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

BACKGROUND: Adult Refsum's 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. METHODS: Patients established on the Chelsea low-PA diet had general diet macronutrients, vitamins and trace elements assessed using 7-day-weighed intakes and serial 24-h recalls. Intakes were compared with biochemical assessments of nutritional status for haematinics (ferritin), trace elements (copper, zinc, iron, selenium), water- (vitamin B6 , B12 and folate) and fat-soluble vitamins (A, D, E and K). RESULTS: Eleven subjects (four women, seven men) were studied. Body mass index was 27 ± 5 kg/m(2) (range 19-38). All subjects had high sodium intakes (range 1873-4828 mg). Fat-soluble vitamin insufficiencies occurred in some individuals (vitamin A, n = 2; vitamin D, n = 6; vitamin E, n = 3; vitamin K, n = 10) but were not coincident. Vitamin B6 levels were normal or elevated (n = 6). Folate and 5-methyltetrahydrofolate concentrations were normal. Metabolic vitamin B12 insufficiency was suspected in four subjects based on elevated methylmalonic acid concentrations. Low copper and selenium intakes were noted in some subjects (n = 7, n = 2) but plasma levels were adequate. Iron, ferritin and zinc intakes and concentrations were normal. CONCLUSION: Subjects with ARD can be safely managed on the Chelsea low PA without routine micronutrient supplementation. Sodium intake should be monitored and reduced. Periodic nutritional screening may be necessary for fat-soluble vitamins, vitamin B12 , copper or selenium.

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) micromol/l and declined by 89+/-11% to 85 (10-1325) micromol/l. Levels of phytanic acid were completely normalised (<30 micromol/l) in 30%; partially normalised (30-300 micromol/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.

Metabolism of phytanic acid and 3-methyl-adipic acid excretion in patients with adult Refsum disease.

Adult Refsum disease (ARD) is associated with defective alpha-oxidation of phytanic acid (PA). omega-Oxidation of PA to 3-methyl-adipic acid (3-MAA) occurs although its clinical significance is unclear. In a 40 day study of a new ARD patient, where the plasma half-life of PA was 22.4 days, omega-oxidation accounted for 30% initially and later all PA excretion. Plasma and adipose tissue PA and 3-MAA excretion were measured in a cross-sectional study of 11 patients. The capacity of the omega-oxidation pathway was 6.9 (2.8-19.4) mg [20.4 (8.3-57.4) micromol] PA/day. 3-MAA excretion correlated with plasma PA levels (r = 0.61; P = 0.03) but not adipose tissue PA content. omega-Oxidation during a 56 h fast was studied in five patients. 3-MAA excretion increased by 208 +/- 58% in parallel with the 158 (125-603)% rise in plasma PA. Plasma PA doubled every 29 h, while 3-MAA excretion followed second-order kinetics. Acute sequelae of ARD were noted in three patients (60%) after fasting. The omega-oxidation pathway can metabolise PA ingested by patients with ARD, but this activity is dependent on plasma PA concentration. omega-Oxidation forms a functional reserve capacity that enables patients with ARD undergoing acute stress to cope with limited increases in plasma PA levels.

[Refsum's disease: evolution 35 years after diagnosis]. / Maladie de Refsum avec 35 ans de recul.

Refsum's disease (Heredopathia atactica polyneuritiformis) is an autosomal recessive disease caused by a defective alpha oxidation of a C20 fatty acid: the phytanic acid. Deficiency of a peroxysomal enzyme called "Phytanoyl-Co-A alpha hydroxylase" leads to an accumulation of phytanic acid. The clinical picture include retinitis pigmentosa, peripheral neuropathy, ataxia and elevated cerebrospinal fluid protein concentration. Firstly described in 1946 by Sigvald Refsum, dietary treatment leads to an improvement of neurological symptoms but does not affect retinal changes. To our knowledge, there is no data in the literature on long term follow-up. A patient with Refsum's disease diagnosed in 1965 presented with facial paralysis. The phytanic acid concentration was low, CSF protein level was normal leading to diagnosis of Bell's palsy. This observation is of particular interest because after 35 years evolution of the disease, the only handicap was visual impairment, with no loss of muscle strength or sensory deficit.

Phytanic acid storage disease (Refsum's disease): clinical characteristics, pathophysiology and the role of therapeutic apheresis in its management.

