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]

Synonyms and keywords: Anderson-Fabry disease; angiokeratoma corporis diffusum universale; alpha-galactosidase A deficiency; ceramide trihexosidase deficiency; hereditary dystopic lipidosis; GLA deficiency; Sweeley-Klionsky disease

Classification

• Non-neuropathic form
• Neuropathic form
  • Infantile form
  • Juvenile form

Pathophysiology

• Fabry's disease follows an X-linked recessive inheritance pattern.
• A deficiency of the enzyme alpha galactosidase A causes a glycolipid known as globotriaosylceramide (also abbreviated as Gb3, GL-3, or ceramide trihexoside) to accumulate within the blood vessels, mononuclear phagocytes, neurons, other tissues, and organs.
• This accumulation leads to an impairment of their proper function. The condition affects hemizygous males, as well as both heterozygous and homozygous females; males tend to experience the most severe clinical symptoms, while females vary from virtually no symptoms to those as serious as males.
• This variability is thought to be due to X-inactivation patterns during embryonic development of the female.

Epidemiology and Demographics

The prevalence of Fabry disease is estimated to range from 1:17,000 to 1:117,000 males in Caucasian populations.

Diagnosis

Symptoms

• 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)

Physical Examination

Appearance

• Severe growth retardation
• Extreme mental and motor retardation

Vital Signs

• Irregularly irregular pulse may be present from cardiac arrhythmias
• Blood pressure may be raised
• Pyrexia of unknown origin

Skin

• Angiokeratomas
• Hypohidrosis
• Rash
• Telangiectasias

Head

• Neck retraction

Eyes

• Decreased visual acuity: Loss of vision or blurring of vision
• Corneal opacities
• Fundoscopy:
  • Retinal pathology may be found

Ear

• Sensorineural hearing loss may be present

Heart

• Palpation:
  • Precordial heave
  • Thrill
• Auscultation:
  • S3 may be heard
  • Holosystolic murmur from mitral regurgitation

Abdomen

• Hepatomegaly
• Splenomegaly

Extremities

• Raynaud phenomenon

Neurologic

• Mental retardation
• Growth retardation
• Gradual loss of intellect
• Motor retardation
• Ataxia
• Seizures
• Spasticity
• Peripheral neuropathy

Other

• Fractures from osteoporotic bone
• Delayed puberty: lack of development of secondary sexual characteristics
• Male infertility
• Priapism

Laboratory Findings

• Blood tests
  • Anemia
  • Serum creatinine may be raised from chronic renal failure
  • Serum urea may be elevated
  • BUN may be raised
• Urinalysis:
  • Hematuria
  • Proteinuria

ECG abnormalities

• AV node conduction block
• PR interval shortening
• Arrhythmias

Ultrasound

• Hemangiomas

Treatment

• Until recently, treatment of Fabry's disease targeted the symptomatic effects. However, it is currently being treated at the cellular level through enzyme replacement therapy using Agalsidase alpha (Replagal) and Agalsidase beta (Fabrazyme®).
• The cost of these drugs is problematic (approximately $170,000 US a year/patient) and remains a barrier to many patients in some countries. Enzyme replacement therapy (typically infused every two weeks) may be performed in the patient's home by the patients themselves. Enzyme replacement therapy is not a cure, and must be infused recurrently for maximum benefit.

External links

• Fabry Support & Information Group
• Template:NINDS
• Fabry's disease at NLM Genetics Home Reference
• Fabry's Disease Association

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