Anderson-Fabry Disease

Synonyms:Fabry Disease, alpha-galactosidase A deficiency, hereditary dystopic lipidosis, GLA deficiency

• Anderson-Fabry is an X-linked recessive inborn error of glycosphingolipid metabolism caused by deficiency of alpha-galactosidase A.¹
• It was first described independently in 1898 by Anderson and Fabry but the enzyme deficiency was not defined until the 1960s. The enzyme deficiency leads to defective storage of sphingolipid and progressive endothelial accumulation causing abnormalities in skin, eye, kidney, heart, brain and peripheral nervous system.
• The gene responsible for alpha-galactosidase is located on the long arm of the X chromosome. There have been almost 200 mutations identified.
• Along with Gaucher disease it is one of the most prevalent metabolic storage diseases (or lysosomal storage diseases) and in common with Gaucher disease the gene mutation and enzyme deficiency result in insufficient activity of enzymes required for the breakdown of substances that arise from cell turnover in the body.²

• It is estimated to occur in 1 in 40,000-60,000 males in the classical form but the atypical variant may be more common.
• It has been described in many racial groups.
• As an X-linked recessively inherited condition female carriers exist and can exhibit mild to moderate symptoms (variable expression according to random X inactivation of the affected gene in embryogenesis).

There are 3 distinct clinical entities.

Male homozygotes with classical manifestation

No alpha-galactosidase activity in plasma.

• Onset in childhood or early adolescence. Often patients have slight builds with characteristic coarse facial features and delayed puberty.
• Early symptoms of burning pain and paraesthesia in the extremities (acroparaesthesia) are a major cause of morbidity. Painful crises may be triggered by temperature change, fever, sun, physical exertion etc.General fatigue and weakness is common.
• Progressive development of symptoms consistent with disease affecting many different systems. For example:
  • Skin.Angiokeratomas occur early and are small punctate red to blue-black telangiectasiae typically in a 'bathing suit' distribution. Hypohydrosis. Lymphoedema in lower extremities.
  • Eye. Lens, cornea, conjunctiva and retina may all be involved. Particular types of pathognomic lens opacity have been described (the propeller or wedge shaped opacity and the Fabry cataract).
  • Cardiovascular system. Problems typically develop in the fourth decade.This can produce anginal pain in adulthood with varied complications ranging from arrhythmias to myocardial infarction and heart failure.³
  • Cerebrovascular disease. This can produce problems ranging from personality change and psychosis to varied manifestations of multifocal cerebrovascular disease. It typically develops in the fourth decade.
  • Gastrointestinal disease. This can include symptoms of diarrhoea, weight loss abdominal pain, nausea and vomiting.
  • Renal disease. This produces hypertension, proteinuria and progressive renal failure. Such symptoms typically develop in the second and third decade.
  • Other organs and systems. Widespread involvement produces many other manifestations of the disease including cough, breathlessness, wheeze etc.

Male homozygotes with atypical manifestation

Some alpha-galactosidase activity in plasma (5-35%). Probably the most common variant.

• Often asymptomatic
• Adult onset
• Present late, often sixth to eighth decade
• Usually present with cardiac involvement including cardiomegaly, mitral insufficiency, cardiomyopathy
• Can present with proteinuria
• Occasionally develop acroparaesthesia

Female heterozygotes

Variable (0-100%) plasma alpha galactosidase activity depending on random X-chromosomal activation.

• Variable presentation
• Adult onset
• Dystrophy of cornea in the subepithelial layer with whorled streaks in 70%
• Angiokeratomas in 30%
• Occasionally acroparaesthesia
• Rarely hypohidrosis and other organ involvement (Renal failure less than 1%)

There is a big list of possible differential diagnoses according to the varied clinical presentations. Correct diagnosis is important because of the progressive morbidity associated with advancing disease. Early diagnosis is now important because some disease manifestations (Fabry cardiomyopathy) can be modified with enzyme replacement therapy.^4,5

• Confirmation of diagnosis is by demonstration of absent or deficient levels of alpha-galactosidase A in leucocytes, plasma or cultured fibroblasts.
• Glycosphingolipid is deposited in urine in complexes. Urine microscopy with polarised light may show 'maltese cross' appearance (birefringent lipid molecules).
• Prenatal diagnosis is possible by detecting deficient enzyme activity (alpha-galactosidase activity can be measured from chorionic villus biopsy in the first trimester or cultured amniotic cells in the second trimester) or by detecting specific mutations in chorionic villi. Heterozygote female fetuses can be identified if the family mutation is known
• Other helpful investigations include ECG, MRI,⁶ echocardiography etc. Eye examination may show diagnostic corneal or lenticular deposits.⁷

• General support and advice:
  • Psychological support (patient and families)
  • Avoidance of precipitating factors for pain (acroparaesthesia) and tiredness (limiting physical exertion)
  • Maintaining increased fluid intake during exercise and in warm weather
  • Avoid smoking (cardiovascular and cerebrovascular risk)
  • Low fat diet (may help gastrointestinal symptoms)
  • Mild renal dysfunction: low-sodium and low-protein diet
• Drug treatments:
  • Prophylactic antibiotics should be considered (see Prevention of Endocarditis article)
  • Carbamazepine and phenytoin may help with prevention of pain attacks
  • Antiplatelet agents or anticoagulants(preventive for cerebrovascular disease)
• Management of advanced disease
  • End-stage renal disease: renal dialysis, renal transplantation (but disease develops in transplanted kidneys eventually)
  • Cardiac intervention, e.g. pacemakers, valve and coronary artery surgery
  • Dermatological treatment: laser therapy for removal of angiokeratomas
  • Enzyme replacement therapy is available and well-tolerated. There is evidence that this may reduce pain and improve cardiac and renal function.^8,9
  • Enzyme replacement therapies have been limited by the blood-brain barrier, but new therapies such as gene therapy have been initiated.²
• Genetic counselling is very important where there is a family history

Before dialysis and renal transplantation, death often occurred in the fourth or fifth decade in male homozygotes particularly. Treatments now available can improve both morbidity and mortality.^6,10 It is likely that for maximum benefit these treatments will have to be started early and given long term.¹¹