Refsum’s syndrome

This rare condition was first discovered in 1937, but not reported until 1945 by S. Refsum, who termed it heredoataxia hemeralopia polyneuritiformis. (57) Refsum s syndrome is caused by an autosomal recessive genetic defect in several peroxismal enzymes. It is primarily due to a phytanic acid-a-hydroxilase deficiency. This causes an increase in phytanic acid levels in the serum, with subsequent deposition of the substance in liver, brain, kidney and skin tissues. Clinical examination reveals... 

Toussaint D, Danis P. 1971. An ocular pathologic study of Refsum s syndrome. Am J Ophthalmol 72 342-347. 

Klenk, E. Kahlke, W. (1963) Hoppe Seylers. Z. Physiol. Chem. 333, 133-139. Ueber das Voikommen der 3,7,11,15-Tetramethylhexadecansaure (phytansaure) in den Cholesterinestem und anderen Lipoid-fraktionen der Organe bei einem Krankheitsfall unbekanter Genese (Verdacht auf Heredopathia atactica polyneuritiformis, Refsum s syndrome). 

Figure 10.2). Various branched-chain fatty acids exist in most animals (Nuhn et al., 1985) and others are still being discovered (Ratnayake et al., 1989a). The isoprenoid fatty acids (Ackman and Hooper, 1973a) remain of clinical interest (ten Brink et al., 1992) because of their role in a rare genetic disease called Refsum s syndrome (Yao, 1992). 

Alexander, W. S. Phytanic acid in Refsum s syndrome. J. Neurol. Neurosurg. Psychiat. (1966) 29, 412. Personal communication. 

Baum, J. L., M. Tannenbaum, and E. H. Kolodny Refsum s syndrome with comeal involvement. Amer. J. Ophthal. 60, 699 (1965). 

Fleming, R. Refsum s syndrome. An unusual hereditary neuropathy. Neurology (Minneap.) 7, 476 (1957). 

Gordon,N., and R.E.B.Hudson Refsum s Syndrome.Heredopathia atactica polyneuritiformis. A report of three cases, including a study of the cardiac pathology. Brain 82,41 (1959). 

Heycock, j. B., and J. Wilson Diabetes mellitus in a child showing features of Refsum s syndrome. Arch. Dis. Childh. 33, 320 (1958). 

Richterich, R., W. Kahlke, P. van Mechelen u. E. Rossi Refsum s Syndrom (Heredopathia atactica polyneuritiformis) Ein angeborener Defekt im Lipoidstoffwechsel mit Speicherung von 3, 7,11, 15-Tetramethylhexadecansaure. Klin. Wschr. 41, 800 (1963). 

Stoffel, W., and W. Kahlke The transformation of phytol into 3, 7,11, 15-tetramethyl-hexadecanoic (phytanic) acid in heredopathia atactica polyneuritiformis (Refsum s syndrome). Biochem. biophys. Res. Commun. 19, 1 (1965). 

The commonest polymethyl-branched fatty acid is probably phytanic or 3,7,11,15-tetramethylhexa-decanoic acid, which is a metabolite of phytol, and can be found in trace amounts in many animal tissues. It becomes a major component of the plasma lipids in Refsum s syndrome, a rare condition in which there is a deficiency in the enzymatic fatty acid alpha-oxidation system. Lough [562] has reviewed the occurrence and biochemistry of this and other isoprenoid fatty acids. Similar fatty acids are present in the lipids of the preen gland of birds and in those of tubercle bacilli. 

Further reading Steinberg, D. (1978). Phytanic acid storage disease Refsum s syndrome. In Stanbury, J.B., Wyngaarden, J.B. and Fredrickson, D.S. (eds.) The Metabolic Basis of Inherited Disease, 4th Edn., p. 688. (N w York McGraw-Hill)... 

Steinberg, D., 1972, Phytanic acid storage disease Refsum s Syndrome, In "The Metabolic Basis of Inherited Disease," J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson, eds., p. 588. McGraw Hill, New York. 

Acquired ichthyosis Refsum s syndrome Normal range... 

