Fabry disease

Fabry disease
Name	Fabry disease
Synonyms	Anderson–Fabry disease, alpha-galactosidase A deficiency
Field	Medical genetics, Metabolic disorder
Symptoms	Acroparesthesia, angiokeratoma, hypohidrosis, corneal verticillata
Complications	Chronic kidney disease, cardiomyopathy, cerebrovascular accident
Onset	Childhood or early adulthood
Duration	Lifelong
Types	Classic, late-onset
Causes	Mutations in the GLA gene
Risks	Family history
Diagnosis	Enzyme assay, genetic testing
Differential	Rheumatic fever, multiple sclerosis, hypertrophic cardiomyopathy
Prevention	Genetic counseling
Treatment	Enzyme replacement therapy, migalastat, supportive care
Medication	Agalsidase alfa, agalsidase beta, migalastat
Prognosis	Variable; reduced life expectancy in classic form
Frequency	Estimated 1 in 40,000 to 60,000 males

Fabry disease is a rare, inherited lysosomal storage disorder caused by deficient activity of the enzyme alpha-galactosidase A. This deficiency leads to the progressive accumulation of globotriaosylceramide and related glycosphingolipids in the lysosomes of cells throughout the body. The resulting cellular dysfunction manifests primarily in the vascular endothelium, renal epithelium, cardiomyocytes, and neurons of the peripheral nervous system and autonomic nervous system.

Signs and symptoms

The clinical presentation varies significantly between the severe, classic phenotype and milder, late-onset forms. Classic symptoms often begin in childhood or adolescence and include episodes of severe acroparesthesia and neuropathic pain, a reduced ability to sweat known as hypohidrosis, and characteristic skin lesions called angiokeratoma. Gastrointestinal disturbances, such as abdominal pain and diarrhea, are common. Ocular signs, particularly corneal verticillata, are a frequent finding upon slit lamp examination. As the disease progresses, major organ involvement becomes apparent, leading to proteinuria, progressive chronic kidney disease often culminating in end-stage renal disease, left ventricular hypertrophy, arrhythmias, and an increased risk of transient ischemic attack and stroke. The late-onset form typically presents in adulthood, often with isolated cardiac or renal manifestations.

Genetics

Fabry disease is inherited in an X-linked recessive pattern. The causative mutations occur in the GLA gene located on the X chromosome, which provides instructions for making the alpha-galactosidase A enzyme. Males with a single mutated gene on their sole X chromosome are hemizygous and typically express the full disease spectrum. Females, who have two X chromosomes, can be heterozygous carriers; due to X-inactivation, their presentation ranges from asymptomatic to as severe as affected males, though they often have a later onset and slower progression. Notable cases have been identified in families worldwide, with hundreds of different mutations, including missense mutations, nonsense mutations, and splice site mutations, documented in the Human Gene Mutation Database.

Pathophysiology

The fundamental defect is a deficiency in the lysosomal hydrolase alpha-galactosidase A. This enzyme is responsible for cleaving the terminal galactose residue from globotriaosylceramide and other glycosphingolipids. Its absence results in the progressive lysosomal accumulation of these substrates, primarily globotriaosylceramide, within cells. This accumulation, particularly in vascular endothelial cells, smooth muscle cells, and podocytes, triggers a cascade of secondary pathological events. These include cellular hypertrophy, inflammatory response activation, oxidative stress, and ultimately, fibrosis and ischemia in affected organs like the kidney, heart, and brain. The mechanism of neuropathic pain is linked to damage of small fiber neuropathy and the dorsal root ganglion.

Diagnosis

Diagnosis is confirmed through biochemical and molecular testing. In males, the initial test is typically an enzyme assay measuring alpha-galactosidase A activity in leukocytes, plasma, or dried blood spots, which shows markedly reduced or absent activity. In females, enzymatic activity can be normal due to X-inactivation, making genetic testing of the GLA gene the definitive diagnostic method. Prenatal diagnosis is available via chorionic villus sampling or amniocentesis. Biopsy of tissues such as skin or kidney may show characteristic lipid inclusions, but is rarely needed. The disease is often included in the differential for conditions like familial hypertrophic cardiomyopathy or idiopathic renal failure.

Treatment

Management involves specific therapy and comprehensive supportive care. The cornerstone of specific treatment is lifelong enzyme replacement therapy with intravenous infusions of recombinant alpha-galactosidase A, available as agalsidase alfa or agalsidase beta. An oral pharmacological chaperone therapy, migalastat, is approved for patients with amenable GLA gene mutations. Supportive treatments are critical and may include anticonvulsants like gabapentin or carbamazepine for neuropathic pain, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers for proteinuria and renal protection, and management of cardiac arrhythmia with devices like pacemakers. Ultimately, some patients may require kidney transplantation or heart transplantation.

Epidemiology

Fabry disease has a reported incidence of approximately 1 in 40,000 to 60,000 live male births, though newborn screening studies suggest the frequency of late-onset variants may be higher. It affects all ethnic groups. Due to its X-linked inheritance, the disease is more severe and diagnosed more frequently in males, but an estimated 20-30% of heterozygous females develop significant symptoms. Studies from institutions like the National Institutes of Health and international registries like the Fabry Outcome Survey have helped characterize its natural history. The disease is named for the dermatologist Johannes Fabry and the surgeon William Anderson, who independently described its features.

Category:Lysosomal storage diseases Category:Inborn errors of lipid metabolism Category:X-linked recessive disorders