Fabry's disease
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2] Neepa Shah, M.B.B.S.[3]
Synonyms and keywords:
Overview
- Fabry disease (also known as alpha-galactosidase A deficiency, ceramide trihexosidase deficiency, angiokeratoma corporis diffusum, Anderson Fabry disease) is an X-linked recessive inherited lysosomal storage disorder.
- X linked inherited disorders are transmitted
- It occurs as a result of the body's inability to make the enzyme alpha-galactosidase A. This enzyme encoded by the GLA gene located on the long arm of the X chromosome (q21-22) is in-turn responsible for breaking down a type of fat called globotriaosylceramide (Gb3 or GL-3) into building blocks that are used by the cells of the body.
- The Glycosphingolipid storage initiates a cascade of events that begins with the dysfunction of basic metabolic processes on the cellular level followed by progression to cell death, inflammatory events, and progressive major organ dysfunction.[2]
- Three main organ systems commonly affected include the brain, heart and kidney.
- Prenatal and neonatal studies of the histopathology of Fabry disease have confirmed that pathogenic GL3 accumulations occur in the maternal region of the placenta, fetal tissues, and the fetal placenta regions of affected males. In male fetuses affected these accumulations have been found in renal, myenteric plexus, and liver cells.This prenatal storage suggests that the process of Fabry disease may lead to early childhood symptoms[3][4]
- Fabry disease is a rare condition that can affect people regardless of their ethnic background. The prevalence for Fabry's disease is estimated to range from 0.27 to 1.69 per 100,000 in men, and 0.33 to 3.47 per 100,000 in women.
- The disorder is termed X linked as the mutated gene is located only on the X chromosome. In males (who have only one X chromosome), one altered copy of the GLA gene is sufficient to cause the condition however since females have two copies of the X chromosome, one altered copy of the gene in the cells usually leads to less severe symptoms in females than in males and in some cases none at all.
- The significance of Fabry's disease stems from data that suggests significant medical problems in many females who have only one altered copy of the GLA gene unlike other X linked diseases that generally have most women carriers remaining asymptomatic. The women carrying this mutation only on one X chromosome can experience many of the classic features of the disorder, including nervous system abnormalities, kidney failure and heart disease. Other possible symptoms reported include high blood pressure, chronic pain and fatigue.
- A small percentage of females who carry a mutation in one copy of the GLA gene never develop signs and symptoms of Fabry disease.[5]
Historical Perspective
- Anderson - Fabry disease was first described at the end of the 19th century by two dermatologists, Johannes Fabry in Germany and William Anderson in England.
- In 1989 the origin of one of its many clinical names, "angiokeratoma corporis diffusum" was first identified by fabry as he described a clinical case of a13-year-old patient affected by nodular purpura and subsequent albuminuria. In that same year Anderson described the clinical case of a systemic disorder affecting a patient aged 39 with angiokeratomas, proteinuria, finger deformities, varicose veins and lymphedema.
- The first ten years of the 20th century identified other similar cases.
- In the year 1912, Madden illustrated the clinical case of a young Egyptian patient with diffuse angiokeratomas followed in 1915 by Fabry who reproposed this condition as "Angiokeratoma corporis naeviforme".
- In 1947 Pompen speculated the origin of Anderson - Fabry disease as rather “familial” after the clinical case of two brothers dying of a similar disease was identified.
- Anderson - Fabry Disease is a multi-systemic disorder caused by the build-up inside lysosomes of globotriaosylceramide or Gb3, the accumulated lipid material discovered in 1963 by Sweeley e Klionsky.In
- In 1964 the clinical features of the main two phenotypes of the disease, the classical form and the atypical variants were described.
- In the ‘70s the enzyme involved in the metabolism of Gb3 was found to be α-galactosidase A, whose functional deficit causes the disease. The enzyme is encoded by the GLA gene - described in 1974 - located in the long arm of the X chromosome (q21-22).
- In the mid-1990s the many efforts to replace the lacking enzyme were successful and further led to the enzymatic replacement therapy for Anderson - Fabry disease.[1]
Classification
- Classic form- Most commonly seen in males and is the severe form of the disease
- Atypical variant -mMilder, late-onset forms of the disorder are probably more common than the classic, severe form.
- Based upon complications
- Cardiac variant
- Renal variant
- Non-neuropathic form
- Neuropathic form
- Infantile form
- Juvenile form
Pathophysiology
Causes
Differentiating Fabry's disease from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
- The first clinical symptoms interfering with the child's well-being and performance arise in childhood, typically between the ages of 3 and 10 years, and generally a few years later in girls than in boys
- Lack of sweating (anhidrosis) or decreased sweating
- Fatigue
- Red spots on skin (angiokeratomas): tiny, painless papules that appear at any region of the body, but are predominant on the thighs, buttocks, lower abdomen, and groin.
- Burning pain of the extremities. This pain can become very intense, especially when one has a fever.
- Loss of vision or blurry vision from corneal opacities.
- Difficulty swallowing (dysphagia)
- Abdominal pain
- Greasy stools (steatorrhea)
- Chest pain and palpitations
- Delayed puberty
- Pyrexia of unknown origin
- Cyanosis of extremities on exposure to cold (Raynaud's phenomenon)
- Hearing loss
- Loss of sensations in extremities
- Telangiectasis
- Lack of coordination of muscle movement (ataxia)
Echocardiography or Ultrasound
Treatment
Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigation Therapies
Case Studies
External links
- Fabry Support & Information Group
- Template:NINDS
- Fabry's disease at NLM Genetics Home Reference
- Fabry's Disease Association
References
[1] Caterina Bartolotta, Marcello Filogamo, Paolo Colomba, Carmela Zizzo, Giuseppe Albeggiani, Simone Scalia, Daniele Francofonte, Giuseppe Cammarata, Vincenzo Savica, Giovanni Duro, FP907 HISTORY OF ANDERSON - FABRY DISEASE, Nephrology Dialysis Transplantation, Volume 30, Issue suppl_3, 1 May 2015, Page iii379, https://doi.org/10.1093/ndt/gfv186.08
[2] Eng CM, Germain DP, Banikazemi M, et al. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med 2006;8: 539–548.
[3] Elleder M, Poupĕtová H, Kozich V . Fetal pathology in Fabry’s disease and mucopolysaccharidosis type I. Cesk Patol 1998;34:7–12.
[4] Thurberg BL, Politei JM . Histologic abnormalities of placental tissues in Fabry disease: a case report and review of the literature. Hum Pathol 2012;43:610–614. [5] Deegan PB, Baehner AF, Barba Romero MA, Hughes DA, Kampmann C, Beck M; European FOS Investigators. Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet. 2006 Apr;43(4):347-52. Epub 2005 Oct 14. Citation on PubMed or Free article on PubMed Central