a) Parametri Genetici delle Neuropatie Sensomotorie Ereditarie (HMSN)

ix) MORBO DI REFSUM
 (REFSUM DISEASE)

Alternative names :
INFANTILE PHYTANIC ACID STORAGE DISEASE

DESCRIPTION

Patients with the infantile form of phytanic acid storage disease show both clinical and biochemical differences from patients with the classic form of Refsum disease.
Features include early onset, mental retardation, minor facial dysmorphism, retinitis pigmentosa, sensorineural hearing deficit, hepatomegaly, osteoporosis, failure to thrive, and hypocholesterolemia.
The biochemical abnormalities are not restricted to phytanic acid but also include accumulation of very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid. Deficiency of peroxisomes in hepatocytes and cultured skin fibroblasts is demonstrable (Wanders et al., 1990).
A relationship between the infantile form of Refsum disease (IRD) and Zellweger syndrome (ZWS) was suggested by the observations of Poulos et al. (1984) in 2 patients.
In the infantile form of Refsum disease, as in Zellweger syndrome, peroxisomes are deficient and peroxisomal functions are impaired (Schram et al., 1986).
Clinically, infantile Refsum disease, ZWS, and adrenoleukodystrophy have several overlapping features.
Biochemically, IRD patients show accumulation of phytanic acid as in the classic form of Refsum disease but in addition they show defective bile acid metabolism as in ZWS (Stokke et al., 1984).
In IRD, manifestations date from birth. Features in addition to those of Refsum disease include some seen in Zellweger syndrome : delayed development, mental retardation, hepatomegaly, and skeletal changes.
The levels of VLCFAs are elevated in ZWS and IRD but not in classic Refsum disease.
In infantile Refsum disease, Zellweger disease, and the rhizomelic form of chondrodysplasia punctata (CDPR), also a peroxisomal disorder, the activity of the peroxisomal enzyme acyl-CoA-dehydroxyacetonephosphate acyltransferase is low in platelets and fibroblasts, plasmalogens are deficient, and the plasma phytanic acid levels are usually elevated in patients over the age of 5 months.
Wanders et al. (1986) found restoration of acyltransferase activity when CDPR cells and infantile Refsum cells were fused.
When infantile Refsum cells and Zellweger cells were fused, restoration of enzyme activity was not observed.
Wanders et al. (1986) felt that this did not necessarily indicate that these are allelic disorders. In 4 cases, Roels et al. (1986) could visualize no peroxisomes by light microscopy after cytochemical staining for catalase, a marker enzyme for this organelle.
Absence of peroxisomes was confirmed by electron microscopy in 3 patients and, in the fourth, organelles of peculiar size and shape, with minimal catalase activity, were seen.
Birefringent macrophages containing PAS-positive material, on light microscopy, was considered another useful finding.
Poll-The et al. (1987) compared IRD with neonatal ALD and Zellweger syndrome. The studies of Brul et al. (1988) suggested that one form of Zellweger syndrome, the infantile form of Refsum syndrome, and hyperpipecolic acidemia are allelic; they failed to show complementation after somatic cell fusion.

Goez et al. (1995) described 2 IRD infants who had neonatal cholestatic jaundice as the sole initial clinical presentation of their disorder and no accompanying clinical features that would indicate peroxisomal disease.
Parental consanguinity was present in both cases.
The correct diagnosis was made by evaluation of plasma VLCFAs. Both families were Israeli-Arabs.
The 2 parental couples met by chance in the hospital corridor and realized for the first time that all 4 were relatives.

SEE ALSO

Ogier et al. (1985) ; Poll-The et al. (1985) ; Poll-The et al. (1986) ; Scotto et al.(1982) ; Van Crugten et al. (1986) ; Wanders et al. (1986)

REFERENCES


1. Brul, S.; Westerveld, A.; Strijland, A.; Wanders, R. J. A.; Schram, A. W.; 
   Heymans, H. S. A.; Schutgens, R. B. H.; van den Bosch, H.; Tager, J. M. : 
   Genetic heterogeneity in the cerebrohepatorenal (Zellweger) syndrome and 
   other inherited disorders with a generalized impairment of peroxisomal 
   functions: a study using complementation analysis. 
   J. Clin. Invest. 81: 1710-1715, 1988. 


2. Goez, H.; Meiron, D.; Horowitz, J.; Schutgens, R. H.; Wanders, R. J. A.; 
   Berant, M.;Mandel, H. : 
   Infantile Refsum disease: neonatal cholestatic jaundice presentation of 
   a peroxisomal disorder. 
   J. Pediat. Gastroent. Nutr. 20: 98-101, 1995.

3. Ogier, H.; Roels, F.; Cornelis, A.; Poll-The, B. T.; Scotto, J. M.; 
   Odievre, M.; Saudubray, J. M. : 
   Absence of hepatic peroxisomes in a case of infantile Refsum's disease. 
   (Letter) Scand. J. Clin. Lab. Invest. 45: 767-768, 1985.

