Fabry Disease

Some cases show no significant clinical manifestations. In other cases, the clinical manifestations of Fabrys disease appear early in life. With age, these manifestations may increase in severity.

One of the common clinical features of this disease is pain. This pain is usually episodic. It may appear in the whole body or may be localized to the arms and legs. In the latter case, the pain is referred to as acroparesthesia [1]. This pain is usually of a burning sensation and is often further localized to the most distal parts of the limbs, i.e. the hands and the feet. It is believed that this pain results from damage to the peripheral nerves. Pain also commonly occurs in gastrointestinal tract, is of a diffuse nature and results from a generalized obstruction in the lipid laden blood vessels of the gastrointestinal tract. Episodes of pain can be triggered by a number of factors such as physical activity, fatigue, fever, stress and environmental changes.

A number of skin abnormalities frequently occur in the sufferers of Fabry diseases. Raised papules called angiokeratomas are common. These are dark red rashes and can occur anywhere on the body; but usually occur only on the lower half; more particularly around the umbilicus & on the thighs, buttocks and legs. Sweat gland dysfunction is also present in most cases. Usually there is reduced sweating but cases of excessive sweating have also been seen.

Ocular changes are very frequent in Fabry disease. The corneas of both eyes are typically affected. They have visible clouding which upon closer inspection is found to consist of golden brown lines arranged in a whorled pattern. This is known as cornea verticillata or whorl keratopathy. It is one of the most characteristic features of Fabry disease. However it must be noted that despite the apparent clouding of the cornea, there is no disturbance in vision.

With time, lipids deposit in the heart, kidneys and nerves of the patient. Symptoms related to these organs begin to manifest after the age of 30. Glycolipid deposition in the heart predisposes the heart to the development of various kinds of diseases. Cardiovascular disorders such as hypertension and cardiomyopathies, most particularly, left ventricular hypertrophy, are very common in the sufferers of Fabry disease [2]. Patients of Fabry disease may suffer from angina and myocardial infarction. Syncope and dyspnea are also seen in a majority of the patients with cardiovascular manifestations. Conduction defects such as VT that occur in these patients may be secondary to cardiomyopathies.

Chronic lipid deposition in the nephrons results in the renal manifestations of Fabry disease. The earliest clinical feature is proteinuria. The urine has a higher viscosity and may even appear foamy. There is progressive deterioration in the function of the kidney, causing renal insufficiency. Later, the kidneys may shut down completely and cause renal failure [3].

The diagnosis of Fabry disease can be made by demonstrating below normal levels of the enzyme alpha galactosidase (or its activity) either in the blood plasma, white blood cells or other cultured cells. While this is an effective diagnostic method in males, it can be unreliable in females as it fails to identify the carrier state of this disease [4]. The carrier state results from X chromosome inactivation in some females, usually heterozygotes with one normal and one affected X chromosome. Recently, LysoGb3 has been introduced as a new biomarker, which is especially valued for therapeutic monitoring.

Another approach for diagnosing this disease is molecular genetic testing. Although expensive, it is a much more reliable method for the definite diagnosis of this disease in both males and females. Mutations in the GLA gene are identified through advanced biotechnological methods. If mutations exist, the diagnosis can be made with certainty. Mutations in several genes other than GLA are also attributed to be the cause of Fabry disease but their diagnostic importance is very limited.

Usually, Fabry disease is treated symptomatically. Medications are given to relieve pain in the body and the limbs. Pain in Fabry disease is often difficult to treat and does not respond to most of the over-the-counter pain medications. The drugs commonly used include diphenylhydantoin, carbamezipine, gabapentin and metoclopramide. Renal manifestation of proteinuria are treated either by ACE inhibitors (Angiotensin converting enzyme inhibitors) such as captopril; or angiotensin receptor blockers such as losartan. When renal failure starts to ensue, the patient has to resort to routine dialysis. Later when both the kidneys have failed, transplant is the only option.

In recent years, Enzyme Replacement Therapy (ERT) has emerged as one of the methods to manage and treat Fabry disease [5]. The patient is given recombinant forms of alpha galactosidase; such as agalsidase alpha and beta. The iminosugar 1-deoxygalactonojirimycin (migalastat), a pharmacological chaperone, is an analog of the terminal galactose of globotriaosylceramide and a reversible inhibitor of alpha-galactosidase A, which may increase the activity of mutant variants of alpha-galactosidase A. In addition, the effect of ERT is increased.

