Molecular basis of lipoamide dehydrogenase deficiency in Ashkenazi Jews

We studied 13 patients with lipoamide dehydrogenase (LAD) deficiency, origi nating from seven Ashkenazi Jewish families. Their disease was characterize d by recurrent attacks of vomiting, abdominal pain, and encephalopathy acco mpanied by elevated liver transaminases, prolonged prothrombin time, and oc casionally associated with lactic and ketoacidemia or with myoglobinuria. T wo patients who presented neonatally suffered from residual neurological da mage with attention deficit hyperactive disorder, mild ataxia, motor incoor dination, muscle hypotonia, and weakness. Nine patients who presented in ea rly childhood or later suffered from exertional fatigue between decompensat ion episodes but were otherwise asymptomatic. Two patients died because of intractable metabolic acidosis and multi-organ failure. In all patients LAD activity was reduced to 8 to 21% of the control in muscle or lymphocytes. In four patients LAD protein in muscle was reduced to 20 to 60% of the cont rol. Direct sequencing of the cDNA of the LAD gene showed that 12 of the 14 mutated alleles carried the G229C mutation and two carried an insertion mu tation 105insA (Y35X). The patients who presented neonatally and had more s evere sequelae were compound heterozygotes for the two mutations; patients who presented in early childhood or later were homozygous for the G229C mut ation. Using an allele-specific oligonucleotide hybridization technique, ni ne heterozygotes for the G229C mutation were identified among 845 anonymous individuals of Ashkenazi Jewish origin disclosing a carrier rate of 1:94. Because of the significant morbidity associated with the disease, screening for the G229C mutation among Ashkenazi Jewish couples should be considered . (C) 1999 Wiley-Liss, Inc.