linked inheritance pattern
- Hemizygous men are most commonly affected. Up to 70% of female heterozygotes have mild to pronounced features.
- Genetic testing is available. If family history suggests a diagnosis of Fabry disease, genetic testing and counseling should be offered to all family members, regardless of sex.
General Prevention
In those with Fabry disease who have had a stroke, traditional secondary stroke prevention strategies should be used.
Diagnosis
History
- Due to multisystem involvement, symptoms are often nonspecific and vague and may include visual changes, disequilibrium, peripheral edema, shortness of breath, palpitations, chest pain, high blood pressure, or signs of renal failure.
- Painful, burning sensation in the extremities (acroparesthesias). The peripheral neuropathy is chronic with episodic flaring, often exacerbated by psychological or environmental extremes (1).
- Skin lesions with a distribution typically between the umbilicus and knees.
- Suspect in young patients with signs and symptoms of a stroke, renal impairment or failure, or heart disease along with a history of skin lesions.
- Males fully manifest the disease usually by the 2nd and 3rd decades of life, whereas female heterozygotes present later, often by the 4th decade.
- Cardiac manifestations may include left ventricular hypertrophy, conduction defects, valvular abnormalities, and myocardial infarctions.
- Family history may be positive given that it is a genetic disease following X-linked inheritance.
Physical Exam
- Punctate, red-blue, nonblanching skin lesions (angiokeratomas)
- Peripheral neuropathy/acroparesthesias
- Hypohidrosis (inability to perspire)
- Ocular findings can range from diplopia and posterior cataracts to lenticular opacities and vascular lesions of the conjunctivae and retina.
- Neurologic findings may include hemiparesis, dysarthria, or other signs of stroke.
- Rhythm abnormalities may be found on cardiac auscultation and cardiomegaly on palpation.
- Pulmonary signs are of an obstructive nature with dyspnea and wheezing (2).
- Peripheral edema and other signs of renal impairment may be present.
Differential Diagnosis
Other causes of acute stroke such as dissection syndromes or cardioembolic stroke
Diagnostic Tests & Interpretation
Initial Lab Tests
- Electrolyte imbalances reflecting renal failure can be seen.
- Urine analysis: proteinuria, epithelial cells with intracellular lipid (Cells show birefringence when viewed under polarized light. A Maltese cross configuration may be visible.)
Imaging
- Chest radiograph (CXR): cardiomegaly
- Echocardiography: ventricular hypertrophy, valvular abnormalities, mitral valve prolapse (MVP), and wall motion abnormalities
- MRI/CT: acute stroke assessment using diffusion-weighted and perfusion-weighted images
- Vascular lesions can be identified using CT angiography and MR angiography.
Follow-up tests & special considerations
- Quantitative enzyme-linked immunosorbent assay (ELISA) of plasma, tissue, and urinary sediment to assess for globotriaosylceramide.
- Enzyme analysis of plasma or leukocytes for deficiency of α-galactosidase A
- Genetic/molecular diagnosis for confirmation
Diagnostic Procedures/Biopsy
- Nerve conduction: prolonged distal latencies and decreased conduction velocities
- Electrocardiogram (ECG): conduction abnormalities, left ventricular hypertrophy (LVH), and changes associated with previous myocardial infarctions
- Renal biopsy: Cellular inclusions with positive toluidine blue staining in glomerular podocytes, tubular epithelial cells, and extraglomerular vascular cells confirm the diagnosis.
- Skin biopsy: cells with increased lipid content
Pregnancy Considerations
Prenatal diagnosis (using amniocentesis or chorionic villus sampling) is possible (3). Postnatal testing is also available.
Treatment
Medication
- Enzyme replacement therapy, with either agalsidase beta (Fabrazyme) or agalsidase alpha (Replagal), reduces painful neuropathies and may stabilize renal and cardiovascular disease (4)[A]. It has been shown to be a safe and effective treatment (5,6)[A].
- Anticonvulsants such as carbamazepine and phenytoin are used successfully to treat painful peripheral neuropathies/acroparesthesias.
- Antiplatelet agents (aspirin, ticlopidine, clopidogrel, Persantine) should be used as a part of stroke prevention strategies.
- In the case of embolic stroke, anticoagulation such as using warfarin may be appropriate.
Issues for Referral
- Those with renal failure should have nephrology referral.
- Neurology referral is needed in cases of stroke due to Fabry disease and may also be useful for those with difficult to manage peripheral neuropathy.
- Consider cardiology referral in those with cardiovascular complications and in those with stroke thought secondary to embolic event.
- Physical therapy/rehabilitation can improve functional status for those patients recovering from cardiovascular or neurologic complications.
Additional Therapies
Research into replenishing deficient enzymes by means of gene transfer is in development.
Surgery/Other Procedures
Kidney transplantation is indicated in cases of end-stage renal disease, although it has not been shown to alter the progression of Fabry disease in other organ systems.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
Patients with Fabry disease should be monitored for and receive primary and secondary risk reduction treatments for known complications.
Prognosis
- Progressive and fatal disease due to its effects on vital organs
- After a first stroke, recurrent stroke is frequent in those with Fabry disease.
- Patients with Fabry disease often die prematurely due to complications from strokes, heart disease, or renal failure.
- Typically fatal in men by the 5th decade of life and women by the 7th decade.
Complications
- Painful peripheral neuropathy
- Depression
- Behavioral abnormalities
- Angiokeratotic skin lesions
- Arthritis
- Cataracts
- Stroke
- Myocardial infarction
- Congestive heart failure
- Ventricular hypertrophy
- Valvular heart disease
- Renal failure
References
1.Banerjee TK. Fabry disease with special reference to neurological manifestations. Eur Rev Med Pharmacol Sci. 2004;8(6):275-281.
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2.Brown LK, Miller A, Bhuptani A, et al. Pulmonary involvement in Fabry disease. Am J Respir Crit Care Med. 1997;155(3):1004-1010.
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3.Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.
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4.Mignani R, Cagnoli L. Enzyme replacement therapy in Fabry's disease: recent advances and clinical applications. J Nephrol. 2004;17(3):354-363.
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5.Brady RO, Schiffmann R. Clinical features of and recent advances in therapy for Fabry disease. JAMA. 2000;284(21):2771-2775.
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6.Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human alpha-galactosidase A-replacement therapy in Fabry's disease. N Engl J Med. 2001;345:9-16.
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Additional Reading
- Fabry Support & Information Group: http://www.fabry.org
- http://www.fabrycommunity.com
- National Fabry Disease Foundation: http://www.fabrydisease.org
- National Institutes of Health: http://www.ninds.nih.gov/disorders/fabrys
Codes
ICD09
- 272.7 Lipidoses
- 429.3 Cardiomegaly
- 356.9 Unspecified hereditary and idiopathic peripheral neuropathy
- 705.0 Anhidrosis
ICD10
- E75.21 Fabry (-Anderson) disease
- I51.7 Cardiomegaly
- G62.9 Polyneuropathy, unspecified
- L74.4 Anhidrosis
SNOMED
- 16652001 Fabry's disease (disorder)
- 55827005 left ventricular hypertrophy (disorder)
- 302226006 peripheral nerve disease (disorder)
- 45004005 Hypohidrosis (disorder)
Clinical Pearls
- First described in 1898 independently by two physicians, Johannes Fabry (a dermatologist) and William Anderson.
- Fabry disease is often misdiagnosed due to the nonspecific symptoms and the rarity of the disease, which many times leads to a significant delay in correct diagnosis and in effective treatment.