The urinary excretion of glutarylcarnitine is an informative tool in the biochemical diagnosis of glutaric acidemia type I.

Glutaric acidemia type I (GA-1) is a progressive neurodegenerative inborn error of metabolism that typically manifests acutely in infants during an intercurrent illness. The diagnosis is established biochemically by the detection of glutaric acid and 3-hydroxy glutaric acid in urine and glutarylcarnitine in plasma. However, some patients excrete only small amounts of glutaric acid and may be overlooked, especially if the plasma concentration of glutarylcarnitine is not elevated. To test the hypothesis that measuring the excretion of glutarylcarnitine may improve the recognition of GA-1 patients without significant glutaric aciduria, urine glutarylcarnitine was analyzed in 14 cases. Five of them lacked significant glutaric aciduria, 9 (of 10 available) had a normal plasma glutarylcarnitine concentration. As controls, we also evaluated 54 subjects with glutaric aciduria secondary to other causes (16-7509 mmol/mol creatinine; reference range: <15; no significant amounts of 3-hydroxy glutaric acid detectable). The excretion of glutarylcarnitine was significantly elevated in all GA-1 patients (14-522 mmol/mol creatinine; reference range: <5.2) and in none of the controls with glutaric aciduria. These findings suggest that the urinary excretion of glutarylcarnitine is a specific biochemical marker of GA-1 which could be particularly useful in the work up of patients with suggestive clinical manifestations but without glutaric aciduria and with normal plasma acylcarnitine profiles.

Newborn screening compared to clinical identification of biochemical genetic disorders.

A group of 28 patients with inherited metabolic disease (homocystinuria galactosaemia, maple syrup urine disease and biotinidase deficiency) diagnosed by screening were compared with a group of 17 similar patients identified clinically. The rate of hospitalization was similar for the two groups. The patients diagnosed clinically showed a higher incidence of mental retardation and their parents experienced greater stress and found greater difficulty in meeting their child's needs.

Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial.

CONTEXT: Heterozygous familial hypercholesterolemia (HeFH) is a common disorder associated with early coronary artery disease, especially in men. The age at which drug therapy should be started is still controversial, as is the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). OBJECTIVE: To assess the lipid-lowering efficacy, biochemical safety, and effect on growth and sexual development of lovastatin in adolescent boys with HeFH. DESIGN: One-year, double-blind, placebo-controlled, balanced, 2-period, 2-arm randomized trial. In the first period (24 weeks), lovastatin was increased at 8 and 16 weeks and the dosage remained stable during the second period (24 weeks). The study was conducted between 1990 and 1994. SETTING: Fourteen pediatric outpatient clinics in the United States and Finland. PATIENTS: Boys aged 10 to 17 years with HeFH. Of 132 randomized subjects (67 intervention, 65 placebo), 122 (63 intervention, 59 placebo) and 110 (61 intervention, 49 placebo) completed the first and second periods, respectively. INTERVENTION: Lovastatin, starting at 10 mg/d, with a forced titration at 8 and 16 weeks to 20 and 40 mg/d, respectively, or placebo. MAIN OUTCOME MEASURES: The primary efficacy outcome measure was low-density lipoprotein cholesterol (LDL-C). Primary safety measures were growth and sexual development. RESULTS: Compared with placebo, LDL-C levels of patients receiving lovastatin decreased significantly (P<.001) by 17%, 24%, and 27% receiving dosages of 10, 20, and 40 mg/d, respectively, and remained 25 % lower than baseline at 48 weeks. Growth and sexual maturation assessed by Tanner staging and testicular volume were not significantly different between the lovastatin and placebo groups at 24 weeks (P = .85) and 48 weeks (P = .33); neither were serum hormone levels or biochemical parameters of nutrition. However, the study was underpowered to detect significant differences in safety parameters. Serum vitamin E levels were reduced with lovastatin treatment consistent with reductions in LDL-C, the major carrier of vitamin E in the circulation. CONCLUSIONS: This study in adolescent boys with HeFH confirmed the LDL-C-reducing effectiveness of lovastatin. Comprehensive clinical and biochemical data on growth, hormonal, and nutritional status indicated no significant differences between lovastatin and placebo over 48 weeks, although further study is required.

Oto-palato-digital syndrome, type II--an X-linked skeletal dysplasia.

We report on two male infants with a lethal skeletal dysplasia characterized by cleft palate, midface hypoplasia, downward-slanting palpebral fissures, small thorax, and bowed limbs with absent fibulae. The clinical and radiographic changes are similar to those seen in the recently proposed oto-palato-digital syndrome, type II [Fitch et al, 1983]. The disorder is X-linked with heterozygous females being more mildly affected.

Quantitation of beta-lipoprotein in cord serum by rate nephelometric immunoassay: a potential screening test for familial hypercholesterolemia.

We measured beta-lipoprotein in 232 cord sera by rate nephelometry and compared the results with those obtained by electroimmunoassay. The mean (mean +/- two standard deviations) was 544 (293-1009) mg/L by rate nephelometry and 503 (265-955) mg/L by electroimmunoassay. The between-assay correlation coefficient was 0.891. Between-run coefficients of variation were 3.5-4.4% for nephelometry and 11-14% for electroimmunoassay. Nephelometry was faster, more precise, and less labor intensive than electroimmunoassay. For these reasons, rate nephelometry appears to be a more suitable assay system for mass screening, should detection of familial hypercholesterolemia prove feasible and desirable.

Dihydropteridine reductase deficiency associated with severe neurologic disease and mild hyperphenylalaninemia.

A deficiency of hepatic dihydropteridine reductase (DHPR) activity was found in a neurologically impaired infant with mild hyperphenylalaninemia and normal levels of hepatic phenylalanine hydroxylase. DHPR is required for the regeneration of tetrahydrobiopterin, an essential cofactor in aromatic amino acid hydroxylation, a necessary step in the biosynthesis of the neurotransmitters, dopamine and serotonin. Evidence for decreased synthesis of these transmitters in this patient was provided by the finding of reduced levels of homovanillic acid and 5-hydroxyindole acetic acid, metabolites of dopamine and serotonin, respectively, in the cerebrospinal fluid and urine. Treatment with dopamine and serotonin precursors, L-3,4 dihydroxyphenylalanine and 5-hydroxytryptophan, respectively, was associated with improvement in temperament and motor tone and less frequent seizures. However, there was no improvement in gross motor function or language development.