Holocarboxylase synthetase (HCS) deficiency is a disorder of biotin metabolism characterised by metabolic ketoacidosis and skin lesions due to reduced activities of multiple biotin-dependent carboxylases. The onset of this disease is usually between the neonatal and infantile period. Here we report the molecular analysis of an atypical case of HCS deficiency, where the patient developed his first episode of acidosis at age 8 years and had an exceptionally slow response to biotin therapy. A homozygous mutation was identified at the + 5 position of the splice donor site in intron 10 of the HCS gene (IVs10 + 5(g-->a)), resulting in abnormal splicing of HCS mRNA. A moderate decrease in the amount of normal HCS mRNA may account for the atypical, late-onset phenotype of this patient. Conclusion Molecular analysis is a useful tool for understanding the phenotypic variations in holocarboxylase synthetase deficiency.
The principal aim of this study was to examine the clinical manifestations, biochemical features, and molecular genetic characteristics of Chinese patients with ornithine transcarbamylase deficiency (OTCD) at a single medical center. We retrospectively analyzed 24 patients (17 males and 7 females) diagnosed with OTCD between 2006 and 2015. Five male patients had a neonatal presentation; 12 male patients had late onset disease and 7 female patients presented as symptomatic. Patients with a neonatal presentation had the highest peak plasma ammonia and glutamine levels at diagnosis with a high mortality (80% vs 16% in late onset disease). Most of the male late onset disease cases displayed neurologic damage with a mild elevation in plasma ammonia, and a significant increase in serum glutamine, which was commonly misdiagnosed as intracranial infection. In the symptomatic female group, mortality was abnormally high in China with some patients dying at the time of presentation during the first episode of hyperammonemia. Refractory hyperammonemia, serious hepatic function damage, recurrent infection and lethal mutation are the main reasons for poor clinical outcomes of the symptomatic females. Molecular analyses identified 19 different mutations, including 3 novel mutations (c.103insA, c.591C>A and c.805G>A).
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