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.

Hearing loss in adult Refsum's disease.

Refsum's disease is characterized by defective peroxisomal alpha oxidation of phytanic acid, with clinical features that include retinitis pigmentosa, polyneuropathy, anosmia and hearing loss. Although hearing loss in Refsum's disease is common, there are few detailed assessments of the site of the abnormality. We examined the audiometric findings in patients with biochemically diagnosed Refsum's disease in order to assess the site of origin of the hearing loss. We found hearing loss, ranging from mild, predominantly high frequency to moderate degree, in seven out of nine patients with biochemically diagnosed adult Refsum's disease. In addition, we found evidence to suggest subtle auditory nerve involvement in six out of the seven patients with hearing loss and in one out of the two patients with a normal pure tone audiogram, on the basis of the ABR test results. We conclude that patients with Refsum's disease who report hearing difficulties should have full audiometric investigations in order to provide appropriate audiological rehabilitation.

Identification of genetic heterogeneity in Refsum's disease.

Refsum's disease (MIM 266500) is a recessive disorder characterised by defective peroxisomal alpha-oxidation of phytanic acid. A Refsum's disease gene, phytanoyl-CoA hydroxylase (PAHX), has been localised to chromosome 10p13 between the markers D10S226-D10S223. This study investigated whether all cases of Refsum's disease were linked with chromosome 10p13. Eight genetically informative families comprising 92 individuals including 17 living patients with a Refsum's disease phenotype and initial plasma phytanic acid > 200 micromol/L were recruited. Linkage to the 10pter-10p11.2 region was investigated using a panel of eight dinucleotide repeat markers. Linkage analysis of this phenotypically identical cohort suggested that Refsum's disease was genetically heterogeneous (Zmax = 5.28, alpha = 0.45). Two subgroups were identified. One group of four families with eight affected individuals had a maximum multipoint lod score for linkage of 3.89 in the region D10S547 to D10S191, whilst in another three families with nine affected individuals linkage to this region was definitely excluded. Our results show that Refsum's disease is genetically heterogeneous, with up to 55% of cases not being linked to the PAHX gene locus at D10S547 to D10S223. This suggests that Refsum's disease, in common with other peroxisomal 'diseases', may be more accurately described as a heterogeneous syndrome.

Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin.

PURPOSE: Lamotrigine is an effective add-on therapy against a range of epileptic seizure types. Comparative studies with carbamazepine (CBZ) as monotherapy in newly diagnosed epilepsy suggest similar efficacy. In this study, lamotrigine (LTG) and phenytoin (PHT) are compared. METHODS: In a double-blind parallel-groups study, 181 patients with newly diagnosed untreated partial seizures or secondarily or primary generalised tonic-clonic seizures were randomised to two treatment groups. One group (n = 86) received LTG titrated over 6 weeks from a starting dose of 100 mg/day. The other (n = 95) received PHT titrated from 200 mg/day. Treatment continued for < or =48 weeks. RESULTS: The percentages of patients remaining on each treatment and seizure free during the last 24 and 40 weeks of the study, and times to first seizure after the first 6 weeks of treatment (dose-titration period), did not differ significantly between the treatment groups. These were measures of efficacy. Time to discontinuation, a composite index of efficacy and safety, likewise did not distinguish between treatments. Adverse events led to discontinuation of 13 (15%) patients from LTG and 18 (19%) from PHT. The adverse-event profile for LTG was dominated by skin rash [discontinuation of 10 (11.6%) patients compared with five (5.3%) from PHT] rather than central nervous system side effects: asthenia, somnolence, and ataxia were each significantly more frequent in the PHT group. The high rate of rash with LTG was probably due to the high starting dose and may be avoidable. A quality-of-life instrument, the SEALS inventory, favoured LTG. Patients taking PHT showed the biochemical changes expected of an enzyme-inducing drug, whereas those taking LTG did not. CONCLUSIONS: LTG and PHT monotherapy were similarly effective against these seizure types in patients with newly diagnosed epilepsy. LTG was better tolerated, more frequently causing rash, but with a lower incidence of central nervous system side effects.

