Elsevier

The Lancet

Volume 372, Issue 9647, 18–24 October 2008, Pages 1427-1435
The Lancet

Series
Fabry's disease

https://doi.org/10.1016/S0140-6736(08)61589-5Get rights and content

Summary

Fabry's disease is an X-linked lysosomal storage disorder caused by abnormalities in the GLA gene, which leads to a deficiency in α-galactosidase A. The consequent abnormal accumulation of glycosphingolipids results in several clinical signs and symptoms and substantial morbidity and mortality. This review covers all basic aspects of the disease such as epidemiology, pathophysiology, clinical presentation by systems, diagnosis, management, prevention, and repercussions on quality of life. With the development of enzyme replacement therapy in the past few years, early initiation of treatment is key for improvement in major affected organs with decreased cardiac mass and stabilisation of kidney function, and improvement in neuropathic pain, sweating, gastrointestinal symptoms, hearing loss, and pulmonary symptoms. However, treatment of individual symptoms in addition to enzyme replacement therapy seems to be needed for many patients, especially those who have had some degree of organ dysfunction. Additional data are needed to document long-term treatment outcomes.

Introduction

Fabry's disease (Anderson–Fabry's disease, Online Mendelian Inheritance in Man [OMIM] number 301500) is an X-linked lysosomal storage disorder initially described in 1898, which is caused by deficiency of α-galactosidase A.1 Usual onset of first symptoms is in childhood. By middle age, life-threatening complications often develop in untreated patients. The life expectancy in untreated men is reduced by about 20 years from that of the general population of 50 years, with a steep decline in survival after 35 years.2 Women can also have symptoms, but onset is generally later than for men and life expectancy is reported to be reduced by about 15 years.3

Section snippets

Epidemiology

The incidence of Fabry's disease has been estimated at one in 40 000 to one in 117 000 worldwide.4 We do not know of any ethnic predisposition, but regional pockets with increased incidence can occur because of founder effects, as has been documented in Nova Scotia, Canada, and West Virginia, USA. Fabry's disease is probably underascertained, because presenting symptoms are non-specific. Residual enzyme activity might lead to slow progression of the disease and result in the so-called cardiac

Pathophysiology

Deficiency of α-galactosidase A leads to storage of neutral glycosphingolipids, particularly globotriaosylceramid and galactosylceramide, in many tissues and cell types. As little as 5–10% of residual enzyme activity seems to be sufficient to prevent clinically significant accumulation of globotriaosylceramid.11 Progressive storage of these molecules eventually leads to cellular dysfunction, which might in turn trigger inflammation or fibrosis, or both. These processes lead to organ dysfunction

Clinical presentation

Progression of clinical symptoms in Fabry's disease can be divided conceptually into three consecutive age periods. Although the disease process begins early with evidence of storage even in the prenatal period, symptoms do not develop until early childhood.25

Early symptoms in children include burning pain in the hands and feet, hypohydrosis, nausea, abdominal pain, postprandial diarrhoea, poor growth, and school difficulties (primarily frequent absences, poor participation especially in

Diagnosis

Diagnosis is frequently delayed by several years because of the non-specific nature of the presenting complaints.26, 27, 28 In children the presence of acute, unexplained episodes of pain or chronic pain in the limbs, exercise intolerance, unexplained gastrointestinal disturbances, hypohidrosis, and angiokeratomas are the most common presenting signs and symptoms (figure 3). Characteristic corneal lesions are seen in most affected children even early in the disease course. Mild proteinuria

Management

Theoretically, reversal of the abnormal accumulation of sphingolipids from target organs should lead to clinical improvement or stabilisation.85 Enzyme replacement therapy has now been available for several years and received approval in Europe in 2001 and the USA in 2003. Additionally, other treatment options are being studied. The advent of specific treatment has increased the need for early recognition to help treatment and delay or prevent complications.

In Europe, two preparations of the

Conclusion

More data are needed to document long-term treatment outcomes, which would ideally come from a combination of long-term observational studies and well designed randomised trials. Studies are needed to evaluate the effect of treatment on various aspects of the disease process, different dose regimens of the two available preparations, and their comparison at the recommended doses and equivalent doses. Studies of the effect of treatment at different stages of the disease are also needed,

Search strategy and selection criteria

We searched PubMed (past 10 years) for the terms “Fabry disease”, alone and in combination with “clinical manifestations” or “enzyme replacement therapy”. We translated all publications not in English that resulted from this search. We mostly selected publications in the past 5 years, including major randomised trials, but additional relevant and frequently referenced older publications were also reviewed. Review articles were also included, because of their comprehensive overviews of

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