Angiokeratoma Corporis Diffusum (Fabry Syndrome)

Updated: Feb 09, 2016
  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: William D James, MD  more...
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Overview

Background

Angiokeratoma corporis diffusum (Fabry disease) is an X-linked inherited disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase. This inborn error of metabolism results in unremitting deposition of neural glycosphingolipids in the lysosomes of the vascular endothelium; in fibroblasts; and in pericytes of the dermis, heart, kidneys, and autonomic nervous system. The Fabry disease gene is now known as the GLA gene, which stands for alpha-galactosidase. More than 370 GLA gene mutations have been cloned, all with a cytogenetic location of Xq22, located between base pairs 100,539,452 and 100,549,606. [1]

Beta-mannosidosis, a lysosomal enzyme disorder (which also results in mental retardation, hearing loss, and renal failure); fucosidosis; sialidosis; galactosialidosis; aspartyl-glycosaminuria; GM1 gangliosidosis; and Kanzaki disease can also be causes of angiokeratoma corporis diffusum. [2]

Additionally, several patients without detectable abnormalities have been reported.

Nucleoside sequencing of the entire GLA gene has enabled theoretical treatment using recombinant technology.

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Pathophysiology

A defect in the activity of alpha-galactosidase, a lysosomal enzyme, results in the insidious storage of 2 neutral glycosphingolipids: trihexosylceramide (galactosylgalactosylglucosylceramide) and digalactosylceramide (galabiosylceramide). These glycosphingolipids accumulate in many different types of cells. The most affected are the vascular endothelium and smooth muscle cells. Deposition of glycosphingolipids can be attributed to both endogenous production and diffusion of material from the circulation. As a result of the lack of this lysosomal enzyme that breaks down the glycolipid, persons with Fabry disease have 3-10 times the normal amount in their serum.

Larralde et al [3] have extensively explained the mechanism behind Fabry disease. The enzymatic defect in Fabry disease results in the accumulation of uncleaved glycosphingolipids in many human cell types. Particular types consist of endothelial cells, blood vessel cells, pericytes, vascular smooth muscle cells, renal epithelial cells, myocardial cells, skin structure cells, neuronal cells, and corneal cells.

Important mouse model work involving cardiomyopathy and enzyme replacement continues to be done. [4]

Persons with Fabry disease who have type AB or B blood also accumulate blood group B glycosphingolipids (those with alpha-galactosyl-terminated residues) and can have more severe Fabry disease (related to greater body substrate mass) than patients with blood group A. This is because these blood groups have 2 additional terminal alpha-galactosyl moieties.

Specifically, deposits in lysosomes of endothelial, perithelial, and smooth muscle cells of blood vessels cause swelling into the hollow bore of the blood vessel. In so doing, the vessels are narrowed and reactively expand, which leads to ischemia and infarction. This occurs, to a greater or lesser extent, in all affected cells, underlying the protean manifestations of Fabry disease.

In 2004, Larralde et al [3] report that most families have "private" mutations (ie, mutations found only in that particular family). Fabry disease is transmitted in an X-linked recessive pattern. The gene is located at band Xq22. Similar to other entities with this inheritance pattern, hemizygous males are most severely affected. The female carrier of this disease has diminished levels of alpha-galactosidase, which is enough to cause some symptoms but also to be spared the full clinical manifestations. Deficient alpha-galactosidase A activity can be present in the plasma in persons who do not have the full manifestations of Fabry disease. The deficiency must be extensive for full effects to manifest.

Molho-Pessach et al, [5] in 2007, reported a 36-year-old Arab woman with beta-mannosidosis who presented with mental retardation and multiple angiokeratomas with a novel null mutation involving a G→A transition in exon 6 at nucleotide position c.693, resulting in the formation of a stop codon (W231X).

Researchers found increased serum levels of vascular endothelial growth factor-A (VEGF-A), an endothelial cell mitogen, in 35 patients with angiokeratoma corporis diffusum (Fabry disease) versus matched controls, suggesting VEGF-A might be involved with vascular damage in angiokeratoma corporis diffusum (Fabry disease); however, additional research is needed to clarify the significance of this finding. [6]

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Epidemiology

Frequency

United States

Angiokeratoma corporis diffusum (Fabry disease) is rare; the estimated incidence is 1 case per 40,000 population. Others believe this prevalence is an overestimation. According to Larralde et al, [3] inheritance of the abnormal gene among whites (resulting in a hemizygous boy or a heterozygous girl) has been estimated to occur once in every 117,000 live births.

International

Most occurrences of angiokeratoma corporis diffusum (Fabry disease) are in whites; however, Fabry disease has been reported to occur in black persons, Latin Americans, Native Americans, Egyptians, and Asians.

Race

While angiokeratoma corporis diffusum (Fabry disease) is most common in whites, it has been reported in black persons, Latin Americans, Native Americans, Egyptians, and Asians.

Sex

Because angiokeratoma corporis diffusum (Fabry disease) is an X-linked recessive disease, only men are fully afflicted. Heterozygous women, in addition to transmitting the condition, may develop symptoms.

Age

In males, signs and symptoms of angiokeratoma corporis diffusum (Fabry disease) begin in late childhood or adolescence. By age 20-29 years, most affected men experience the full brunt of the disease. Heterozygous women first note symptoms by age 20 years to early 30 years. Möhrenschlager et al [7] report that the Anderson-Fabry disease register shows the median cumulative survival of hemizygous men with Fabry disease is 50 years, compared with 70 years for females. This means that men live approximately 20 years less than unaffected men and that women live 15 years less than unaffected women. Some men, however, even without enzyme replacement, live to their 70s.

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Prognosis

Few afflicted men live to be older than 50 years. A male cardiac variant exists in which patients have enough alpha-galactosidase to stave off the renal, neurologic, and skin changes typical of Fabry disease. Patients develop cardiac manifestations, especially cardiomyopathy.

Before the advent of enzyme replacement therapy, renal failure secondary to uremia and hypertension was the major cause of death for men with angiokeratoma corporis diffusum (Fabry disease) aged 30-39 years, followed by congestive heart failure and cerebrovascular accidents. Currently, mortality due to renal pathology seems to be decreasing, leaving cardiac issues as an increasing cause of morbidity and mortality among patients with Fabry disease. [8]

Heterozygous women have a longer lifespan with the disease because if they develop renal and cardiac symptoms, they do so later in life. Heterozygous females develop angiokeratomas and cataracts and experience a milder clinical course. Some patients may have more serious involvement; however, lifespan is longer for women than for men diagnosed with this disease.

A variety of clinical findings occur in female carriers. The scope is vast and ranges from asymptomatic carriers to carriers with fully expressed Fabry disease. Asymptomatic corneal dystrophy occurs in approximately 70% of carriers. This is an indication of the carrier state. Approximately 30% of female carries have angiokeratomas, with less than 10% having paresthesias. A 2004 study by Larralde et al [3] of obligate female carriers found significant disease manifestations in 20 of 60 women. Another study performed on 20 carriers of Fabry disease showed that each woman had some symptom of Fabry disease, with a wide scope of manifestations. Larralde et al [3] concluded that Fabry disease might be designated a storage disease transmitted as an X-linked–dominant, not X-linked–recessive, disease.

Hormonal function and fertility rates are normal in both male and female Anderson-Fabry patients compared with controls.

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Patient Education

Genetic counseling is urged. Both affected men and heterozygous women can transmit the gene. Sons of affected men are free of the gene, but daughters can pass the gene to future generations. In the offspring of heterozygous women, 50% of male children may have the disease and 50% of female children may become carriers.

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