Refsum's Disease

Refsum's disease is an inherited disorder of fatty acid oxidation. It is characterised by phytanic acid accumulation in the blood and tissues, causing a motor and sensory neuropathy.

The diagnostic features of Refsum's disease are:^[1]

• Retinitis pigmentosa
• Peripheral polyneuropathy
• Cerebellar ataxia

It was first described by Sigvald Refsum in 1945.^[2]He observed it in two unrelated Norwegian families with consanguineous parents.

Aetiology

Classical Refsum's disease is one of a group of disorders of the peroxisome. There is a single enzyme deficiency, phytanoyl-coenzyme A hydroxylase, the gene for which (PAHX, also called PHYH) is found on chromosome 10 (autosomal recessive).

Both point mutations and deletions have been described on PAHX associated with Refsum's disease.^{[3, 4]}

Pathogenesis

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.

Presentation^{[5, 6]}

Refsum's disease presents with anosmia and early-onset retinitis pigmentosa, with variable neuropathy, deafness, ataxia and ichthyosis. The age of presentation varies from age 7 months to over 50 years. Cardiac arrhythmia and heart failure (caused by cardiomyopathy) may develop later in life. 

• 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 subacute 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, and intention tremor, and there are bladder problems.

Other features

• Atypical retinitis pigmentosa. Progressive concentric restriction of visual fields. Cataracts and photophobia caused by impaired pupillary light responses.^[7]
• 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.
• Ichthyosis, hyperkeratosis plantaris and palmaris may be seen.
• Epiphyseal dysplasia - leading to characteristic shortening of the fourth toe, hammer toe, pes cavus and osteochondritis.

Differential diagnosis

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

Investigations

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

• Plasma levels of phytanic acid of >200 μmol/L (normal levels <18 μmol/L).^[5]
• CSF protein levels are usually elevated.
• LDL and HDL cholesterol levels are decreased.

Imaging

• Plain X-rays can monitor bone changes.
• MRI scan 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 biopsies from affected patients have onion bulb formation and targetoid inclusions have been described in Schwann's cells.
• Electroretinogram may be grossly abnormal.

Management

General principles

• Phytanic acid is almost only of dietary origin:
  • Restriction of the diet reduces plasma and tissue levels.^[5]
  • The average daily intake of phytanic acid is 50-100 mg/day and this should ideally be reduced to 10-20 mg/day.^[8]
  • Fish, beef, lamb and dairy products should be avoided.
  • Poultry, pork, fruit and other vegetables are allowed.
  • It is present in green vegetables but is tightly bound to chlorophyll.^[9]
  • Diets that are very low in phytanic acid (<10 mg/day) are unpalatable and associated with low patient compliance.
  • 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. Patients should avoid fasting or sudden weight loss.
  • The diet should be lifelong.
• Dermatological preparations may help with softening the skin - eg, urea for hyperkeratosis.

Interventions

• Plasma exchange/plasmapheresis:
  • Used mainly when the condition is severe or rapidly worsening (acute arrhythmias or extreme weakness) and produces rapid clinical improvement.^[8]
  • Another indication is failure of dietary management.
• Cascade filtration is as efficient as plasmapheresis and removes the need for albumin replacement.^[10]

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

Complications

• Cardiac involvement (with conduction abnormalities and cardiomyopathy) has been associated with premature death.^[5]
• Aminoaciduria is associated with reversible renal involvement as a result of extremely high phytanic acid levels.

Prognosis

• 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.^[11]

Genetic counselling^[5]

Refsum's disease is inherited in an autosomal recessive manner. Each sibling of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of being unaffected and not a carrier.

Carrier testing for at-risk relatives and prenatal diagnosis in at-risk pregnancies is possible if the PEX7 or PAHX disease-causing mutations have been identified in an affected family member.