Long-term strategies for the treatment of Refsum's disease using therapeutic apheresis.

Refsum's disease is a rare autosomal recessive disorder of fatty acid metabolism. Poorly metabolized phytanic acid accumulates in fatty tissues, including myelin sheaths and internal organs, leading to retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, and renal, cardiac or liver impairment. Dietary restriction of phytanic acid in some cases is not sufficient to prevent acute attacks and stabilize the progressive course. Phytanic acid bound to large low density lipoproteins (LDL) and very low density lipoproteins (VLDL) molecules offers the possibility of extracorporeal elimination by lipid apheresis. We report on the long-term lipid apheresis treatment of four patients with severe Refsum's disease. Retinitis pigmentosa, peripheral polyneuropathy, cerebellar ataxia, anosmia, and sensorineural hearing loss were major symptoms exhibiting a progressive course. Lipid apheresis was performed for 5-13 years without severe complications. Maximum levels of phytanic acid before commencing chronic lipid apheresis were >300 mg/l. During steady state with lipid apheresis, mean phytanic acid before treatments was 87 mg/l and was reduced to 36 mg/l. Mean reduction rate was 59% per treatment. In all patients, abnormal motor nerve conduction velocity with signs of chronic denervation improved, morphological and functional stabilization of eye involvement was observed. Lipid apheresis prevented the extension of the disease to previously unaffected organs in three patients. Extracorporeal elimination of lipoprotein-phytanic acid complexes by lipid apheresis represents a pathophysiologically guided therapeutic approach, resulting in long-term improvement or stabilization of overall rehabilitation in patients with progressive Refsum's disease.

[Adult Refsum disease. A retinal dystrophy with therapeutic options]. / Die Adulte Refsum-Erkrankung. Eine Netzhautdystrophie mit therapeutischen Optionen.

Adult Refsum disease is one of the few forms of tapetoretinal degenerations accessible for therapy. The disease is characterized by an elevated plasma phytanic acid level and high concentrations of phytanic acid in a variety tissues. Beside tapetoretinal degeneration, additional symptoms are chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, anosmia, ichthyosis, skeletal malformations, and cardiac abnormalities. A diet low in phytanic acid leads to an amelioration of polyneuropathy and ataxia and slows or even stops the other manifestations. This beneficial effect of dietary precautions requires the need to get hold of as much patients as possible but better all of them. The ophthalmologist plays a crucial role to this end because of the early manifestation of the tapetoretinal degeneration. A delay of 11 years between the appearance of first symptoms and the diagnosis of Refsum disease, as reported in the literature, is not acceptable.

Membrane differential filtration is safe and effective for the long-term treatment of Refsum syndrome--an update of treatment modalities and pathophysiological cognition.

Refsum's disease is a complex and difficult to diagnose storage disease caused by complex autosomal recessive peroxisomal disorder in which mutations of phytanolyl/pristanoyl-CoA-hydroxilase are the main cause. Poorly metabolised phytanic acid (PA), pristanic acid (PrA) and picolenic acid (PiA) accumulates in fatty tissues, myelin sheaths, heart, kidneys and retina, leading to retinitis pigmentosa, peripheral dissociative polyneuropathy, cerebellar ataxia ("sailors" walk), renal, cardiac and liver impairment. 65% of plasma PA and PrA is localized within VLDL, LDL and HDL lipoprotein particles. Dietary restriction of PA is mostly not sufficient to prevent acute attacks and stabilize the progressive course. LDL and VLDL bound PA/PrA can be effectively eliminated from plasma with extracorporal LDL-apheresis using membrane differential filtration. Mostly additive malnutrition will become worse the clinical picture. Latest experience with black cumin oil (nigella sativa) in a dose of 3 g/day shows a support and a regression of some malnutrition effects in PA restricted dietary and a supportive effect to MDF.

[Pauci-symptomatic sensory polyneuropathy in Refsum's disease]. / Polyneuropathie sensitive pauci-symptomatique au cours d'une maladie de Refsum.

Refsum's disease is an autosomal recessive disease caused by defective alpha-oxidation of phytanic acid. The usual clinical presentation is the association of retinitis pigmentosa, ataxia and chronic severe sensorimotor polyneuropathy. A case of mild purely sensory neuropathy in a 40-year-old patient associated to high CSF protein level led to the diagnosis of Refsum's disease. The paucity of sensory symptoms and signs of neuropathy contrasted with severe reduction of motor and sensory nerve conduction velocities and markedly signs of sensory neuropathy observed in the nerve biopsy. Typical ring-scotomas, retinitis pigmentosa, anosmia, deafness, and high plasma phytanic acid level were present in extensive examination. There was no other case in the family.

[Refsum disease]. / La maladie de Refsum.

Refsum's disease, firstly described almost 50 years ago by the Norvegian neurologist Sigvald Refsum, is an autosomic recessive disease affecting mostly the Scandinavians and the populations originating from Northern Europe. The disease results from a specific enzyme deficiency of the first step of phytanic acid catabolism pathway. This deficiency leads to an accumulation of this C20 fatty acid in the serum and the tissues with a preference for adipose tissue, liver and kidneys. The clinical picture includes retinitis pigmentosa, peripheral neuropathy, ataxia and elevated cerebrospinal fluid protein concentration. Other less frequent manifestations include cranial nerves deficiency, myocardiopathy, renal tubular dysfunction and ichtyosis. The diagnosis relies on serum phytanic acid measurement. The treatment consists of a phytanic-acid free diet sometimes associated with plasmapheresis. This treatment is generally effective on neuropathy but not on cranial nerves dysfunction and retinitis pigmentosa.

[Refsum disease]. / Refsum-kór.

For the first time in literature the authors interpret the pathography of Refsum's disease, in the case of their patient, as pseudo-hypervitaminosis A. The biochemical basis of the clinical picture is a defect in the activity of phytanic-acid-alpha-hydrolase belonging to the peroxisomal system. As a consequence, phytanic acid accumulates in the serum and in the parenchymal tissues. Retinol, an alcohol with high molecular weight, is a natural ligand of nuclear RXR (retinoid-X-receptor), which plays an important role in the regulation of peroxisoma synthesis. In Refsum's disease the phytanic acid accumulated because of the enzyme defect competes with the biotransformation derivates (all-trans-retinoic acid, 9-cis-retinoic acid) of the all-trans-retinol (vitamin A) for the nuclear RX receptor binding sites, and as a very potent receptoractivator it causes the intestinal symptoms of hypervitaminosis A. The authors review the procedure of fatty-acid chromatography necessary for the establishment of the diagnosis and discuss--in addition to dietary restrictions--recent therapeutic possibilities, like plasmapheresis, cascade filtration, lipapheresis and oral batylalcohol treatment.

[Clinical picture and pathogenesis of the Refsum syndrome]. / K kliniki i patogenezu sindroma Refsuma.

The author reports of 2 cases (sisters of 13 and 15 years old) with the Refsum syndrome. The disease had its onset at the age of 12 and 5 years with a progressive development and remissions. The clinical picture was characterized by a recurrent syndrome of polyradiculoneurites with a slight protein cellular dissociation in the CSF, an expressed sensitive ataxia with elements of cerebellar disorders, a drop in the acuity of sight, audition, intellectual level and a deformation of the talipes of the Friedreich type. In a single examination of fatty acids in the blood serum by the method of gas chromotography there were no data pointing to the existence of 3, 7, 11, 15-tetra metylhexadecone acids. On the basis of an immunological study the author discusses the role of autoimmune reactions in the pathogenesis of the diseases. A differential diagnosis was conducted between acanthocytosis and porphyria with recommendations in regard to treatment.

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.