REFSUM DISEASE
 
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REFSUM DISEASE

 

DEFINITION:

A disorder of peroxisomes characterized by the accumulation of phytanic acid resulting in the classic triad of peripheral neuropathy, retinitis pigmentosa, and cerebellar ataxia.

EPIDEMIOLOGY:

  • incidence: rare, over 100 cases reported
  • age of onset:
    • nightblindness can occur as early as adolescence
  • risk factors:
    • familial - autosomal recessive
      • chrom.#: ?
      • gene: phytanoyl-CoA hydroxylase (PhyH)
    • M = F

PATHOGENESIS:

1. Background

  • also called Phytanic Acid Storage Disease, Heredopathia Atactica Polyneuritiformis
  • PhyH is a peroxisomal enzyme which catalyzes the first step in the alpha oxidation of phytanic acid to alpha-hydroxyphytanic acid
  • mutations within the PhyH gene of patients with Refsum Disease were first identified by G.A. Jansen et al., Nature Genetics 17(2):190-194 (1997) and include a single nucleotide deletion, a 111 nucleotide deletion, and a point mutation

2. Pathogenesis

  • mutations of PhyH gene -> diminished activity of phytanoly-CoA hydroxylase -> accumulation of phytanic acid in the blood and tissues -> neurologic and ophthalmologic manifestations

CLINICAL FEATURES:

1. Neurological Manifestations

1. Peripheral Neuropathy (in 90% of patients)

  • motor weakness
  • muscular atrophy
  • absent deep tendon reflexes
  • loss of sensation to pain, touch, vibration, temperature
  • paresthesias or muscle pain

2. Cerebellar Ataxia

  • seen in 75% of patients

3. Others

  • sensorineural hearing loss (in 50% of patients)
  • anosmia (in 35%)
  • nystagmus (in 25%)

2. Ophthalmologic Manifestations

1. Retinitis Pigmentosa

  • nightblindness
  • concentric narrowing of the visual fields
  • retinal degeneration
  • atypical retinal pigmentation

2. Others

  • cataracts (in 40%)
  • pupillary abnormalities (in 40%)
  • miosis
  • glaucoma

3. Others

1. Musculoskeletal (in 60%)

  • pes cavus
  • kyphoscoliosis
  • shortening of the metatarsals
  • Osteochondritis Dissecans

2. Skin

  • ichthyotic changes involving the trunk, palms, and soles

3. Cardiac

  • arrhythmias

4. Respiratory

  • respiratory paralysis

5. Renal

  • impaired renal function

INVESTIGATIONS:

1. Diagnosis

  • PCR identifying mutations within the PhyH gene
  • deficiency of PhyH activity in cultured skin fibroblasts
  • prenatal
    • deficiency of PhyH activity in cultured amniocytes
  • elevated levels of phytanic acid in the blood and tissues (liver, kidneys)

2. Cerebral Spinal Fluid

  • elevated protein
  • no increase in cells

3. Evoked Potentials

  • prolonged somatosensory evoked responses
  • abnormal auditory and visual evoked responses

4. EMG

  • evidence of muscular denervation
  • prolonged nerve conduction velocities

5. ECG

  • non-specific ST-T changes in the precordial leads
  • conduction defects
  • left ventricular hypertrophy

MANAGEMENT:

1. Supportive

  • multidisciplinary approach
    • Paediatrics, Neurology, Ophthalmology, Cardiology, PT, etc
    • genetic counselling

2. Diet

  • limiting phytanic acid and its precursor phytol in the diet
  • avoid dairy products (butter, milk, cheese), meats of ruminants (beef, sheep, lamb), seafood, chlorophyll-containing foods
  • frequently moniter plasma phytanate levels

3. Medical

  • plasmaphoresis or plasma exchange for acute exacerbations

4. Prognosis

  • slowly progressive if left untreated with frequent exacerbations and remissions with shortened life expectancy
  • exacerbations are triggered by viral illnesses and pregnancy
  • cardiac and respiratory complications may lead to sudden death
  • positive clinical response to phytanic acid restriction

ADDITIONAL REFERENCES:

1. Rudolph, A.M., Rudolph's Pediatrics (19th Edition). p. 1863-1864, (1991).

 

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