M. D. Feher

Refsum's disease: a peroxisomal disorder affecting phytanic acid α-oxidation

Refsums disease (hereditary motor sensory neuropathy type IV, heredopathia atactica polyneuritiformis) is an autosomal recessive disorder the clinical features of which include retinitis pigmentosa, blindness, anosmia, deafness, sensory neuropathy, ataxia and accumulation of phytanic acid in plasma‐ and lipid‐containing tissues. The transport and biochemical pathways of phytanic acid metabolism have recently been defined with the cloning of two key enzymes, phytanoyl‐CoA 2‐hydroxylase (PAHX) and 2‐hydroxyphytanoyl‐CoA lyase, together with the confirmation of their localization in peroxisomes. PAHX, an iron(II) and 2‐oxoglutarate‐dependent oxygenase is located on chromosome 10p13. Mutant forms of PAHX have been shown to be responsible for some, but not all, cases of Refsums disease. Certain cases have been shown to be atypical mild variants of rhizomelic chondrodysplasia punctata type 1a. Other atypical cases with low‐plasma phytanic acid may be caused by α‐methylacyl‐CoA racemase deficiency. A sterol‐carrier protein‐2 (SCP‐2) knockout mouse model shares a similar clinical phenotype to Refsums disease, but no mutations in SCP‐2 have been described to‐date in man. This review describes the clinical, biochemical and metabolic features of Refsums disease and shows how the biochemistry of the α‐oxidation pathway may be linked to the regulation of metabolic pathways controlled by isoprenoid lipids, involving calcineurin or the peroxisomal proliferator activating α‐receptor.

Erectile dysfunction and statin treatment in high cardiovascular risk patients.

Erectile dysfunction (ED) has been associated with risk factors for atherosclerosis. Medications used for atherosclerosis have also been implicated in ED. The aim of this study is to investigate the relationship of erectile function to cardiovascular risk factors and specific drug therapies before and after 6 months of statin therapy.

The effectiveness of long-term dietary therapy in the treatment of adult Refsum disease

Objective To evaluate the long-term effectiveness of dietary therapy with regular dietetic reinforcement for adult Refsum disease. Methods Retrospective case note analysis of records of plasma phytanic acid and hospital admission of 13 patients with adult Refsum disease who attended the specialist centre and repeatedly received dietary instruction for a minimum of 10 years. Results Patients undergoing review had attended for 11–28 years totalling 237 years. Median baseline phytanic acid concentrations at presentation were 1631 (370–2911) μmol/l and declined by 89±11% to 85 (10–1325) μmol/l. Levels of phytanic acid were completely normalised (<30 μmol/l) in 30%; partially normalised (30–300 μmol/l) in 50% and remained >300 pmol/l in 15%. The time required for phytanic acid levels to halve was 44.2±15.9 months in patients compliant with diet. No patient required admission or plasmapheresis/apheresis during this period for acute neuro-ophthalmological complications despite occasional spikes in phytanic acid levels attributable to intercurrent illness, surgery, sudden weight loss or psychological illness. Interpretation Dietary modification with regular reinforcement in Adult Refsum Disease can significantly reduce phytanic acid levels with time.

Smell testing: an additional tool for identification of adult Refsum’s disease

Background: Adult Refsum’s disease (ARD) is characterised by the presence of retinitis pigmentosa, ataxia, deafness, sensory neuropathy, and bony changes. The diagnosis is confirmed by the presence of phytanic acidaemia. Although reduced smell function has been described in ARD, its value in the diagnosis of the condition has not been fully evaluated. Objective: To investigate the prevalence and degree of olfactory dysfunction in patients with ARD. Method: The olfactory function of 16 patients with ARD was assessed using the quantitative University of Pennsylvania Smell Identification Test (UPSIT). Results: All patients had complete anosmia or grossly impaired smell function with a mean UPSIT score of 14.7 (SD 4.7) (normal>34) despite having been treated with an appropriate diet for a median of 15 years (range 1–25). Conclusions: Identification of ARD patients can be facilitated by using the UPSIT in combination with the presence of retinitis pigmentosa, even if they have no neurological or bony features. Phytanic acid screening should be performed in any patient manifesting these two signs.

Adult Refsum disease: a form of tapetoretinal dystrophy accessible to therapy.

Adult Refsum disease is characterized by an elevated plasma phytanic acid level and high concentrations of phytanic acid in a variety of tissues. Besides tapetoretinal degeneration, additional symptoms are anosmia, skeletal malformations, chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, ichthyosis, and cardiac abnormalities. A diet low in phytanic acid ameliorates polyneuropathy and ataxia and slows or even stops the other manifestations. In order to be able to apply dietary therapy, as many patients as possible (even better if all of them are) have to be identified at an early stage. The ophthalmologist plays a crucial role in achieving this goal because of the early manifestation of the tapetoretinal degeneration.

Safety of long-term restrictive diets for peroxisomal disorders: vitamin and trace element status of patients treated for Adult Refsum Disease.

Adult Refsums Disease (ARD) is caused by defects in the pathway for alpha‐oxidation of phytanic acid (PA). Treatment involves restricting the dietary intake of phytanic acid by reducing the intake of dairy‐derived fat. The adequacy of micronutrient intake in patients with ARD is unknown.