Fabry disease: what it is and what the symptoms are
Fabry disease (also known as Anderson-Fabry disease) is a genetic lysosomal storage disorder, characterised by the progressive accumulation of glycosphingolipids in tissues and organs throughout the body
This accumulation is caused by partial (or total) deficiency of the enzyme α-galactosidase (α-Gal) A, resulting from an X-chromosome mutation, which causes glycolipid accumulation in tissues and/or occlusion of blood vessels 1,2.
The estimated incidence is approximately 1:40,000 men3 and 1:20,000 women 4.
Fabry Disease is hereditary and can be transmitted from parents to children
Human cells contain chromosomes, which are thread-like structures that carry genetic information.
Females have two X chromosomes in each cell (each X is inherited from one of their parents), while males have one X and one Y chromosome (the X chromosome is inherited from the mother, while the Y chromosome is inherited from the father)7.
The mutated gene responsible for Fabry Disease is located on chromosome X8.
Women who carry the mutated gene on only one X chromosome are usually affected by Fabry Disease, but show less severe symptoms and manifest later in life than men9.
Signs and symptoms of Fabry disease
Fabry disease presents with different, non-specific symptoms involving several organs10.
The most common signs and symptoms are 11:
- hearing problems: ringing in the ears (tinnitus) or hearing loss;
- impaired sweating, which can cause frequent fever and low resistance to heat or exercise;
- abdominal problems such as pain, nausea, vomiting or diarrhoea;
- fatigue and depression;
- changes in the eyes such as clouding of the cornea;
- heart problems;
- the most serious problems are those affecting the heart, kidneys, nervous system and these can be seen in older patients and in advanced stages of the disease;
- small, raised, dark-red spots on the skin (angiokeratomas);
- pain and burning in the limbs.
Diagnosis
Many patients are misdiagnosed due to the high variability in the development of Fabry disease over time1,12.
Early diagnosis is essential to appropriately manage the effects of the disease on the major organs affected9.
In males, diagnosis is based on analysis of α-Gal A activity and is confirmed by genetic testing; in females, diagnosis must necessarily be based on genetic testing as α-Gal A activity may be within the normal range1,13.
Treatment: to date, several therapies are available for Fabry disease
It is essential to refer to a Centre for Rare Diseases for appropriate evaluation.
Bibliography
Mehta A et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004;34:236–42.
Hagège AA et al. Screening patients with hypertrophic cardiomyopathy for Fabry disease using a filter-paper test: the FOCUS study. Heart 2011;97:131–6.
Spada M et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Human Genet 2006; 79:31–40.
Meikle PJ et al. Prevalence of lysosomal storage disorders. JAMA 1999;281:249–54
Gal A et al. Toward a consensus in the laboratory diagnostics of Fabry disease – recommendations of a European expert group. Inherit Metalab Dis 2011; 34:509–514.
Germain DP. General aspects of X-linked diseases. In: Mehta, A. et al (eds). Fabry disease: perspectives from 5 years of FOS. Oxford: Oxford PharmaGenesis; 2006. Chapter 7.
Chromosomes Fact Sheet National Human Genome Research Institute (NHGRI). Disponibile al sito: https://www.genome. gov/26524120/chromosomes-fact-sheet/ (Utlimo accesso: 26/03/2018).
Desnick RJ. A-Galactosidase A deficiency: Fabry disease. In: Scriver, CR. et al (eds). The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2001: 3733–74.
Mehta A, et al. Fabry disease: a review of current management strategies. Q J Med 2010; 103(9): 641–59.
Ries M, Gal A. Genotype–phenotype correlation in Fabry disease. In: Mehta, A. et al (eds). Fabry disease: perspectives from 5 years of FOS. Oxford: Oxford PharmaGenesis; 2006. Chapter 34.
Germain DP. Fabry disease. Orphanet J Rare Dis 2010; 5: 30.
Beck M. In: Mehta A, et al. (eds). Fabry disease: perspectives from 5 years of FOS. Oxford: Oxford PharmaGenesis. 2006; Chapter 16.
Gupta S et al. The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a cross-sectional study of a large cohort of clinically affected heterozygous women. Medicine (Baltimore) 2005;84:261–8.
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