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Case Details

A 6-year- old child with progressive hearing loss wasbrought for consultation. History revealed that the child was born normal butprogressively developed loss of hearing and loss of smell.  From the past few months the child wasfinding it difficult to locate the things at night time.

The child had dysmorphic features, a flat bridge of nose,and low-set ears.

On examination, pulse was irregular and the liver was enlarged.Laboratory investigations revealed low levels of plasma cholesterol, HDL andLDL. A diagnosis of Refsum disease was made.

 What is the defectin this disease?

Refsum disease

Refsum disease (RD) is a neurocutaneous syndrome that is characterized biochemically by the accumulation of phytanic acid in plasma and tissues. Refsum first described this disease. Patients with Refsum disease are unable to degrade phytanic acid because of a deficient activity of Phytanic acid oxidase enzyme catalyzing the phytanic acid alpha-oxidation.

Peripheral polyneuropathy, cerebellar ataxia, retinitis pigmentosa, and Ichthyosis (rough, dry and scaly skin) are the major clinical components. The symptoms evolve slowly and insidiously from childhood through adolescence and early adulthood.

Biochemical defect

Refsum disease is an Autosomal recessive disorder characterized by defective alpha-oxidation of phytanic acid. Consequently, this unusual, exogenous C20-branched-chain (3, 7, 11, 15-tetramethyl hexadecanoicacid) fatty acid accumulates in brain, blood and other tissues. It is almost exclusively of exogenous origin and is delivered mainly from dietary plant chlorophyll and, to a lesser extent, from animal sources. Blood levels of phytanic acid are increased in patients with Refsum disease. These levels are 10-50 mg/dL, whereas normal values are less than or equal to 0.2 mg/dL, and account for 5-30% of serum lipids. Phytanic acid replaces other fatty acids,including such essential ones as Linoleic and Arachidonic acids, in lipid moieties of various tissues. This situation leads to an essential fatty acid deficiency, which is associated with the development of ichthyosis.



                                                  Phytanic acid

This process involves hydroxylation of the alpha carbon, removal of the terminal carboxyl group and concomitant conversion of the alpha hydroxyl group to a terminal carboxyl group, and linkage of CoA to the terminal carboxyl group. This branched substrate will function in the beta-oxidation process, ultimately yielding propionyl-CoA, acetyl Co As and, in the case of phytanic acid, 2-methyl propionyl CoA (Iso butyryl Co A).



Figure- showing steps of oxidation of phytanic acid. Pristanic acid is formed by alpha oxidation which subsequently undergoes beta oxidation to yield the final products.

Clinical manifestations

Refsum disease is rare, with just 60 cases observed so far.

Classic Refsum disease manifests in children aged 2-7 years; however, diagnosis usually is delayed until early adulthood.

Infantile Refsum disease makes its appearance in early infancy. Symptoms develop progressively and slowly with neurologic and ophthalmic manifestations. The disease is characterized by

·        Night blindness due to degeneration of the retina (retinitis pigmentosum)

·        Loss of the sense of smell (anosmia)

·        Deafness

·        Concentric constriction of the visualfields

·        Cataract

·        Signs resulting from cerebellar ataxia –

o   Progressive weakness

o   Foot drop

o   Loss of balance

·        Cardiac arrhythmias

·        Some individuals will have shortened bones in their fingers or toes.

·        The children usually have moderately dysmorphic features that may include epicanthal folds, a flat bridge of the nose,and low-set ears.

Laboratory Diagnosis

  • Levels of plasma cholesterol and high- and low-density lipoprotein are often moderately reduced.
  • Blood phytanic acid levels are elevated.
  • Cerebrospinal fluid (CSF) shows a protein level of 100-600 mg/dL.
  • Routine laboratory investigations of blood and urine do not reveal any consistent diagnostic abnormalities.
  • Phytanic oxidase activity estimation in skin fibroblast cultures is important


Skeletal radiography is required to  estimate bone changes. 


  • Eliminate all sources of chlorophyll from the diet.
    • The major dietary exclusions are green vegetables (source of phytanic acid) and animal fat (phytol).
    • The aim of such dietary treatment is to reduce daily intake of phytanic acid from the usual level of 50 mg/d to less than 5 mg/d.
  • Plasmapheresis – Patients may also require plasma exchange (Plasmapheresis) in which blood is drawn, filtered, and re infused back into the body, to control the buildup of phytanic acid.
    • The main indication for Plasmapheresis in patients with Refsum disease is a severe or rapidly worsening clinical condition.
    • A minor indication is failure of dietary management to reduce a high plasma phytanic acid level.


Prognosis in untreated patients generally is poor. Dysfunction of myelinated nerve fibers and the cardiac conduction system leads to central and peripheral neuropathic symptoms, impaired vision, and cardiac arrhythmias. The latter frequently are the cause of death.

In early diagnosed and treated cases, phytanic acid decreases slowly, followed by improvement of the skin scaling and, to a variable degree, reversal of recent neurological signs. Retention of vision and hearing are reported.

Pharmacological up regulation of the omega-oxidation of phytanic acid may form the basis of the new treatment strategy for adult Refsum disease in the near future.

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