Lethal fetal and early neonatal presentation of adenylosuccinate lyase deficiency: observation of 6 patients in 4 families.

OBJECTIVE: To characterize a new lethal fetal and early postnatal variant of adenylosuccinate lyase (ADSL) deficiency. STUDY DESIGN: This was a retrospective analysis of 6 patients with very early presentation of ADSL deficiency. RESULTS: Most of the 6 patients had impaired intrauterine growth, microcephaly, fetal hypokinesia, and a lack of fetal heart rate variability. Postnatally, they shared severe muscular hypotonia necessitating mechanical ventilation, intractable seizures, and early death. All 6 patients had biochemical evidence of severe (type 1) disease and low residual ADSL activities. All were compound heterozygous for mutations that, based on expression studies, have a pronounced effect on ADSL activity and/or stability. CONCLUSIONS: ADSL deficiency may present with prenatal growth restriction, fetal and neonatal hypokinesia, and rapidly fatal neonatal encephalopathy. This clinical presentation is associated with genotypes resulting in very low residual enzyme activity.

Hereditary renal hypouricemia. Isolated tubular defect of urate reabsorption.

A consanguineous Iraqi Jewish kindred is presented in which asymptomatic and apparently benign hypouricemia, secondary to an isolated renal defect, segregates as an autosomal recessive trait affecting four of eight siblings. The 8-year-old proband was ascertained during an evaluation for an apparently unrelated inherited neurologic disorder with which an older normouricemic sibling was also affected. Urate clearance in three affected siblings was 22.6, 35.2, and 60.8 ml/minute, while that in normouricemic siblings was 8.6 to 10.6 ml/minute. Pyrazinamide administration to one affected sibling reduced the urate clearance from 61 to 14.7 ml/minute. A recessively inherited single gene lesion producing a tubular defect is postulated; the exact site(s) is uncertain.