Refsum syndrome

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Classification according to ICD-10
G60.1 Refsum disease
ICD-10 online (WHO version 2019)

The Refsum syndrome (Synonyms: Refsum kahlke's disease , Refsum Thiebaut disease , Heredopathia atactica polyneuritiformis , Refsum disease ) is a Phytansäurespeicherkrankheit. These peroxisomal metabolic disorder is autosomal - recessive inherited and after the describer, the Norwegian doctor Sigvald Refsum named (1907-1991). This form of hereditary ataxia is counted among the hereditary motor-sensitive neuropathies (type IV).

Cause, symptoms and course

Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is a branched-chain fatty acid that occurs as a breakdown product of chlorophyll . The inability to break down this fatty acid leads to Refsum's disease

In 1963, Professor Winfried Kahlke, who now teaches in Hamburg, achieved the first biochemical evidence of a hereditary lipid metabolism disorder when he identified the substrate of Refsum's syndrome, phytanic acid. By means of gas chromatography, Kahlke found the exogenous cause of the hereditary lipid metabolism disorder, a breakdown product of chlorophyll ingested with food, 3.7.11.15-tetramethylhexadecanoic acid (phytanoic acid). This discovery spurred metabolic research worldwide.

The main biochemical abnormality is the accumulation of phytanic acid , a saturated branched chain fatty acid that is only ingested with food. Since phytanic acid has a methyl group at the β position, this fatty acid cannot be metabolized directly by mitochondrial or peroxisomal β oxidation . According to this, it is subjected to peroxisomal α-oxidation , for which the enzyme phytanoyl-CoA-hydroxylase is responsible. If this enzyme is defective, the clinical appearance of Refsum's disease occurs. The disease is genetically heterogeneous: the defective enzyme is either phytanoyl-CoA hydroxylase itself or peroxin-7 , the transport protein responsible for transporting phytanol-CoA hydroxylase into the peroxisomes.

The main features of the syndrome are retinopathia pigmentosa with night blindness and progressive visual field impairment, peripheral polyneuropathy , cerebellar ataxia, and developing deafness . Other more common symptoms are nystagmus , ichthyosis , cataracts , a loss of smell ( anosmia ), and skeletal deformities in dysplasia of the epiphyses .

The first symptom is often night blindness . The course is relapsing with partial remissions and acute exacerbations , especially in the case of metabolic stress during operations, infections, reduced supply of nutritional energy , pregnancy or serious illnesses in which a lot of phytanic acid is released from the liver and body fat tissue. The symptoms begin at an age from early childhood up to 50 years, but mostly in the 2nd or 3rd decade of life. Men and women are equally affected. If left untreated, people become deaf and blind around the age of 40. The acute cardiac arrhythmias that occur during exacerbations can be life threatening.

Diagnosis

The diagnosis is made by laboratory tests for phytanic acid in plasma and urine . Even healthy people who are heterozygous carriers can be recognized in this way.

Differential diagnosis

Among other things, the Flynn-Aird syndrome must be distinguished .

treatment

A cure for Refsum's syndrome is not yet known. However, the disease can largely be brought to a standstill by a consistent low-phytanic acid diet . It is recommended to keep the amount of phytanic acid ingested below 10 mg / day (the amount of phytanic acid ingested with a normal diet is around 100 mg / day). Foods with a high phytanic acid content are, in particular, meat from ruminants such as cattle and dairy products. In addition to a vitamin-rich diet low in phytanic acid, a sufficient intake of calories is also important in order to avoid uncontrolled mobilization of phytanic acid from adipose tissue.

If the diet is followed, the peripheral neuropathy can come to a standstill and the skin changes can also heal; in the eye and ear area, at least, the disease does not progress any further. If dietary measures are insufficient for a satisfactory reduction in the concentration of phytanic acid in the blood plasma, this can be achieved through regular plasmapheresis or selective lipid apheresis . Lipid apheresis makes use of the fact that phythanic acid is bound to cholesterol in the blood plasma and is removed with it.

Individual evidence

  1. ↑ E. Klenk, W. Kahlke: About the occurrence of 3.7.11.15-tetramethyl-hexadecanoic acid (phytanic acid) in the cholesterol esters and other lipoid fractions of the organs in a case of illness of unknown origin (suspected heredopathia atactica polyneuritiformis [Refsum syndrome]). In: Hoppe Seylers Z Physiol Chem . 333, 1963, pp. 133-139.
  2. ↑ W. Kahlke: Refsum syndrome. Lipoid chemical investigations in 9 cases. In: Klin Wochenschr . 42, 1964, pp. 1011-1016.
  3. ^ Karl F. Masuhr: The Refsum-Kahlke disease. In: Akt Neurol. 40 (01), 2013, p. 58.
  4. ↑ Thomas M. Devlin (Ed.): Textbook of Biochemistry with Clinical Correlations. 6th edition. Wiley & Sons, 2006, ISBN 0-471-67808-2 , p. 686.
  5. ↑ JP Hungerbühler et al.: Refsum's disease: management by diet and plasmapheresis. In: Eur Neurol. 24 (3), 1985, pp. 153-159. PMID 2581787 .
  6. ↑ FB Gibberd include: Heredopathia atactica polyneuritiformis (Refsum's disease) Treated by diet and plasma exchange. In: The Lancet . 1 (8116), 1979, pp. 575-578. PMID 85164 .
  7. ↑ K. Rüther: Adult Refsum disease. A retinal dystrophy with therapeutic options. In: Ophthalmologist. 102 (8), 2005, pp. 772-777. PMID 15990985 .
  8. ↑ D. Zolotov, S. Wagner, K. Kalb, J. Bunia, A. Heibges, R. Klingel: Long-term strategies for the treatment of Refsum's disease using therapeutic apheresis. In: J Clin Apher. 27 (2), 2012, pp. 99-105. PMID 22267052 .

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