Clinical description:

Fabry disease is a rare, complex lysosomal storage disease with multisystemic involvement due to the progressive accumulation of globotriaosylceramide (GL-3) in the vascular endothelium. There is a phenotypic spectrum ranging from the severe, classic phenotype, to an attenuated phenotype, to atypical cardiac or renal variants.

Clinical subtypes:

Heterozygous females—Females heterozygous for a GLA pathogenic variant may remain clinically asymptomatic, present with an attenuated form of the disease, or manifest the full clinical spectrum of symptoms observed in males with classic Fabry disease.

Cardiac variant—This phenotype generally presents in males with greater than 1% enzymatic activity. Cardiomyopathy develops in the sixth to eighth decade of life and is characterized by left ventricular hypertrophy, hypertrophy of the interventricular septum, mitral valve insufficiency, and/or conduction abnormalities. Proteinuria may also be a feature, but end stage renal disease is typically absent.

Renal variant—This variant presents in males with greater than 1% enzymatic activity and has been diagnosed in Japanese patients with end stage renal disease and a prior diagnosis of chronic glomerulonephritis. Other symptoms of classic Fabry disease are generally absent, although moderate-to-severe left ventricular hypertrophy acroparesthesias and hypohidrosis have also been reported with the cardiac variant.

Symptoms include:

• periodic severe pain crises in the extremities (acroparesthesias)
• vascular cutaneous lesions (angiokeratomas), typically in the bathing-suit area
• sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis)
• exercise, heat, or cold intolerance
• characteristic corneal and lenticular opacities (corneal whorls), observed by slit lamp examination
• unexplained stroke (thrombosis, transient ischemic attacks [TIA], basilar artery ischemia and aneurysm, seizures, hemiplegia, hemianesthesia, aphasia, labyrinthine disorders, frank cerebral hemorrhage)
• cardiac disease (including mitral insufficiency, left ventricular enlargement, valvular involvement, and/or conduction involvement)
• renal insufficiency
• GI disturbances (episodic diarrhea, nausea, vomiting, bloating, cramping, abdominal pain, and/or intestinal malabsorption)

The classic phenotype in hemizygous males is the most commonly reported. Symptom onset generally occurs in childhood or adolescence, with the median reported age of 6 years in males and 9 years in females. The first detectable symptoms are usually acroparesthesias, angiokeratomas, hypohidrosis, and/or ocular findings. Cardiac and cerebrovascular disease is usually evident by middle age. Chronic kidney disease is present by the third decade of life and progresses to end stage renal disease (ESRD) by the fifth decade of life unless treated by chronic hemodialysis or renal transplant. Untreated Fabry disease causes a significantly reduced lifespan; the major causes of morbidity and mortality are renal failure, cardiovascular disease, and stroke. Heterozygous females may remain asymptomatic with a normal lifespan, have an attenuated form of the disease, or manifest all features of the severe, classic disease. Milder, non-classical variants include a cardiac form that has isolated cardiac symptoms developing in both males and females during sixth to eighth decade of life, and a renal form that leads to end stage renal disease occurring in the same time frame as males with the classic form of the disease. Symptoms such as milder left ventricular hypertrophy, acroparesthesias, and hypohidrosis have also been reported in cases with the renal variant.

Clinical sensitivity:

More than 99% of patients with a clinical diagnosis of Fabry disease have an identifiable pathogenic mutation in GLA.