Pain is a common early and disabling manifestation of the disease. Patients typically report acral paresthesias and can develop pain crises that can be triggered by hot weather, stress or physical illness.
Angiokeratomas are the most common and classic skin manifestation of Fabry disease. These are purplish-red lesions that develop across the umbilicus, groin and upper thighs. Other skin findings include telangiectasias and hypohydrosis.
Cardiac complications are well described in Fabry disease with the most common manifestation being that of hypertrophic cardiomyopathy. Other changes include left ventricular hypertrophy, mitral valve regurgitation, diastolic heart failure, ischemia and cardiac arrhythmias.
The frequency of strokes and transient ischemic attacks is much higher in this population compared to the general population. Gastrointestinal (GI) manifestations can include nausea, vomiting, diarrhea and abdominal pain all of which have significant impacts on quality of life (QoL) in these patients. Additionally, hearing loss is more common in those with Fabry disease (usually sensori-neural in nature) compared to the age-matched general population. Psychiatric manifestations, corneal opacities, lymphedema and azoospermia may also occur.
Diagnosis is often delayed due to varied and often non-specific symptoms. However, once suspected, the diagnosis can be reliably made by checking for alpha-GAL levels in plasma or peripheral leukocytes (which is low or undetectable in Fabry disease) and by genetic sequencing of the GLA gene (to identify mutations). Detection of elevated levels of lyso-CTH (lyso-ceramide trihexoside) can further confirm the diagnosis and this can be used to monitor response to enzyme replacement therapy or oral chaperone therapy.
A basic blood panel should include troponin and BNP (brain natriuretic peptide) levels apart from blood counts, kidney function and liver function tests. Urine should be evaluated for microscopy and quantification of proteinuria. Electrocardiogram, echocardiogram, cardiac and brain MRI (magnetic resonance imaging), audiometry, pain evaluation and QoL questionnaires are often part of initial work-up and need to be repeated every 1-3 years as clinically indicated.
Kidney biopsy is indicated in cases of declining kidney function or urinary abnormalities. Kidney biopsy is diagnostic with light microscopy demonstrating accumulation of GB3 in podocytes and distal tubular cells with smaller amounts scattered in the mesangium, endothelium, proximal tubule and peritubular capillaries. Other non-specific changes in advanced disease include glomerulosclerosis, interstitial fibrosis and tubular atrophy. Notably, the glomeruli on the biopsy sample may appear white (rather than red) to the naked eye. Electron microscopy classically shows ‘zebra bodies’ most prominently in the podocytes and distal tubules – these represent the accumulated GB3 within lysosomes which appear as lamellated structures.
Treatment is often multi-pronged with multiple specialists involved in providing care. Management focuses on symptom control, Fabry-specific therapy and surveillance of organ systems.
Fabry-specific treatment includes enzyme replacement therapy (ERT) and oral chaperone therapy (Table 1). ERT refers to humanized alpha-GAL and is currently available in two formulations, namely agalsidase alpha (Replagal) and agalsidase beta (Fabrazyme), which can often be administered at home by trained nursing staff. Adverse effects commonly include infusion reactions and rarely the development of neutralizing antibodies to agalsidase; the latter is manifested by loss of ERT efficacy and rising lyso-CTH substrate levels in blood. ERT has been shown to reduce symptom burden (pain, GI symptoms), perhaps stabilize left ventricular mass and clear substrate from kidneys.
Migalastat is an oral chaperone therapy that can be used in certain amenable GLA gene mutations (this can be confirmed via the Galafold amenability website). These patients are able to make some alpha-GAL enzyme that is capable of degrading substrate. However, because of a genetic mutation, the produced enzyme is not effectively delivered to lysosomes. Migalastat acts by binding to the site of the mutated enzyme, stabilizing it and allowing its passage into the lysosomes. The drug then dissociates from the enzyme, thereby allowing alpha-GAL to catabolize the substrate.