#266510
ICD+
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| REFSUM DISEASE, INFANTILE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| IRD INFANTILE PHYTANIC ACID STORAGE DISEASE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that the infantile form of Refsum disease can be caused by mutation in the PEX1 (602136), the PEX2 (170993), or the PEX26 (608666) genes. 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 (266500). 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 and Zellweger syndrome (ZWS; 214100) 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 (300100) 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; 215100), 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 adrenoleukodystrophy (NALD; 202370) 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 (239400) 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. Bader et al. (2000) reported 4 Amish sibs from a consanguineous (second-cousin) marriage with clinical and biochemical findings of IRD. At least 3 of the 4 had characteristic poorly formed yellow-orange teeth. In addition, the 2 affected females had a pronounced behavior/mood problem which was most apparent after puberty. Reuber et al. (1997) demonstrated a gly843-to-asp mutation (602136.0001) in the PEX1 gene in infantile Refsum disease. The patients fell into complementation group 1 (CG1) which includes cases of the more severe NALD and the most severe, Zellweger syndrome. In a patient with infantile Refsum disease complementation group 10 (group F), Shimozawa et al. (1999) identified a missense mutation leading to the substitution of lysine in place of glutamic acid at position 55 (E55K) in the PEX2 gene product (170993.0002). This mutation was found in compound heterozygosity with R119X (170993.0001), a known nonsense mutation detected in ZS patients. The patient, a Welsh female, presented at 1 year with delayed milestones and extreme joint laxity. Later, retinitis pigmentosa was diagnosed, and biochemical investigations showed accumulation of very long chain fatty acids and phytanic acid and an abnormal bile acid profile. DHAP-AT activities were reduced in platelets and fibroblasts. Transfection experiments demonstrated that cells containing the E55K mutation had mosaic activities of peroxisomal function, while those with the nonsense mutation did not. Shimozawa et al. (1999) concluded that allelic heterogeneity affects peroxisomal protein import and functions and regulates the clinical severity in peroxisome biogenesis disorders. Jansen et al. (2004) pointed out that infantile Refsum disease was called such because at the time it was first described, Refsum disease was the only known disorder characterized by the accumulation of phytanic acid. Subsequent studies showed that these patients had metabolite patterns typical of generalized peroxisomal biogenesis disorders and, indeed, morphologic studies of liver showed a strong deficiency of peroxisomes. Jansen et al. (2004) concluded that infantile Refsum disease is an unfortunate name for this peroxisome biogenesis disorder, and suggested that the term be discarded. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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