Carol L. Clow

Advocacy and compliance in genetic screening. Behavior of physicians and clients in a voluntary program of testing for the Tay-Sachs gene.

Abstract The relation between advocacy and compliance was evaluated in a voluntary testing program to identify carriers of the Tay—Sachs gene among 30,000 eligible subjects. The overall compliance ...

Plasma free amino acid values in normal children and adolescents

We measured plasma free amino acids in 52 children (mean age 8 years) and 80 adolescents (mean age 16 years); conditions of diet and time of day were similar in the two groups. The protocols allowed us to compare their interindividual variation with values previously reported by us for adults. In children, the values for all but seven amino acids were normally distributed; in adolescents there were only six exceptions. Effects of age were apparent: values for only two amino acids were higher in children than adolescents. Values were significantly lower for ten amino acids in children v adolescents and for 11 amino acids in younger children (1 to 6 years) v older children (7 to 12 years). An effect of sex was apparent for five amino acids in adolescents; such differences were not apparent in children. All differences were quasicontinuous and occurred within the global distributions that define values for plasma amino acids in normal children and adolescents. Two artifacts (choice of anticoagulant and delay in deproteinization) affected values for taurine and cystine, respectively.

Cystinuria: Increased Prevalence in Patients with Mental Disease

Abstract The prevalence of homozygous cystinuria was studied in two populations. One group comprising 4714 persons represented patients found in the general medical population, and the other (1400 ...

Management of hereditary metabolic disease. The role of allied health personnel.

Abstract Hereditary metabolic disease yields a cumulative patient load requiring diagnosis, continuous counseling and long-term treatment. The current emphasis on mass screening has amplified the r...

Methylmalonic acidemia with a severe chemical but benign clinical phenotype

A 5-year-old boy of West African origin had methylmalonic acidemia with a mut- enzyme phenotype, no clinical response to hydroxycobalamin, and metabolite measurements indicative of the severe form of mutase deficiency. His development, both mental and physical, was satisfactory and he had no episodes of metabolic decompensation. The explanation for the neurotoxic effects and metabolic decompensation in typical methylmalonic acidemia and the (allelic) genotype that explains this patients phenotype are uncertain.

Effect of nitrous oxide anaesthesia on homocystine excretion.

Research into the biotransformation of inhaled general anaesthetic agents, including nitrous oxide, has led to a better understanding of the underlying mechanisms. It is now known that nitrous oxide can react chemically with vitamin B12, oxidizing Cob(I)alamin to the inactive Cob(III) alamin form. Clinical and experimental evidence in mammals has confirmed that nitrous oxide toxicity, with symptoms suggestive of clinical vitamin B12 deficiency, occurs on exposure to nitrous oxide in a way which is dose and time related and reversible on withdrawal of the nitrous oxide. Nitrous oxide depresses the two known vitamin B12 dependent enzymes methylmalonyl CoA mutase and methionine synthetase by inactivation of their coenzymes adenosylcobalamin and methylcobalamin respectively. Methionine synthetase catalyses the conversion of homocystine to methionine, so interference with this reaction should cause methionine to be depleted and homocysteine to accumulate and to be excreted in the urine. We postulated that the detection of homocystinuria would therefore be an early indicator of nitrous oxide toxicity. Accordingly, we tested the first urine voided postoperatively of 41 patients undergoing nitrous oxide anaesthesia (17 neonates exposed to 50-66 per cent nitrous oxide for a mean of 3.0 hr, and 24 older patients exposed to 66 per cent nitrous oxide for a mean of 7.2 hr). None of these patients demonstrated homocystinuria.RésuméGrâce aux recherches récentes on comprend mieux maintenant le mécanisme de la biotransformation des agents anesthésiques. On sait que le protoxyde d’azote peut réagir chimiquement avec la vitamine B12 en oxydant la Cob(I)alamine en une forme inactive la Cob(III)alamine. Des études en clinique et en laboratoire ont montré que la toxicité du protoxyde d’azote se manifeste par des symptômes suggestifs d’une déficience en vitamine B12 et que sa gravité est proportionnelle à la durée d’exposition du sujet ainsi qu’à la concentration du protoxyde d’azote utilisée, et disparait à l’arrêt de son administration. Le protoxyde d’azote déprime l’activité des deux enzymes contrôlées par la vitamine B12, la méthylmalonyl CoA mutase et la métionine synthétase par inactivation de leur coenzymes adénosylcobalamine et méthylcobalamine. La méthionine synthétase catalyse la conversion de l’homocystine à méthionine, de sorte que l’interférence avec cette réaction devrait causer une déplétion de la méthionine et l’accumulation d’homocystine qui sera éventuellement excrétée dans l’urine. Nous avons postulé que la détection d’homocystinurie pourrait être un indicateur de toxicité au protoxyde d’azote. Nous avons donc analysé la première évacuation d’urine post-opératoire de 41 patients sous protoxyde d’azote (17 nouveaux-nés exposés à des concentrations de 50 à 66 pour cent pendant une période moyenne de 3.0 heures et 24 patients plus âgés exposés à une concentration de 66 pour cent pour une période moyenne de 7.2 heures). Aucun de ces patients n’a montré d’homocystinurie.