Phytanic acid storage disease (known also as Refsum's Disease) is caused by inherited defects in the metabolic pathway for phytanic acid, a dietary branched-chain fatty acid. Poorly metabolized phytanic acid accumulates in fatty tissues, including myelin sheaths, and in organs including the liver and kidneys. Over time, affected individuals may develop classical diagnostic features of retinitis pigmentosa, cerebellar ataxia, peripheral polyneuropathy and an elevated protein content in the cerebrospinal fluid. Liver, kidney, and heart disease may also develop. Dietary restriction of phytanic acid is useful in preventing acute attacks and arresting the progression of organ impairment, especially in the peripheral nervous system. Therapeutic plasma exchange has been shown to be particularly useful for rapidly lowering plasma phytanic acid levels during acute attacks and may play a significant role as maintenance therapy as well.

Phytanic acid alpha-oxidase deficiency (Refsum disease) presenting in infancy.

This report describes a patient with high serum phytanic acid concentration due to phytanic acid alpha-oxidase deficiency (classical Refsum disease). He presented unusually early, hypotonia and developmental delay being apparent by 7 months. A generalized peroxisomal disorder (so-called 'infantile Refsum disease') was excluded by analyses of pristanic acid, very long-chain fatty acids, bile acids and plasmalogen synthesis. The early presentation raises the possibility of in utero exposure to phytanate.

[Refsum syndrome in a pair of monozygotic twins]. / Refsum-Syndrom bei einem eineiigen Zwillingspaar.

We report the case of a pair of twins with the ophthalmological and functional findings of Refsum syndrome. The twins were monozygotic twin brothers whose ophthalmological symptoms were noticed when they were in their forties. The diagnosis in the first brother led to a search for findings in the second. It was possible to attribute the non-specific subjective complaints to this as yet unknown syndrome. No causal therapy can be offered the patients. However, knowledge of the biochemical basis of the disease makes it possible to treat it by means of diet. In patients with retinopathia pigmentosa, an attempt should be made to identify Refsum syndrome if neurological symptoms are found in addition.

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.

[Refsum's disease. Apropos of 2 cases disclosed by myocardiopathy]. / La maladie de Refsum. A propos de deux cas révélés par une myocardiopathie.

Refsum's disease is a polyneuropathy due to a hereditary error in the metabolism of a fatty acid, phytanic acid, usually leading to cardiac failure only at an advanced stage of the disease. The authors report the case of two brothers with Refsum's disease revealed by a heart failure before the clinical stage of the peripheral neuropathy. In the younger brother, the affection started at the age of 22 years by an acute pulmonary oedema which revealed a dilated, hypokinetic myocardiopathy, associated with retinitis pigmentosa, ptosis, anosmia and biological myolysis. The normal plasma concentration of phytanic acid measured several times led to the conclusion of Kearns-Sayre syndrome even if certain aspects were atypical (moderate conduction disorders, no characteristic aspect in the muscle biopsy). Five years later, the older brother, aged 28, presents a dyspnea on effort which leads to the discovery of a hypokinetic, hypertrophic myocardiopathy, slightly dilated, associated with cardiac conduction disorders, retinitis pigmentosa, anosmia and biological myolysis. The plasma concentration of phytanic acid being very high. Refsum's disease was diagnosed and the diagnosis of younger brother was corrected. From the study of these two cases, the characteristics of the cardiac disorders can be specified: the cardiopathy can reveal the disease and correspond to a dilated or hypertrophic myocardiopathy. The diagnosis of the disease can be difficult because the plasma phytanic acid may remain at normal level, thus requiring the assay of the activity of phytanate oxydase. The existence of ophthalmologic signs (retinitis pigmentosa or progressive ophthalmoplegia externa) associated with a myocardiopathy must systematically lead to a search for Refsum's disease, this diagnosis having fundamental therapeutic implications (died, even plasmapheresis).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

A child with Refsum's disease: successful treatment with diet and plasma exchange.

A child with Refsum's disease presented with cardiac failure, marked muscle wasting, weakness and inco-ordination. Management with multiple plasma exchanges and dietary restriction of phytanic acid intake has reversed the disabling features of the disease, although levels still remain higher than target values. Low phytanic acid intake is being achieved by restriction of total fat to 10 to 12 g/day, while allowing free amounts of fruit and green vegetables.