What are the symptoms in men with type 1 classic and type 2 later onset Fabry disease?
Clinical manifestations in Type 1 Classically affected males begin in childhood or adolescence. Most often, the first symptoms are painful acroparesthesias (especially during febrile illnesses); hypohidrosis; and gastrointestinal symptoms, including postprandial abdominal cramping, bloating, and diarrhea. Small petechial-like angiokeratomas, the classic cutaneous vascular lesions, typically are present in the umbilical and swimsuit regions in childhood. Type 1 Classically affected males also have a distinctive corneal dystrophy observed by slit-lamp microscopy, which does not affect vision. Microvascular involvement of the kidney begins in childhood; progresses to isothenuria, proteinuria, and tubular dysfunction; then, with advancing age, results in progressive kidney disease and ESKD typically by age 35 to 45 years. Dialysis and kidney transplantation are effective in correcting the kidney disease, and kidney transplants are not affected by the disease. All potential family donors should be evaluated to ensure that they are not affected or heterozygotes.
Other manifestations include lower extremity edema in the absence of significant kidney disease, hypoproteinemia, or varices; the lymphedema results from the accumulation of GL-3 in the lymphatic vessels and nodes. Cardiac manifestations include arrhythmias (initially sinus bradycardia), valvular abnormalities, and left ventricular hypertrophy, which may lead to hypertrophic cardiomyopathy. Cerebrovascular disease manifests as transient ischemic attacks and stroke: the strokes often result from the cardiac arrhythmias. Progressive high-frequency hearing loss occurs in Type 1 Classically affected males in the third to fifth decades of life.
In contrast, males with the Type 2 Later-Onset phenotype lack the microvascular endothelial glycolipid deposition that leads to the early manifestations in Type 1 Classic males. Type 2 males develop renal disease and/or heart disease in their third decade of life, or later. The renal disease is characterized by increasing proteinuria due to progressive podocyte glycolipid accumulation, and can progress to renal failure. The heart disease is characterized by progressive cardiomyocyte glycolipid accumulation and typically results in the development of left ventricular hypertrophy (LVH) leading to hypertrophic cardiomyopathy (HCM). Type 2 males also may develop transient ischemic attacks (TIA) and strokes primarily due to cardiac arrhythmias.