709 OUTCOME OF EARLY AND LONG-TERM MANAGEMENT OF CLASSICAL MAPLE SYRUP URINE DISEASE

We describe the outcome of 8400 treatment days in the lives of four classical MSUD patients (present ages: 1 3/12, 5 7/12, 7 1/12 and 8 11/12 yrs). All were diagnosed on clinical signs (vs newborn screening). Acute-phase treatment, beginning on or before the 12th day of life, comprised peritoneal dialysis, intravenous lipid, and early intestinal alimentation. Mean age at discharge from hospital was 29 dy. Parents were taught to monitor urine keto acid excretion (by 2,4-DNPH reaction) and to make up weighed diets. There were only 16 readmissions to hospital for loss of metabolic control (plasma [leu] >1 mM) in the group (89 dys; 1.05% treatment days); serious neurological symptoms were avoided. The group mean plasma leucine level (for levels below 1 mM) during treatment was 0.44 mM (normal for age range, 0.077±0.021 mM; mean and SD); 8.6% of 1042 values exceeded 1 mM during treatment. Group mean plasma valine and isoleucine levels were 60% and 70% of the plasma leucine value. Tolerance for dietary leucine did not exceed 620 mg/dy in any patient. Somatic growth was normal and the mean current IQ/DQ score is 101; the three oldest patients attend normal schools. A characteristic EEG pattern was observed in 3 patients in the acute stage but not during long-term treatment. These results were obtained in an ambulatory program with home visiting.

41 PREDICTION AND PREVENTION OF MATERNAL PHENYLKETONURIA (mPKU) WITH A REGISTRY

Successful treatment and normal development of patients with PKU or Hyperphe. will yield ∼ 250 fertile females in Canada and 2,500 in the USA by 2000 AD. Because unmodified mPKU (and mHyperphe) has a high risk of fetopathy, counseling and birth control, or treatment, of mPKU are indicated. Intrapartum treatment alone during pregnancy is insufficient to prevent the fetopathy; combined preconception & intrapartum treatment of 5 known cases has improved outcome for offspring (Lenke, R.R. and Levy, H.L. NEJM 303:1202, 1980; Brenton, D. Pers. comm. 1980). A register, to follow potential mPKU subjects, would provide a systematic mechanism for preconception counseling. Otherwise, the incidence of mental retardation (MR) due to mPKU in 2000 AD could equal the incidence of MR due to PKU itself before the advent of newborn screening. The RPMG has diagnosed 65 PKU/Hyperphe cases (26F) under 12 yrs. of age. All cases are now registered anonymously in the RPMG data bank. Regional centers caring for the patients, report entries which are recalled on the 12th birthday and returned to reporting centers. Data can be reentered and recalled yearly thereafter, as required. Decisions to proceed with counseling, birth control or pregnancy management rest with the patients physician. The register permits prediction of risk and potential prevention of MR by preconception management of mPKU; it will also facilitate research on mPKU.