Fabry disease

Fabry disease, also known as Anderson-Fabry disease, is a multisystem disorder resulting from an X-linked inborn error of metabolism, and is a lysosomal storage disorder. The disease results from genetic mutations which cause decreased or absent expression of hydrolase alpha-galactosidase A, ultimately resulting in abnormal accumulation of globotriaosylceramide (Gb₃) in various organ systems ⁸.

The clinical manifestations are variable and may depend on the specific gene defect and degree of residual enzyme activity. Both male and heterozygous females can exhibit a severe phenotype.

Clinical presentation

Fabry disease was initially described in males with a form of severe disease, a phenotype known as a "classic" Fabry. However, it is now recognized that there are both early and late-onset forms of the disease in males, depending on the genetic aberration and degree of enzymatic compromise ⁸.

Similarly, females that have heterozygous genetic involvement have a spectrum of presentation ranging from asymptomatic to severe. This may be explained by variable expression of the mutated X-linked gene ⁸.

Neurological

Small vessel ischaemia is the main mechanism of central nervous system manifestations, with ischaemic strokes, especially of the posterior circulation being common. Multi-infarct dementia can ensue, although MRI T2 hyperintensities in the white matter of the frontal and parietal lobes can be seen in asymptomatic patients. MRI is used to monitor treatment response.

T1 weighted images also demonstrate high signal in the deep grey matter especially that of the pulvinar, relating to mineralisation (see basal ganglia T1 hyperintensity). Exclusive involvement of pulvinar is thought to be characteristic of the condition ⁴.

Additionally basilar artery dolichoectasia is characteristic for this disease 13.  

Both T2 and T1 changes have been seen to regress with treatment if instituted early enough.

Acroparesthesia is a common manifestation, more so than ischaemic changes described above, and can be debilitating ⁶.

Autonomic (sympathetic) nervous system involvement can lead to gastrointestinal autonomic dysfunction.

Renal

Renal involvement begins with proteinuria progressing to end stage renal failure usually in the 4^th decade. On imaging, the kidneys have non-specific findings of medical renal disease including increased echogenicity, thinned renal cortex, and multiple renal cysts. The cysts are perhaps the most specific sign, typically small and of uniform size, located just beneath the capsule, aiding in differentiating these from autosomal dominant polycystic kidney disease (ADPKD).

Ocular

Fabry disease is affiliated with corneal verticillata and lenticular abnormalities. Recent studies have proposed eye signs in Fabry disease in association with α-galactosidase A mutations could be an indicator of disease severity ⁷.

Cardiac

Focal myocardial fibrosis leads to left ventricular hypertrophy, with eventual restrictive ventricular physiology with diastolic dysfunction. Thickening and redundancy of the atrioventricular valves is often seen, which may result in functional mitral regurgitation. While systolic function is typically spared until late in the disease course, regional wall motion abnormalities may occur early, preferentially in a posterolateral distribution ¹¹.

Transthoracic echocardiography allows differentiation from other restrictive cardiomyopathies; the "binary" appearance imparted by the notably echo-poor subendocardium intercalated between the strongly echogenic endocardium and myocardium is relatively specific. It is not, however, pathognomonic, and may be occasionally found in patients with hypertrophic cardiomyopathy

Musculoskeletal

Avascular necrosis of the femoral head has been described.

Pulmonary

There can be chronic obstructive airways disease like symptoms with bronchial wall thickening.

Treatment and prognosis

Enzyme substitution (hydroxylase alpha-galactosidase) is efficacious in rectifying the metabolic deficit. It consists of an intravenous infusion which is typically given every two weeks ⁸. Enzyme replacement has been shown to improve some deposition-related components of the disease, including some reversal in cardiac enlargement and clearance of excessive glycolipids from renal podocytes ⁹.

A modestly-sized (n=110) retrospective Dutch study showed median life expectancy of 57 years for males and 72 for females ¹⁰.

History and etymology

First described in 1898 by Johanne Fabry,German dermatologist (1860-1930) ¹².