Refsum disease

Refsum disease is an autosomal recessive inborn error of metabolism characterized by a defect in alpha-oxidation occurring in peroxisomes. Alpha-oxidation is a pathway of catabolism that is used to degrade certain branched fatty acids such as phytanic acid.

Phytanic acid is a saturated fatty acid that originates from the digestion of chlorophyll in the stomach of ruminants, involving bacteria. People obtain phytanic acid from the diet, mainly it is present in red meat (beef and sheep) and dairy products. Phytanic acid is degraded in the peroxisomes and mitochondria of cells.

Refsum disease results in the accumulation of phytanic acid in blood plasma and some tissues, especially adipose, nervous and cardiac tissue. It is caused by a deficiency in a peroxisomal enzyme, known as phytanoyl-CoA hydroxylase, which degrades phytanic acid in the metabolic process known as alpha-oxidation.

The prevalence of Refsum disease is 1 case per 1,000,000 individuals.

Within Refsum disease there are two subtypes:

• Adult or classic Refsum disease (discussed here) in which there is an accumulation of phytanic acid (a branched-chain fatty acid) from the diet. It affects the gene coding for phytanoyl-CoA hydroxylase.
• Infantile Refsum disease which is of early onset and affects several genes involved in the transport of proteins from the cytosol to the peroxisome. In this case not only phytanic acid accumulates, but also increased levels of very long chain fatty acids or VLCFA, di- and tri-hydroxycholestanoic acids and pipecolic acid.

Symptoms of the classical subtype usually appear in adolescence. Hemeralopathy (loss of vision in the dark) is usually the first symptom to appear, followed by episodes of chronic distal motor polyneuropathy. Other associated clinical signs include perceptual deafness, anosmia, cerebellar ataxia and sometimes severe intellectual deficit. Over time, cutaneous symptoms (ichthyosis), cardiomyopathy, elevated protein content in the cerebrospinal fluid and retinitis pigmentosa, which may eventually lead to blindness, may develop.

Because phytanic acid comes exclusively from the diet, in Refsum patients a strict diet avoiding dairy products, meats and ruminant fats helps partial regression of symptoms.