Refsum's Disease

• Retinitis pigmentosa,
• Peripheral polyneuropathy
• Cerebellar ataxia

It was first described by Sigvald Refsum in 1945.² He observed it in 2 unrelated Norwegian families with consanguineous parents.

Classical Refsum's disease is one of a group of disorders of the peroxisome. There is a single enzyme deficiency, phytanol coenzyme A hydroxylase, the gene for which (PAHX) is found on chromosome 10 (autosomal recessive).
Both point mutations and deletions have been described on PAHX associated with Refsum's disease.^3,4

There is defective alpha oxidation of phytanic acid, a branched chain fatty acid present in a wide range of foodstuffs including dairy produce, meat and fish.
There is toxic accumulation of phytanic acid in blood, fat and neurons. Normally phytanic acid levels are virtually undetectable in plasma. However patients with Refsum's disease have extremely high levels with phytanic acid accounting for 5-30% of their total fatty acids.

• Infants generally seem normal at birth.
• Symptoms begin by late childhood or adolescence, although there are reports of presentation as late as 50 years of age.
• The disease is usually progressive, with periods of remission, although acute and sub-acute presentations have been reported, associated with rapid weight loss, fever and pregnancy.
• The initial presentation is of unsteadiness and/or failing vision.
• There is night blindness, progressive (nerve) deafness, loss of sense of smell, unsteady gait, intention tremor and bladder problems.

• Atypical retinitis pigmentosa. Progressive concentric restriction of visual fields. Cataracts and photophobia caused by impaired pupillary light responses.⁵
• Peripheral polyneuropathy. Absent or diminished deep tendon reflexes. Palpable peripheral nerves secondary to hypertrophy.
• Cerebellar ataxia. Loss of position sense and nystagmus.
• Cardiomyopathy and conduction abnormalities. ECG changes are present.
• Icthyosis, hyperkeratosis plantaris and palmaris may be seen.
• Epiphyseal dysplasia - leading to characteristic shortening of the fourth toe, hammer toe, pes cavus and osteochondritis.

• Friedreich's ataxia
• Mitochondrial cytopathies
• Other hereditary motor and sensory neuropathies
• Abetalipoproteinaemia
• Vitamin E deficiency

Routine investigations of urine or blood do not show any consistent abnormality. However:

• Plasma levels of phytanic acid of > 800 mmol/l are not uncommon at presentation. (Normal levels <18 mmol/l.)
• CSF protein levels are usually elevated.
• LDL and HDL cholesterol levels are decreased.

Imaging

• Plain x-rays can track bone changes.
• MRI may show symmetrical changes of the corticospinal tracts, cerebellar dentate nuclei and corpus callosum.

Other tests

• Slow conduction velocities are found in nerve conduction studies.
• Nerve biopsy from affected patients have onion bulb formation and targetoid inclusions have been described in Schwann cells.
• Electroretinogram may be grossly abnormal.

General principles

• Phytanic acid is almost only of dietary origin:
  • Restriction of the diet reduces plasma and tissue levels.⁶
  • The average daily intake of phytanic acid is 50-100 mg/day and this should ideally be reduced to 10-20 mg/day.
  • Fish, beef, lamb and dairy products should be avoided.
  • It is also present in green vegetables, but is tightly bound to chlorophyll.
  • Diets that are very low in phytanic acid ( <10 mg/day) are unpalatable and associated with low patient compliance.
  • Poultry, pork, fruit and other vegetables are allowed.⁷
  • The diet should contain enough calories (high in carbohydrates) to prevent weight loss, as this will lead to mobilisation of phytanic acid from fat stores.
  • The diet should be lifelong.
• Dermatological preparations may help with softening the skin e.g. urea for hyperkeratosis.

Interventions

• Plasma exchange/plasmapheresis:
  • Used mainly when the condition is severe or rapidly worsening and produces rapid clinical improvement.⁸
  • A minor indication is failure of dietary management to reduce a high plasma phytanic acid level.
• Cascade filtration may be an alternative for plasmapheresis. It is as efficient as plasmapheresis and removes the need for albumin replacement.⁹

NB: Dialysis is ineffective as phytanic acid is tightly bound to lipoproteins.

• Cardiac involvement (with conduction abnormalities and cardiomyopathy) has been associated with premature death.
• Aminoaciduria is associated with reversible renal involvement as a result of extremely high phytanic acid levels.

• Although there are many (often severe) clinical features associated with Refsum's disease, it is partially treatable with dietary restriction.
• The neurological, cardiac and dermatological sequelae can be reversed by the reduction of phytanic acid levels.
• The visual and hearing impairments are less responsive to treatment.¹⁰