4. Poll-The, B. T.; Poulos, A.; Sharp, P.; Boue, J.; Ogier, H.; Odievre, M.; 
   Saudubray, J. M.: 
   Antenatal diagnosis of infantile Refsum's disease. (Letter) 
   Clin. Genet. 27: 524-526, 1985.

5. Poll-The, B. T.; Saudubray, J. M.; Ogier, H.; Schutgens, R. B. H.; 
   Wanders, R. J. A.; Schrakamp, G.; van den Bosch, H.; Trijbels, J. M. F.; 
   Poulos, A.; Moser, H. W.; van Eldere, J.; Eyssen, H. J. : 
   Infantile Refsum's disease: biochemical findings suggesting multiple 
   peroxisomal dysfunction. 
   J. Inherit. Metab. Dis. 9: 169-174, 1986.

6. Poll-The, B. T.; Saudubray, J. M.; Ogier, H. A. M.; Odievre, M.; 
   Scotto, J. M.; Monnens, L.; Govaerts, L. C. P.; Roels, F.; Cornelis, A.; 
   Schutgens, R. B. H.; Wanders, R. J. A.; Schram, A. W.; Tager, J. M. : 
   Infantile Refsum disease: an inherited peroxisomal disorder--comparison 
   with Zellweger syndrome and neonatal adrenoleukodystrophy. 
   Europ. J. Pediat. 146: 477-483, 1987.

7. Poulos, A.; Sharp, P.; Whiting, M. : 
   Infantile Refsum's disease (phytanic acid storage disease): a variant of 
   Zellweger's syndrome?. 
   Clin. Genet. 26: 579-586, 1984. 
  
8. Roels, F.; Cornelis, A.; Poll-The, B. T.; Aubourg, P.; Ogier, H.; 
   Scotto, J.; Saudubray, J.-M. : 
   Hepatic peroxisomes are deficient in infantile Refsum disease: a 
   cytochemical study of 4 cases. 
   Am. J. Med. Genet. 25: 257-271, 1986.

9. Schram, A. W.; Strijland, A.; Hashimoto, T.; Wanders, R. J. A.; 
   Schutgens, R. B. H.; van den Bosch, H.; Tager, J. M. : 
   Biosynthesis and maturation of peroxisomal beta-oxidation enzymes in 
   fibroblasts in relation to the Zellweger syndrome and infantile Refsum 
   disease.
   Proc. Nat. Acad. Sci. 83: 6156-6158, 1986. 

10. Scotto, J. M.; Hadchouel, M.; Odievre, M. : 
    Infantile phytanic acid storage disease, a possible variant of Refsum's 
    disease: three cases, including ultrastructural studies of the liver. 
    J. Inherit. Metab. Dis. 5: 83-90, 1982.

11. Stokke, O.; Skrede, S.; Ek, J.; Bjorkhem, I. : 
    Refsum's disease, adrenoleucodystrophy, and the Zellweger syndrome. 
    (Letter) Scand. J. Clin. Lab. Invest. 44: 463-464, 1984.

12. Van Crugten, J. T.; Paton, B.; Poulos, A. : 
    Partial deficiency of dihydroxyacetone phosphate acyltransferase activity 
    in both classical and infantile Refsum's diseases. 
    J. Inherit. Metab. Dis. 9: 163-168, 1986.

13. Wanders, R. J. A.; Boltshauser, E.; Steinmann, B.; Spycher, M. A.; 
    Schutgens, R. B. H.; van den Bosch, H.; Tager, J. M. : 
    Infantile phytanic acid storage disease, a disorder of peroxisome 
    biogenesis: a case report. 
    J. Neurol. Sci. 98: 1-11, 1990.

14. Wanders, R. J. A.; Saelman, D.; Heymans, H. S. A.; Schutgens, R. B. H.; 
    Westerveld, A.; Poll-The, B. T.; Saudubray, J. M.; Van den Bosch, H.; 
    Strijland, A.; Schram, A. W.; Tager, J. M. : 
    Genetic relation between the Zellweger syndrome, infantile Refsum's 
    disease, and rhizomelic chondrodysplasia punctata. (Letter) 
    New Eng. J. Med. 314: 787-788, 1986.

15. Wanders, R. J. A.; Schutgens, R. B. H.; Schrakamp, G.; van den Bosch, H.; 
    Tager, J.M.;Schram, A.W.; Hashimoto, T.; Poll-The, B.T.; Saudubray, J.M. : 
    Infantile Refsum disease: deficiency of catalase-containing particles 
    (peroxisomes), alkyldihydroxyacetone phosphate synthase and peroxisomal 
    beta-oxidation enzyme proteins. 
    Europ. J. Pediat. 145: 172-175, 1986.