Transport of phytanic acid on lipoproteins in Refsum disease.

Patients with Refsum disease accumulate significant quantities of phytanic acid in adipose and neural tissue. The accumulation can be reversed by following a diet low in phytanic acid, yet the mechanism of transport of this fatty acid is obscure. We investigated the distribution of phytanic acid in different lipoprotein subfractions in 11 patients with Refsum disease and 9 unaffected siblings. Plasma phytanic acid was distributed on VLDL (16.2% +/- 12.2%), IDL (1.77% +/- 1.64%), LDL (34.8% +/- 12.6%) and HDL (14.3% +/- 7.87%). No correlations with any parameter were seen with total phytanic acid content. Weak nonsignificant correlations were found with the fractional distribution of phytanic acid and VLDL triglyceride (r = 0.35; p = 0.12) and plasma HDL-cholesterol (r = 0.32; p = 0.16) and with LDL:HDL cholesterol ratio (r = 0.33; p = 0.14). Significant correlation of the fractional distribution of phytanic acid on lipoprotein particles was noted with the ratio of apolipoprotein B: apolipoprotein A1-containing particles (r = 0.46; p = 0.03) and apolipoprotein B: apolipoprotein A1 in HDL2 (r = 0.53; p = 0.01). This suggests that the import-export balance for phytanic acid in plasma is related to forward and reverse cholesterol transport on lipoprotein particles, and only weakly to plasma cholesterol and triglycerides. These ratios of apolipoprotein particles may play a significant role in determining the rate of phytanic acid elimination in patients with Refsum disease.

Influence of plasma phytanic acid levels in Refsum's disease on the behaviour of the erythrocyte membrane sodium-lithium countertransporter.

BACKGROUND: Abnormal behaviour of the erythrocyte membrane sodium-lithium countertransporter (SLC) is associated with plasma triglyceride concentrations. Refsum's disease is characterized by progressive neurological dysfunction and accumulation of phytanic acid, an isoprenoid fatty acid, in fat-containing tissues. METHODS: This study explored the effects of plasma phytanic acid on SLC kinetics in nine Caucasian patients with Refsum's disease and in age- and sex-matched Caucasian control subjects. RESULTS: A dose-dependent association was seen between countertransporter maximal velocity and phytanic acid content of low-density lipoprotein (LDL)-cholesterol (r = -0.61, r = -0.65 respectively; P = 0.05, P = 0.04) and high-density lipoprotein (HDL)-cholesterol (r = -0.81, -0.82 respectively; P = 0.005, P = 0.003). No significant association was seen with the sodium affinity of the transporter (r = -0.44, P = 0.20, for LDL; and -0.43, P = 0.21, for high-density lipoprotein). CONCLUSION: These findings suggest that phytanic acid may alter the behaviour of the sodium-lithium countertransporter.

Neurological complications associated with pregnancy.

Prospective multidisciplinary audit from both hospital and community has identified neurological complications persisting for more than 6 weeks in association with pregnancy and delivery. They occurred at a frequency of 1 in 2530 deliveries in the North West Thames Region. Extradural analgesia was considered contributory to a neurological disorder in one of 13,007 patients. The woman had prolonged paraesthesiae along a nerve root. The types of sensory, motor and sympathetic neurological problems presented ranged from transient problems to more serious disorders resulting in death in one case. Seven of 19 patients had a continuing neurological disability for more than 1 yr. Although obstetrics may be associated with lumbar and sacral neurological disorders, problems occurred with the same frequency in the upper as in the lower half of the body. Significant morbidity is not being recognized in hospitals where women are being delivered and it is within the community that these disorders are recognized. This has implications for training, audit and risk assessment.

Plasma activities of hepatic enzymes in patients on anticonvulsant therapy.

