Refsum's Disease—Use of the Intestinal Lipase Inhibitor, Orlistat, as a Novel Therapeutic Approach to a Complex Disorder

Nimalie J Perera,Michael Fietz,David R Sullivan,Huy Tran,Barry Lewis

doi:10.1155/2011/482021

Abstract

Refsum's Disease is an inherited metabolic disorder in which a metabolite of branched chain fatty acids accumulates due to lack of appropriate oxidative enzymes. Patients have elevated plasma phytanic acid levels and high concentrations of phytanic acid in a variety of tissues leading to progressive tissue damage. Besides retinal degeneration or retinal dystrophy associated with adult onset retinitis pigmentosa, additional symptoms include chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, anosmia, ichthyosis, as well as skeletal, cardiac, hepatic, and renal abnormalities. Current management includes avoidance of dietary sources of branched chain fatty acids and regular plasmapheresis to prevent accumulation of these compounds to ameliorate progressive neurological deficits. Two brothers with Refsum's disease who experienced progressive symptoms despite optimal diet and plasmapheresis were commenced on a novel therapy. We report the effect of the intestinal lipase inhibitor, Orlistat, which led to significant reduction (P-value <0.001 on 2-sample unpaired t-test) of mean preplasmapheresis phytanic acid levels with retardation of the progression of most of their dermatological and neurological symptoms.

Highlights

Refsum’s Disease, known as heredopathia atactica polyneuritiformis (HAP), was described by Norwegian neurologist Sigvald Refsum in 1946
Individuals with Refsum’s disease are unable to metabolize phytanic acid by the β-oxidation pathway due to deficiency of the peroxisome enzyme phytanoyl-CoA hydroxylase (PAHX) [2,3,4,5] (Figure 1). It is essential for the 3-methyl group in the β-position of this branched-chain fatty acid (BCFA) to be removed by an α-oxidation step, activated by PAHX in order to proceed with the β-oxidation pathway
VF continued to suffer progressive impairment of vision, which has improved following bilateral cataract surgery. During this period AF and VF maintained stable weight most of the time with brief periods of weight loss associated with a slight increase in measured phytanic acid levels resolving with weight stabilisation, (Figure 3(a))

Summary

Introduction

Refsum’s Disease, known as heredopathia atactica polyneuritiformis (HAP), was described by Norwegian neurologist Sigvald Refsum in 1946. It is a rare complex disorder that affects many organs It has an autosomal recessive pattern of inheritance due to mutations on chromosome 10p13. Individuals with Refsum’s disease are unable to metabolize phytanic acid by the β-oxidation pathway due to deficiency of the peroxisome enzyme phytanoyl-CoA hydroxylase (PAHX) [2,3,4,5] (Figure 1). It is essential for the 3-methyl group in the β-position of this BCFA to be removed by an α-oxidation step, activated by PAHX (within the endoplasmic reticulum) in order to proceed with the β-oxidation pathway. In a subset of patients, a mutation of a second gene encoding for PEX7- peroxin 7 receptor protein, involved in peroxisomal import of proteins, has been identified as a cause for the phenotype of Refsum’s disease [2, 5]

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Conclusion