ABSTRACT
A diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency was made in four sibs at different ages. The first three, including a pair of twins, had retarded psychomotor development, poor social contact, and seizures. Biologically, hyperhomocysteinemia and hypomethioninemia were found associated with low folate levels in serum and red cells, especially undetectable methyltetrahydrofolate in red cells. In the fourth child, prenatal diagnosis was not conclusive because of moderate decrease of enzymatic activity in chorionic villi and trophoblast. The girl was also affected, as shown by hyperhomocysteinemia and low folate levels found several days after birth. A 677C-->T (Ala-->Val) mutation was found in a homozygous state in the four children and in the father. Additionally, a second homozygous mutation, 1081C-->T, changing an arginine to cysteine also was identified in all of the children, whereas the distantly consanguineous parents were heterozygous. This amino acid substitution affecting an arginine residue in a sequence located at the end of catalytic domain seems critical for the function of the enzyme. The difficulty of prenatal diagnosis is discussed given the variability found in enzymatic activity and in the clinical phenotypes.
Subject(s)
Diseases in Twins/genetics , Hyperhomocysteinemia/genetics , Oxidoreductases Acting on CH-NH Group Donors/deficiency , Oxidoreductases Acting on CH-NH Group Donors/genetics , Adolescent , Amino Acid Substitution , Child , Child, Preschool , Enzyme Stability , Exons/genetics , Female , Folic Acid/metabolism , Humans , Hyperhomocysteinemia/enzymology , Male , Methylenetetrahydrofolate Reductase (NADPH2) , Mutation , Nuclear Family , Oxidoreductases Acting on CH-NH Group Donors/metabolism , Pedigree , Polymorphism, Genetic , Prenatal DiagnosisABSTRACT
Biochemical studies in five patients with a defect in biotin-responsive holocarboxylase synthesis are reported. The age of onset (2 d to 6 y) as well as the severity of illness varied considerably. In all patients diagnosis was established by the finding of organic aciduria typical for multiple carboxylase deficiency in a catabolic state. In four patients the response to biotin therapy was evaluated by measurement of mitochondrial carboxylase activities in lymphocytes and by monitoring urinary organic acid excretion. In three patients clinical symptoms disappeared with 10-20 mg biotin/d, whereas normalization of the biochemical parameters required higher doses (20-40 mg/d). The fourth patient required a dose of 100 mg biotin/d before her skin rash disappeared. She remains mentally retarded and shows slightly elevated urinary organic acid excretion. Carboxylase activities were clearly deficient in fibroblasts grown in the commonly used medium which contains 10 nmol/L biotin (contributed by FCS in medium) in two patients. Fibroblasts of the other three patients became deficient only in a low biotin medium (0.1 nmol/L). Reactivation of deficient carboxylase activities in relation to time and biotin concentration correlated well with the severity and age of onset of illness in four patients. In one patient, however, carboxylase reactivation followed a more complex pattern requiring the longest incubation time but only a moderately increased biotin concentration of 19 nmol/L compared with 3-5 nmol/L in normal cells and 34-4000 nmol/L in the other four patients. The results in the five patients are in accordance with a primary defect of holocarboxylase synthetase due to a decreased affinity for biotin, in one patient combined with a decreased Vmax.
Subject(s)
Biotin/therapeutic use , Carbon-Carbon Ligases , Carbon-Nitrogen Ligases , Ligases/deficiency , Metabolism, Inborn Errors/enzymology , Acetyl-CoA Carboxylase/deficiency , Acetyl-CoA Carboxylase/metabolism , Adolescent , Age of Onset , Carboxy-Lyases/deficiency , Carboxy-Lyases/metabolism , Cells, Cultured , Child , Female , Fibroblasts/enzymology , Follow-Up Studies , Humans , Infant , Infant, Newborn , Ligases/metabolism , Male , Metabolism, Inborn Errors/drug therapy , Methylmalonyl-CoA Decarboxylase , Pyruvate Carboxylase/metabolism , Pyruvate Carboxylase Deficiency Disease/enzymologyABSTRACT
Brain death can be characterized by cessation of cerebral blood flow. We have measured blood flow velocity in cerebral arteries of 17 comatous children with a transcranial pulsed Doppler equipment. In 11 children who progressed to brain death, we have recorded a progressive decrease of Doppler signal with the following steps: decrease of diastolic velocity, no diastolic velocity, reverse diastolic flow, decrease of systolic signal, no signal at all. In the 6 surviving children (all except one with severe deficits), after an initial reduction but never to a retrograde flow, arterial cerebral blood flow velocity increased to high diastolic values before normalization. Transcranial Doppler technique is non invasive, reliable, can be used at the bedside and repeated; it allows evaluating the cerebral blood flow in comatous children and represents a useful adjunct to brain death diagnosis.
Subject(s)
Brain Death/diagnosis , Echoencephalography , Carotid Arteries/diagnostic imaging , Cerebral Arteries/diagnostic imaging , Child , Child, Preschool , Follow-Up Studies , Humans , Infant , Infant, NewbornABSTRACT
The authors report a massive accidental ingestion of enteric-coated theophylline (Armophilline ) by a young child. A status epilepticus and elevated theophylline serum concentration (167 mg/l) led to use hemodialysis with high dialytic clearance. The elevated clearance was obtained by the use of high permeability membrane, by bicarbonate dialysate and the best quality of vascular access (Hickman catheter).