Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mitochondrial HMG-CoA synthase deficiency or mHS deficiency, OMIM #605911) is an inborn error of metabolism that affects ketone body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycemia and dicarboxylic aciduria. The diagnosis is difficult due to the relatively unspecific clinical and biochemical presentation, and fewer than 30 patients have been described. This work describes three new patients with mHS deficiency and two missense mutations c.334C>T (p.R112W) and c.430G>T (p.V144L) previously not reported. We developed a new method to express and measure the activity of the enzyme and in this work the study is extended to ten new missense variants including those of our patients. Enzymatic assays showed that three of the mutant proteins retained some but seven completely lacked activity. The identification of a patient homozygous for a mutation that retains 70% of enzyme activity opens the door to a new interpretation of the disease by demonstrating that a modest impairment of enzyme function can actually produce symptoms. This is also the first study employing molecular dynamics modelling of the enzyme mutations. We show that the correct maintenance of the dimerization surface is crucial for retaining the structure of the active center and therefore the activity of the enzyme.post-print1746 K

Unilateral bowing of long bones and multiple congenital anomalies in a child born to a mother with gestational diabetes

We report on a new-born girl with multiple congenital anomalies consisting of major skeletal anomalies restricted to the left side, cleft palate, ventricular and atrial septal defect, retromicrognathia, short neck, dysplastic low-set ears and large birth weight. The left-side bony anomalies include shortening and bowing of the femur and tibia, hypoplasia of the fibula, hip dislocation, clubfoot and mild shortening of the long tubular bones in the left arm with elbow dislocation. The pregnancy was complicated by insulin-dependent gestational diabetes mellitus in the mother. The radiographic features were not consistent with the diagnosis of campomelic dysplasia, kyphomelic dysplasia or other skeletal dysplasias characterized by bowing and shortening of the long bones. To our knowledge, the multiple congenital anomalies, including major skeletal malformations, present in our case have never been simultaneously reported until now. A maternal diabetes syndrome in this infant is probable. The occurrence of major congenital malformations in offspring of women with gestational diabetes is reviewed and discussed. We provide evidence that gestational diabetes mellitus could be teratogenic. We recommend a careful diabetic control in every women with a history of gestational diabetes. (C) 2000 Editions scientifiques et medicales Elsevier SAS.SCOPUS: ar.jinfo:eu-repo/semantics/publishe