#202370
ICD+
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| ADRENOLEUKODYSTROPHY, AUTOSOMAL NEONATAL FORM | |||||||||||||||||||||||||||||||||
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| NEONATAL ADRENOLEUKODYSTROPHY; NALD | |||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||
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| Clinical Synopsis | |||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence (Dodt et al., 1995) that the disorder is caused by mutations in the PTS1 receptor gene (PEX5; 600414) or the peroxin-1 gene (PEX1; 602136). NALD has also been observed with mutations in the peroxin-10 gene (PEX10; 602859), the peroxin-13 gene (PEX13; 601789), and the peroxin-26 gene (PEX26; 608666). Benke et al. (1981) reported brother and sister with similar facial features, seizures from birth, delayed neurologic development which began to deteriorate at age 1 year, and sudden death, associated with respiratory infections, before the age of 3 years. Tanning of the skin was noted 2 months before death of the first child; in the second child, blood cortisol levels failed to increase after intravenous ACTH administration. At autopsy, both patients showed adrenal atrophy and degenerative changes of the white matter throughout the neuroaxis. One of the infants had polar cataracts at birth. The characteristic craniofacial changes were dolichocephaly, prominent and high forehead, esotropia, epicanthic folds, broad nasal bridge, high-arched palate, low-set ears, and anteverted nostrils. The female was as severely affected as the male, making X-linked inheritance unlikely. Moser (1981) also suspects that the neonatal form of adrenoleukodystrophy is inherited as an autosomal recessive: the incidence and degree of affection are comparable in boys and girls. The neonatal form of ALD is clearly separate from the X-linked forms of childhood and adult ALD/AMN and also from Zellweger syndrome (214100) to which it bears many clinical and biochemical similarities including the accumulation of very long chain fatty acids (VLCFA), particularly hexacosanoic acid (C26:0). Levels are normal in parents whereas in the X-linked form they are intermediate in the heterozygous female. It also bears similarities to hyperpipecolic acidemia (239400). All are apparently disorders of the peroxisomes, which are lacking in both Zellweger syndrome and neonatal ALD and which are the main site of oxidation of very long chain fatty acids. Since 40 enzymes have been localized to the peroxisome (Tolbert, 1981), there is adequate opportunity for genetic heterogeneity among disorders with phenotypic overlap (cf., the mucopolysaccharidoses). Kelley and Moser (1984) showed that serum pipecolic acid is elevated, often markedly, in patients with NALD but in none of those with X-linked ALD or adrenomyeloneuropathy, or in normal adults and children, or children with cirrhosis or other neurodegenerative disorders. This finding can be added to that of elevated very long chain fatty acids to support a generalized peroxisomal dysfunction and relationship to the Zellweger syndrome. Cystic changes in the kidneys and skeletal changes (very large fontanels and cartilaginous calcifications) occur in Zellweger syndrome but not in NALD. Differentiation is confused by the fact that cases of NALD have been found to have no hepatic peroxisomes (Partin and McAdams, 1982), a finding considered virtually pathognomonic of Zellweger syndrome, whereas 2 sibs with many classic features of Zellweger syndrome and elevated VLCFA and pipecolic acid have normal hepatic peroxisomes (Burton et al., 1981). Kelley et al. (1986) presented 8 new cases and contrasted the findings with those of Zellweger syndrome. See 300100 for a discussion of the usual form of adrenoleukodystrophy. Chen et al. (1987) found that despite the absence of the bifunctional enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, its mRNA could be demonstrated in neonatal ALD fibroblasts. This suggested to them that the protein was rapidly degraded in the cytoplasm before its entry into peroxisomes. In Zellweger syndrome, acyl-CoA oxidase and beta-ketothiolase are also deficient. All 3 enzymes are synthesized on free polyribosomes and then transported into peroxisomes. Paul et al. (1993) described affected male and female infant offspring of first-cousin Egyptian parents who presented with manifestations suggesting infantile progressive spinal muscular atrophy (253300). | |||||||||||||||||||||||||||||||||
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| Moser et al. (1984) | |||||||||||||||||||||||||||||||||
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