It may be that the defect in the plasma membrane phospholipids presumably produced by the EFA deficiency is similar to an abnormality produced by the displacement of linoleic and arachidonic acids by the excess phytanic acid in Refsum s syndrome and that there is a special relationship between the plasma membrane and cell division. The normal rate of cell production in dominant ichthyosis that we have found is in agreement with previous workers and the scaliness in these patients is an optical and sensory effect from the abnormal type of desquamation in these patients rather than an increase in scale production. We believe that the hyperkeratotic type of lamellar ichthyosis is special in that there is a normal or low rate of cell production in contradistinction to the erythrodermatous types. 

It is of interest that in both EFA deficiency and Refsum s syndrome there is an altered phospholipid profile and in contrast with other non-erythematous ichthyotic states there is a marked elevation of epidermopoiesis. All membranes contain much phospholipid. The above observation and the well-known localization of 5-nucleotidase activity in the plasma membrane might suggest a particular relationship between this structure and mitotic activity. 

Ultrastructural Features of Ichthyotic Skin in Refsum s Syndrome... 

We wish to report two cases of Refsum s syndrome, the first coming from the University of Heidelberg, the second from the Dermatology Department of Paris (Professeur Duperrat, Professeur Puissant). Both cases developed ichthyosis and have been investigated for epidermal ultrastructural changes. In the second case, a further biopsy was available after 4 years of a chlorophyll-free diet. 

Refsum s syndrome is inherited as an autosomal recessive trait. It is characterized by an enzymatic defect of cr-oxidation resulting in an accumulation of phytanic acid in many organs and body fluids. This fatty acid is a result of incomplete degradation of phytol, a part of the chlorophyll molecule. 

The diagnosis of Refsum s syndrome in our patients was made — on the clinical features which had developed progressively over many years since early adolescence — and biochemically by the high level of phytanic acid in the... 

We therefore suggest the following hypothesis on the correlation of ichthyosiform skin changes and disturbed lipid metabolism in Refsum s syndrome. High amounts of phytanic acid accumulate due to a gene-dependent enzymatic defect in a-oxidation. Free cholesterol is esterified by phytanic acid and phytanic acid-bound cholesterol is subsequently stored in the epidermal liposome. This leads to a decrease of free epidermal cholesterol and results in disturbances of normal keratinization. The beneficial results of 4 years of chlorophyll-free diet support this hypothesis. 

Refsum s syndrome will only briefly be mentioned here, since our studies together with the dermatologic department of Professor Duperrat and Professor Puissant are reported by Dr. Blanchet-Bardon in more detail (Chapter 9). Though very similar to autosomal dominant ichthyosis vulgaris histopathologically, ichthyosis in Refsum s syndrome may be strictly differentiated from the dominant type by the consistently normal keratohyalin ultra-structure ... 

In our study 2 ml of Silfo was mixed with 2 drops of the catalyst and applied to the skin surface. It was peeled off after 1-2 minutes when dry and subsequently covered with a thin smear of DPX (R. A. Lamb, London) — a styrene based slide mounting medium, and placed in a desiccator for 6 hours. The surface replicas were then removed from the rubber base. These were then sputter coated with gold in a Polaron, E 5000 coater and viewed in a Cambridge scanning electron microscope (SEM) stereoscan, Mark II. Replicas of S.C. from patients with dominant ichthyosis, a patient with Refsum s syndrome and normal controls were studied. 

Figure 12.3 SEM of a skin surface replica from the forearm of a patient with Refsum s syndrome (x 182)...

Careful study of the skin lesions in the syndromes associated with keratinization disorders may show unexpectedly specific changes in the skin itself these may be ultrastructural or biochemical as in Refsum s syndrome (see Chapters 8, 9), or mainly clinical. Thus in the families with palmoplantar hyperkeratosis associated with oesophageal cancer onset of the hyperkeratosis was found to be relatively late in childhood in comparison with the common form unassociated with malignancy, in which most families show onset in the first months of life . 

Refsum s syndrome starts in late childhood and beyond. Generalized, branny dirty scales are present in some cases. Retinitis pigmentosa, progressive polyneuritis and cerebellar signs are the cardinal features of this autosomal recessive disorder. Phytanic acid is present in serum and deposits of lipids are found in all tissues. 

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