Studies on the metabolic error in Refsum's disease
Abstract:
Studies utilizing mevalonic acid-2-(14)C and D(2)O as precursors failed to provide evidence for an appreciable rate of endogenous biosynthesis of phytanic acid in a patient with Refsum's disease. Orally administered tracer doses of phytol-U-(14)C were well absorbed both by seven normal control subjects (61 to 94%) and by two patients with Refsum's disease (74 and 80%). The fraction of the absorbed dose converted to (14)CO(2) in 12 hours was 3.5 and 5.8% in Refsum's disease patients and averaged 20.9% in seven control subjects. Labeled phytanic acid was demonstrated in the plasma of both control subjects and patients given phytol-U-(14)C, establishing phytol in the diet as a potential precursor of phytanic acid. This labeled phytanic acid had disappeared almost completely from the plasma of the seven control subjects by 24 to 48 hours, whereas it persisted at high concentrations in the plasma of the two patients for many days. We conclude that the phytanic acid accumulating in Refsum's disease is primarily of exogenous origin and that patients with Refsum's disease have a relative block in the degradation of phytanic acid and possibly other similar branched-chain compounds. This may relate to a deficiency in mechanisms for release of phytanic acid from stored ester forms or, more probably, to reactions essential to oxidative degradation of the carbon skeleton.
Insights
Refsum's disease patients accumulate phytanic acid primarily from dietary sources, not internal production. Their bodies show a significant block in breaking down phytanic acid, unlike healthy individuals.
Area of Science:
- Biochemistry
- Metabolic Disorders
- Human Physiology
Background:
- Refsum's disease is a rare genetic disorder characterized by the accumulation of phytanic acid.
- The exact origin and metabolic fate of phytanic acid in Refsum's disease have been subjects of investigation.
Purpose of the Study:
- To investigate the endogenous biosynthesis of phytanic acid in Refsum's disease.
- To determine the origin of phytanic acid accumulation in patients with Refsum's disease.
- To elucidate the metabolic pathway of phytanic acid metabolism.
Main Methods:
- Utilized mevalonic acid-2-(14)C and D(2)O as precursors to assess endogenous biosynthesis.
- Administered orally labeled phytol-U-(14)C to normal subjects and Refsum's disease patients.
- Measured the conversion of labeled phytol to (14)CO(2) and traced labeled phytanic acid in plasma.
Main Results:
- No significant endogenous biosynthesis of phytanic acid was detected in Refsum's disease patients.
- Phytol-U-(14)C was well absorbed by both patients and controls, with dietary phytol identified as a precursor.
- Labeled phytanic acid persisted in the plasma of Refsum's disease patients for extended periods, unlike in controls.
Conclusions:
- Phytanic acid accumulation in Refsum's disease is predominantly of exogenous origin.
- Patients with Refsum's disease exhibit a metabolic block in phytanic acid degradation.
- This degradation block may involve impaired release from ester forms or defective oxidative degradation of the phytanic acid carbon skeleton.
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