Neonatal cholestasis: A new presentation of X-linked adrenoleukodystrophy

Abstract

A French-Canadian boy presented with neonatal cholestasis and failure to thrive, bilateral polar cataracts, anemia, thrombocytopenia and hypolonia. Bom at 37 weeks gestational age, he weighed 2450 g (10%ile), with length 46 cm (10%ile) and head circumference 33 cm (50%ile). Jaundice was present at birth. No dysmorphism was noted Transaminases were consistently elevated >2-fold. Liver biopsy showed cholestasis and confirmed the presence of calalase-posilive structures, with normal peroxisomes and mitochondria. HIDA scintigraphy showed mild hepatocellular dysfunction. Other investigations including endoscopy, plasma and urine amino acids, serum copper, alpha-1-antitrypsin levels, erythrocyte galactose-1-phosphate levels, karyotype (46, XY) and TORCH viral studies were non-diagnostic. Brainstem auditory evoked potentials showed mild peripheral hearing loss at 3 weeks of age, and a central loss when repeated at 8 months of age. He developed cachexia, progressive hepatomegaly, splenomegaly, osteopenia, bruxism and opisthotonic posturing, with a progressive motor delay. CT scan revealed cortical atrophy. He died of liver failure at age 12 months after frequent episodes of gastrointestinal bleeding and continued neurological deterioration. Post-mortem, plasma very long-chain fatty acids (VLCFAs) results became available, showing elevation of the C26:C22 ratio. Phytanic acid, assayed on three stored samples was normal in two and 3-fold elevated in one. Other peroxisomal function tests including plasma pipecolic acid and rbc plasmalogen ratios were normal, but C18 DMA levels were somewhat lower than normal. Fibroblast C26:0 and C22 levels were elevated 5-fold, and the C26/C22 ratio, 9-fold. Oxidation of C24:0 was 20% of control values. On immunostaining with antibody to the ALD protein, fibroblasts were CRIM negative. The ALD protein gene contained a previously-unreported mutation, a thymine-to-cytosine transition at nucleotide 1654 in exon 7, predicted to change Ser 552 to Pro in the ATP binding domain. Although the patient's mother had normal plasma VLCFA levels, a subsequent pregnancy showed an elevated C26/C22 ratio in amniocytes and was terminated. A similar patient with biochemically-proven ALD and rapidly-progressive cholestasis was recently reported (Corzo. D. et al., Am J Hum Genet 65, 4 (Suppl.): A1295) demonstrating that the association of mutations in the ALD protein gene and neonatal cholestasis is not spurious, and expanding the phenotypic spectrum of ALD to include neonatal cholestatic jaundice with liver failure.