Spectrum of glutamate dehydrogenase mutations in Japanese patients with congenital hyperinsulinism and hyperammonemia syndrome.

INTRODUCTION: Congenital hyperinsulinism and hyperammonemia (CHH) is caused by gain of function of glutamate dehydrogenase (GDH). The genetic abnormalities are known to be located in three specific regions on the GDH protein. We describe here three different missense mutations identified in five new Japanese patients with CHH. And to study the genotype-phenotype correlations in patients with GLUD1 mutations, we analyzed previously reported Japanese cases. METHODS: An Epstein-Barr virus-transformed lymphoblastoid cell line was established from the 5 patients and control subjects, and was used for enzymatic and molecular analyses. RESULTS: All patients developed seizures with loss of consciousness associated with hypoglycemia and had persistent hyperammonemia. All patients had similar basal GDH activity of lymphoblasts and insensitivity to GTP inhibition. Genetic studies identified heterozygous I444M mutation in Patient 11, S217C mutation in Patient 1, and H262Y mutation in Patients 2, 3, and 4. Patients 3 and 4 were child and father, respectively. COS cell expression study confirmed that I444M and H262Y mutations were disease-causing genes. CONCLUSIONS: We identified three mutations (I444M, H262Y, and S217C), and the former is a newly described mutation. A summary of 17 reported Japanese patients (10 boys and 7 girls) with GDH mutations showed 8 patients had mutation at the site of the GTP-binding region, 2 at the site of the antenna-like structure, and 7 at the site of the hinge region. Analysis of the reported cases showed no clear association between clinical phenotype and mutation sites. However, G446D mutation seems to be associated with serious abnormalities.

[Severe hypoglycemia and clouding of consciousness caused by deficiency of the connecting link acyl CoA dehydrogenase]. / Svaer hypoglykaemi og bevidsthedssløring forårsaget af mangel på mellemkaedet acyl-CoA dehydrogenase.

A case of severe hypoglycaemia precipitated by fasting in a child is described. As a result of the hypoglycaemia, the patient became brain damaged. The mechanism causing the hypoglycaemia was a defect in the fatty acid beta-oxidation enzyme, the connecting link acyl-CoA dehydrogenase. During a prolonged fast, fatty acids are not converted to acetyl-CoA and ketone bodies which participate in Kreb's cycle for production of energy to a sufficient extent. This result in non-ketotic hypoglycaemia with excretion of organic acids in the urine. As a rule, the symptoms occur for the first time during the first to second years of life in connection with common infectious diseases, with vomiting followed by clouding of consciousness and possibly coma, but the condition may also present with sudden unexpected death. Treatment consists of intravenous glucose. The diagnosis is established by testing the urine for hexanoylglycin and other substances and is confirmed by culture of skin fibroblasts and measurement of beta-oxidation activity. The disease is an autosomally recessive inherited condition. In families where there have been cases of unexplained hypoglycaemia and clouding of consciousness and cases of unexplained death in infancy or "near misses", all of the family members should be offered examination for the above mentioned enzyme deficiency.

Myoglobinemia and myoglobinuria in unconscious children.

Myoglobinemia and/or myoglobinuria was demonstrated in 12 of 17 unconscious children studied. Myoglobinemia was noted in patients with serum CPK levels above 200-250 units. Ten of the 12 patients in whom myoglobinemia was present had convulsions. Some degree of renal disturbance was noted in six of seven patients with myoglobinuria. Five patients, including four with renal disturbance, died. In unconscious children with myoglobinuria the possibility of a disturbance of renal function should always be considered.