Introduction
Background
Refsum disease (RD) is a neurocutaneous syndrome that is characterized biochemically by the accumulation of phytanic acid in plasma and tissues. Patients with RD are unable to degrade phytanic acid because of a deficient activity of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal enzyme catalyzing the first step of phytanic acid alpha-oxidation.
Refsum first described this disease in 1946. Peripheral polyneuropathy, cerebellar ataxia, retinitis pigmentosa, and ichthyosis are the major clinical components. The symptoms evolve slowly and insidiously from childhood through adolescence and early adulthood.
Pathophysiology
RD is a recessive disorder characterized by defective peroxisomal alpha-oxidation of phytanic acid. Consequently, this unusual, exogenous C20-branched-chain (3,7,11,15-tetramethylhexadecanoic acid) fatty acid accumulates in blood and 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 RD. 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. A RD gene, phytanoyl-CoA hydroxylase, has been localized to band 10p13 between the markers D10S226 and D10S223. RD is genetically heterogeneous, with up to 55% of cases not being linked to the PAHX gene locus at D10S547 to D10S223. Thus, RD, like other peroxisomal diseases, is a heterogeneous syndrome.
An infantile form of RD also exists that is an autosomal recessive disorder of peroxisomal biogenesis, leading to many biochemical abnormalities, including raised plasma concentration of phytanic acid, pristanic acid, very long chain fatty acids, and C27 bile acids. The disease presents in the first year of life and manifests by developmental delay, visual and hearing disturbances, and dysmorphic features. Ichthyosis is an unusual symptom.
Frequency
International
RD is rare, with just 60 cases published worldwide.
Mortality/Morbidity
In patients who are untreated or diagnosed late, severe neurological impairment, wasting, and depression develop, subsequently leading to a high mortality rate. Attenuation of neurologic, ophthalmologic, and cardiac symptoms requires constant adherence to a suitable diet and plasmapheresis.
Race
No racial predominance is reported.
Sex
Only male cases were reported initially; however, now, neither sex predominates.
Age
Classic RD manifests in children aged 2-7 years; however, diagnosis usually is delayed until early adulthood. Infantile RD makes its appearance in early infancy.
Clinical
History
- Symptoms develop progressively and slowly with neurologic (eg, mild peripheral intermittent neuropathy, tinnitus, anosmia) and ophthalmic (eg, failing vision, night blindness as a result of progressive retinitis pigmentosa) manifestations.
- Ichthyosis may accompany, but most often follows, the occurrence of the above symptoms.
Physical
Pertinent physical findings include neurologic, ophthalmic, cardiac, and skin defects.
- Neurologic/ophthalmologic signs
- Partial intermittent sensorimotor polyneuropathy
- Cataract
- Nystagmus
- Concentric constriction of the visual fields
- Sensorineural deafness
- Signs resulting from cerebellar ataxia
- Progressive weakness
- Foot drop
- Loss of balance
- Cardiomyopathy with a serious conduction defect is a life-threatening sign.
- Hepatic/renal symptoms are clinically silent despite fatty degeneration.
- An ichthyosiform desquamation occurs, resembling a mild acquired ichthyosis vulgaris with a fine, white scaling that is noticeable over the lower trunk but also affects the limbs. Ichthyotic symptoms may range from mild hyperkeratosis of the palms and soles to severe scaling of lamellar ichthyosis type observed on the trunk.
- Skeletal defects (noticed in some patients) are not related directly to phytanic acid levels.
- These defects occur in 35-75% of cases.
- The knees, elbows, and short tubular bones of the hands and feet are affected; in particular, the terminal phalanx of the thumb also is affected.
Causes
RD is caused by mutations in the phytanoyl-CoA hydroxylase (PHYH) and the PTS2 receptor (PEX7) genes. This disorder is inherited in an autosomal recessive mode. A single peroxisomal enzyme defect that causes deficiency of alpha-oxidation leads to accumulation of phytanic acid in blood and tissues of patients with RD. The cytotoxic effect of phytanic acid seems to be due to a combined action of Ca2+ regulation, mitochondrial depolarization, and increased reactive oxygen species generation in brain cells.
More on Refsum Disease |
 Overview: Refsum Disease |
| Differential Diagnoses & Workup: Refsum Disease |
| Treatment & Medication: Refsum Disease |
| Follow-up: Refsum Disease |
| References |
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References
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Further Reading
Keywords
heredopathia atactica polyneuritiformis, RD, neurocutaneous syndromes, peripheral polyneuropathy, cerebellar ataxia, retinitis pigmentosa, ichthyosis
