Fabry disease

Fabry disease is a genetic neurometabolic disorder of lysosomal glycosphingolipid metabolism that can affect the nervous system, mental health, cardiovascular system, kidneys, and multiple other organ systems. It typically occurs as an inherited X-linked genetic condition, although de novo variants can occur; therefore, absence of a relevant family history does not exclude the diagnosis. It affects both males and females; females may have manifestations ranging from mild or asymptomatic disease to clinical involvement as severe as that seen in males, although classic disease is generally more severe and begins earlier in males.

It can present with psychiatric features such as depression, anxiety, fatigue, impaired social functioning, and other neuropsychological or adaptive difficulties. Psychiatric manifestations may become apparent or clinically significant during adolescence or adulthood. Psychosis has been reported but appears to be rare, and its relationship to Fabry disease is not conclusively established.

Other characteristic features include episodic or chronic neuropathic pain and acroparesthesia, hypohidrosis or anhidrosis, small-fibre and autonomic dysfunction, tinnitus or hearing loss, and cerebrovascular disease including transient ischemic attacks and stroke. Characteristic ocular findings include cornea verticillata and lenticular opacities. Cognitive difficulties may occur, particularly in executive functioning and processing speed. Angiokeratomas are characteristic cutaneous vascular lesions and are particularly prominent in classic disease.

From a multisystemic lens perspective, clinical features in other body systems include (but are not limited to):

• Cardiovascular: left ventricular hypertrophy, hypertrophic cardiomyopathy, myocardial fibrosis, conduction abnormalities, cardiac arrhythmias, valvular disease, and myocardial ischemia may occur.

• Renal/electrolytes: proteinuria, progressive renal impairment, and chronic kidney disease may occur, potentially progressing to end-stage kidney disease.

• Respiratory: chronic bronchitis, wheezing, and dyspnea may occur, with obstructive abnormalities on pulmonary function testing in some individuals.

• Gastrointestinal: episodic abdominal pain, nausea, vomiting, diarrhea, bloating, and intestinal dysmotility may occur and can resemble irritable bowel syndrome.

• Dermatologic: angiokeratomas, particularly in the distribution between the umbilicus and knees, are characteristic; hypohidrosis or anhidrosis may also occur.

Early diagnosis is important to recognize a potentially treatable cause of neuropathic pain, neuropsychiatric symptoms, cardiac disease, renal disease, and cerebrovascular disease; identify affected relatives; initiate disease-specific therapy before irreversible organ damage develops; reduce the risk of progressive renal, cardiac, and cerebrovascular complications; and guide appropriate psychiatric, neurologic, cardiovascular, and renal management.