What is Fabry Disease?
Fabry disease (Online Inheritance in Man number – 301500) is a rare lysosomal storage disorder with an estimated incidence of 1:50,000 males worldwide. It was first described by Anderson and Fabry in the 1800s. It is caused by deficiency of the enzyme alpha-galactosidase A, required for the degradation of globotriaosylceramide. Accumulation of the undegraded material occurs in multiple cell types mainly in the vascular endothelium resulting in a multi-system disorde. It is an X- linked disorder affecting mainly males but heterozygous females may also present with some manifestations of the disease.
When to suspect Fabry disease ?
Classically, presentation is in childhood or early adolescence with pain episodes and vascular cutaneous lesions. But onset may be delayed and manifest in the third to fifth decade . These atypical cases present usually as “cardiac” or “renal “ variants and lack the characteristic pain crises and skin lesions.
What are the clinical features?
· Acroparesthesias- periodic crises of severe pain in the extremities usually triggered by exercise, fatigue, stress, or rapid changes in temperature and humidity
· Angiokeratomas- vascular cutaneous lesions (small pin-head like raised areas red in color, usually occurring in cluster) commonly in a “bathing trunk” distribution involving the area between the umbilicus and the knees
· Sweating abnormalities (anhydrosis, hypohydosis, and rarely hyperhidrosis),
· Corneal and lenticular opacities
· Stroke, transient ischemic attacks
· Left ventricular hypertrophy, cardiac conduction abnormalities
· Musculoskeletal involvement in the form of joint limitations and avascular necrosis
· Gastrointestinal manifestations like diarrhea, vomiting , abdominal pain
Fabry disease is known to contribute to 1% of cases with end stage renal disease. Similarly, it can present as cardiomyopathy or stroke at young age. Though the disease is X linked recessive, many carrier females present with varied manifestations of variable severity.
How is Fabry disease diagnosed?
The presence of the characteristic features of acroparesthesias and angiokeratomas in a male should alert any physician to the possibility of Fabry disease. As presentations of only renal, cardiac or neurological symptoms are not uncommon and this disease should be suspected in appropriate clinical situations and investigations of slit lamp examination for corneal opacitites and enzyme assay should be done at early thresh hold. Diagnosis is by enzyme assay in leucocytes with the residual enzyme activity <1% in classical cases. Molecular diagnosis can be done by mutation analysis of the GLA gene. All types of mutations have been reported including missense, nonsense, splicing, frameshift and insertions / deletions.
How to treat Fabry disease?
Treatment has been traditionally in the form of symptomatic management. Drugs used for neuropathic pain include phenytoin, carbamazepine and gabapentin. Surveillance and appropriate management for renal and cardiac complications is warranted.
Enzyme replacement therapy [ERT] has been available since 2001 and the symptomatic improvement is significant, and there may be protective effect on the renal and cardiac involvement. It has to be given as an intravenous infusion every 2 weeks. After the onset of renal failure, ERT will not improve the renal function. Available data shows that ERT has limited effect on quality of life and progression to end organ damage.
What are the implications for the family?
A carrier female has a 50% chance of transmitting the mutation to her offspring. Fifty percent of her sons will be affected and 50% of her daughters will be carriers. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in a family is known.
Testing of asymptomatic relatives is important as early diagnosis and institution of therapy may improve outcome by preventing damage to the organs.
What’s in the future?
Other therapies under investigation include chaperone therapy, substrate reduction and gene therapy. Ongoing research into areas like screening of newborns, understanding of natural course of the disease will provide useful information about decision of selection of patients for ERT and appropriate time to start ERT.
More to readSchuller Y, et al. Pain management strategies for neuropathic pain in Fabry disease--a systematic review. BMC Neurol. 2016 Feb 24;16:25.
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Dr. Shubha R Phadke
Sanjay Gandhi Postgraduate Institute of Medical Sciences