Prenatal diagnosis and fetal pathology in a Turkish family harboring a novel nonsense mutation in the lysosomal alpha-N-acetyl-neuraminidase (sialidase) gene

We report a Turkish family with parental consanguinity and at risk for sial idosis type II, an inherited autosomal recessive disorder caused by lysosom al alpha-N-acetyl-neuraminidase (sialidase, NEU1) deficiency. The proband w as a premature male infant that presented with hydrops, hepatomegaly, respi ratory distress syndrome, and anemia and that died of respiratory insuffici ency 2 months after birth despite intensive care. An abnormally increased [ C-14]methylamine incorporation and an isolated deficiency of lysosomal alph a-N-acetyl-neuraminidase were found in cultured skin fibroblasts. A previou s pregnancy of the mother terminated in a spontaneous abortion in the 13th week of gestation. A successive pregnancy showed hydrops fetalis, and an en zymatic assay of cultured amniotic fluid cells indicated a deficiency of al pha-N-acetyl-neuraminidase. Following pregnancy termination at 20 weeks ges tation, light microscopy of fetal tissues revealed classic vacuolation not only in liver, bone marrow, brain, and kidney, but also in endocrine organs such as the thyroid gland, adrenal gland, hypophysis, and testes, and in t he thymus. DNA analysis of the family showed that both the proband and the third sibling had a novel homozygous nonsense point mutation at nucleotide 87 in exon I of the alpha-N-acetyl-neuraminidase (neu1) gene causing a subs titution of tryptophan at codon 29 by a termination codon (W29X). DNA seque ncing of polymerase chain reaction products identified the parents as heter ozygous carriers. To detect neu I mRNA expression, a real-time reverse tran scription/polymerase chain reaction was performed, and similar rates of neu I mRNA expression were found in the fibroblasts of the fetus, the 2nd sibl ing, and in controls. The very early termination codon with complete loss o f neuraminidase activity is probably the molecular basis of the unusually s evere vacuolation pattern in this form of congenital sialidosis.