Fabry Disease

Overview

Etiology

• X-linked recessive disorder
• Mutation in GLA on chromosome Xq21.3-q22
• Results in a deficiency of lysosomal alpha-Gal A

Classification

• Classic type (early onset)
  • Less common
  • More severe
  • Onset: childhood to teenage years
• Atypical type (late onset)
  • More common
  • Disease presentation based on particular organ system
  • Onset: age ≥ 30 years

Epidemiology

• Prevalence:
  • Classic: 1 in 40,000 males
  • Atypical: 
    • 1 in 1,000–3,000 males
    • 1 in 6,000–40,000 females
• Ethnicity:
  • More common in Caucasians
  • Rare in Asians
  • Also seen in African Americans
• Men > women

Pathophysiology

• Deficiency in alpha-Gal A → accumulation of Gb3 (also known as ceramide trihexoside) in the lysosomes of various cells and tissues
• Gb3 derivatives are:
  • Cytotoxic
  • Proinflammatory
  • Profibrotic
• Vascular endothelial accumulation leads to:
  • Vascular occlusion → ischemia and infarction
  • Narrowing and occlusion of cerebral vessels → cerebral infarcts
• Accumulation in other tissues → organ dysfunction and clinical manifestations

Clinical Presentation

Time course

• Age of onset: 
  • Classic: childhood to teenage years 
  • Atypical: 30 years or older
• Progressive with advancing age
• Life expectancy varies based on the severity of disease.
• Death commonly occurs between the 4th and 5th decade of life due to cardiac, renal, or cerebrovascular complications.

Signs and symptoms

The clinical presentation and severity vary, and men have more severe symptoms than women do.

Musculocutaneous:

• Limb pain (acroparesthesia)
  • Major clinical symptom
  • Particularly affects hands and feet
  • Quality:
    • Numbness
    • Tingling
    • Burning
  • Precipitated by:
    • Stress
    • Extremes in temperature
    • Physical exertion
• Angiokeratoma
  • Raised, red/purplish skin lesions
  • Painless
  • Bathing trunk distribution 
    • Abdomen
    • Genital
    • Proximal lower extremities
• Telangiectasias

GI:

• Abdominal pain
• Nausea and vomiting
• Constipation or diarrhea

Ocular:

• Corneal verticillata
  • Corneal opacity
  • Diffuse haziness or “whorls” on slit lamp exam
• “Fabry cataract” (anterior and posterior subcapsular cataracts)
• Tortuosity and dilation of conjunctival and retinal vessels

Renal:

• Proteinuria
• Hematuria
• Renal failure

Neurologic:

• Transient ischemic attacks
• Ischemic stroke

Cardiac:

• Often extensive and progressive
• Myocardial infarction
• Arrhythmias and conduction abnormalities
• Left ventricular hypertrophy
• Heart failure
• Valvular abnormalities

Auricular:

• Vertigo
• Hearing loss
• Tinnitus

Other:

• Fatigue
• Fever
• Body aches
• Pedal edema
• Exercise, heat or cold intolerance
• Decreased sweating (hypohidrosis) or the absence of sweating (anhidrosis)

Diagnosis and Management

Diagnosis

Clinical suspicion in children or adolescents will lead to testing and diagnosis. However, a late diagnosis is not uncommon given the varied clinical presentation.

• In males, diagnosis is made with alpha-Gal A enzyme assay.
  • < 3% of normal enzyme activity confirms the diagnosis.
  • Not accurate in females, where enzyme activity is normal
• In females, genetic testing for the GLA mutation is used to make the diagnosis.
• A tissue biopsy will show glycolipid deposits.
• Prenatal genetic screening and newborn screening are also available.

Management

• There is no cure for FD.  
• Treatment is multidisciplinary and largely supportive, including:
  • Pain control
  • Medical management of cardiac, renal, and/or cerebrovascular complications
  • Slowing the build-up of fatty substances and progression of disease
    • Enzyme replacement therapy with recombinant alpha-Gal A
    • Chaperone therapy repairs the faulty enzyme.

Differential Diagnosis

• Gaucher disease (GD): a lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside. Infantile GD presents within 6 months of life with progressive neurodegeneration, loss of motor skills, hypotonia, feeding difficulties, hepatosplenomegaly, and death before age 3. Diagnosis is made with measurement of acid beta-glucosidase activity and confirmed with genetic analysis. Management is supportive.
• Tay-Sachs disease: an autosomal recessive lysosomal storage disorder caused by genetic mutations in the hexosaminidase A (HEXA) gene, leading to progressive neurodegeneration. Classic symptoms in infants include rapid degeneration of cognitive and neuromuscular abilities, progressive blindness, and a macular cherry-red spot upon physical examination. Diagnosis is made with measurement of enzyme activity. Management is supportive.
• Niemann-Pick disease type A (NPD-A): a lysosomal storage disorder caused by an acid sphingomyelinase enzyme deficiency. The disease is characterized by progressive neurodegeneration starting within a few months of life and resulting in death by age 3. Clinical manifestations include macular cherry-red spot, difficulty feeding, loss of motor skills, hypotonia, and organomegaly. Diagnosis includes measurement of sphingomyelinase enzyme activity and genetic testing. Management is supportive. 
• Sandhoff disease (SD): a lysosomal storage disorder caused by a deficiency in both HEXA and the hexosaminidase B (HEXB). Juvenile SD is characterized by progressive neurodegeneration starting at 6 months of age. Clinical manifestations include organomegaly, skeletal abnormalities, hyperacusis, macular cherry-red spot, blindness, and seizures. Diagnosis is made by measurement of HEXA and HEXB, as well as genetic analysis. Management is supportive.
• Pompe disease (glycogen storage disease II): a lysosomal and glycogen storage disorder caused by acid alpha glucosidase (GAA) deficiency . There are 3 types with variable onset and presentations. Clinical manifestations include failure to thrive, feeding difficulty, hypotonia, progressive muscle weakness, hypertrophic cardiomyopathy, and respiratory failure. Diagnosis is made with enzyme activity measurement and molecular gene analysis. Management includes supportive measures and enzyme replacement.