The object of the study was to discover the changes in the plasma activities of hepatic enzymes in patients on anticonvulsant drugs. The plasma activities of aspartate transaminase (AST), alkaline phosphatase (ALP), alanine transaminase (ALT) and glutamyltransferase (GGT) were studied in 123 unselected patients on anticonvulsants. The results were compared with 123 control patients not on anticonvulsants matched for age and sex. Patients with known liver disease were excluded. The plasma activities of AST and ALP were similar in the two groups. ALT and GGT were raised in patients on anticonvulsants. No patient developed clinical evidence of liver disease. It was concluded that raised ALT and GGT are not in themselves indications to alter anticonvulsant therapy. Changes in AST and ALP would be more specific markers of liver dysfunction in patients on anticonvulsants.

Plasma exchange for Refsum's disease.

Five patients with Refsum's disease were treated by plasma exchange. Lowering the plasma phytanic acid by plasma exchange in patients acutely ill with Refsum's disease produced clinical improvement. Plasma exchange is indicated in Refsum's disease when there is a worsening clinical condition. Occasionally, failure of dietary control of Refsum's disease may necessitate plasma exchange.

Society of Apothecaries diploma in sports medicine.

The Society of Apothecaries examination in Sports Medicine consists of four parts: a multiple-choice question paper; a written paper; a clinical section; and an oral section. The candidates must have experience in sports medicine and have to submit a dissertation and a case history book. The importance of an examination in sports medicine is discussed.

Refsum disease: the presentation and ophthalmic aspects of Refsum disease in a series of 23 patients.

Refsum disease (heredopathia atactica polyneuritiformis) was first described in 1946 and is a rare recessively inherited metabolic disease affecting phytanic acid metabolism. It causes retinitis pigmentosa, cataracts, a chronic polyneuropathy, cerebellar ataxia and cardiac arrhythmias amongst other clinical signs. By limiting dietary intake, plasma phytanic acid levels fall with an improvement in the neurological signs. The onset of retinitis pigmentosa usually precedes biochemical diagnosis by several years by which time the retinal damage is severe. A series of 23 patients have been reviewed. There was an average delay of 11 years (range 1-28 years) between the patient presenting to the ophthalmologist and being diagnosed as having Refsum disease. Although serial examinations have failed to show a definite change in the course of visual deterioration with treatment, early diagnosis is important to prevent the development of neurological disease.

Plasma exchange in the treatment of Refsum's disease (heredopathia atactica polyneuritiformis).

Five cases of heredopathia atactica polyneuritiformis (HAP--Refsum's disease) were treated by serial plasma exchanges. In all patients a reduction in calorie intake and body weight had been associated with a rise in plasma phytanic acid, followed by an exacerbation of the ataxia and neuropathy. Lowering the plasma phytanic acid by plasma exchange produced a rapid clinical improvement. The main indication for plasma exchange in HAP is a severe or rapidly worsening clinical condition. A lesser indication is failure of dietary management to reduce a high plasma phytanic acid level.

Skeletal abnormalities in Refsum's disease (heredopathia atactica polyneuritiformis).

Refsum's disease is a rare inborn error of phytanic acid metabolism in which skeletal abnormalities are part of the clinical syndrome. The reported incidence of bone changes in patients with Refsum's disease varies widely and reflects the small series published to date. An analysis of the skeletal abnormalities of the largest series of patients in the world is presented.

The significance of plasma phytanic acid levels in adults.

The presence of phytanic acid in tissues and plasma has been considered diagnostic of heredopathia atactica polyneuritiformis (Refsum's disease), but recently slightly raised plasma phytanic acid levels have been reported in other conditions. Forty two normal people were found to have a phytanic acid level of 0-33 mumol/l. Fourteen patients with heredopathia atactica polyneuritiformis had a plasma phytanic acid level before treatment of 992-6400 mumol/l. Five patients with retinitis pigmentosa but not heredopathia atactica polyneuritiformis had plasma levels of 38-192 mumol/l. It was concluded that some patients with retinitis pigmentosa without heredopathia atactica polyneuritiformis but a raised plasma phytanic acid may represent a group of patients with a disease or diseases as yet uncharacterised apart from the retinal condition.