The prognosis of Fabry disease (when properly treated) is very good. Most of the males have more than 80% of the normal life expectancy. Females suffering from Fabry disease have an even better life expectancy than males; most live beyond 93% of their normal life expectancy. Most of the patients require renal transplantation. Death in these patients usually occur due to complications related to the vascular system [6].

Fabry disease is essentially a genetic disease and is caused by mutations in the GLA gene on the X chromosome. Females have two copies of this chromosome and males have one. One defective gene in males can therefore cause the full-fledged disease. In contrast, females who have one normal gene and an inherited mutated gene suffer from a much milder form of the disease, with the symptoms being far less severe. In such instances, there may be little or no symptoms of the disease.

Fabry disease is a rare disease. The incidence, according to a number of surveys, lies somewhere around 1 in 40,000 live births. However, recent newborn screening showed substantially higher rates of deficient α-Gal A activities and α-Gal A mutations.

The GLA gene normally encodes a protein enzyme named alpha galactosidase A (a-GAL). Alpha galactosidase is normally responsible for the breakdown of a lipid named globotriaosylceramide. Mutations in the GLA gene result in a deficiency or abnormal function of this enzyme. As a result, globotriaosylceramide accumulates in the cells of all the tissues of the body; most importantly in the blood vessels, kidneys, heart and nervous system. In the cells, this lipid accumulates in lysosomes, due to which Fabry disease is referred to as one of the lysosomal (lipid) storage diseases. A multitude of signs and symptoms related to various systems of the body thus ensues in this disease.

There is no prevention of Fabry disease.

Fabry disease is a lysosomal lipid storage disease which is caused by low levels of the enzyme alpha galactosidase A. This usually occurs due to defects in the GLA gene which lies on the X chromosome. There is an accumulation of glycosphingolipids in the skin, eyes, heart, kidneys, nervous system and vascular system. This results in a large number of clinical manifestations related to all these organs. Fabry disease has no definite cure but the symptoms can be treated through various groups of drugs. The prognosis of the patients who receive treatment is very good.

Fabry disease is caused by low levels of an enzyme that breaks down a certain lipid in the cells of various tissues of this body. This is due to the inheritance of a mutated gene on X chromosome – one of the two sex chromosomes. As the enzyme required to break the lipid is absent, it accumulates unchecked in the skin, eyes, heart, kidneys, nervous system and circulatory system of the patient. As a result, the patient suffers from a variety of symptoms related to these organs.

Fabry disease has no definite cure. However, it is possible to treat the symptoms of the disease through various medications. People who receive proper treatment live very long and also enjoy a good quality of life.

1. Hoffmann B, Beck M, Sunder-Plassmann G, Borsini W, Ricci R, Mehta A. Nature and prevalence of pain in Fabry disease and its response to enzyme replacement therapy--a retrospective analysis from the Fabry Outcome Survey. Clin J Pain. 2007;23(6):535-542.
2. Linhart A, Kampmann C, Zamorano JL, et al. Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey. Eur Heart J. 2007 28(10):1228-1235.
3. Ortiz A, Oliveira JP, Waldek S, Warnock DG, Cianciaruso B, Wanner C, Fabry Registry. Nephropathy in males and females with Fabry disease: cross-sectional description of patients before treatment with enzyme replacement therapy. Nephrol Dial Transplant. 2008;23(5):1600-1607.
4. Linthorst GE, Poorthuis BJ, Hollak CE. Enzyme activity for determination of presence of Fabry disease in women results in 40% false-negative results. J Am Coll Cardiol. 2008;51(21):2082.
5. Ioannou YA, Zeidner KM, Gordon RE, Desnick RJ. Fabry Disease: Preclinical Studies Demonstrate the Effectiveness of α-Galactosidase A Replacement in Enzyme-Deficient Mice. The American Journal of Human Genetics. 2001;68(1):14-25.
6. MacDermot KD, Holmes A, Miners AH. Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet. 2001;38(11):750-760.

• Fabry Disease
  User43942, 2019-01-15 06:50