glutarylcarnitine and 3-hydroxyglutaric-acid

The clinical, biochemical and genetic findings in two Slovak patients with glutaric aciduria type I (GAI) are presented.. GAI is a rare autosomal recessive neuro-metabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase, which is involved in the catabolic pathways of lysine, hydroxylysine and tryptophan. This enzymatic defect gives rise to elevated levels of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA) and glutarylcarnitine (C5DC) in body fluids.. Biochemical and molecular-genetic tests were performed. Urinary organic acids were analysed by Gas Chromatography/Mass Spectrometry (GC/MS) and the entire coding region of the GCDH gene, including flanking parts, was sequenced.. We found the presence of typical metabolic profile and novel causal pathogenic variants in both GAI patients.. We present the first report of two Slovak patients with GAI, which differed in the clinical and biochemical phenotype significantly. They were diagnosed by two distinct approaches - selective and newborn screening. Their diagnosis was complexly confirmed by biochemical and later on molecular-genetic examinations. Though we agreed with a thesis that early diagnostics might positively influenced patient's health outcome, contradictory facts should be considered. Supposed extremely low prevalence of GAI patients in the general population and/or the existence of asymptomatic individuals with a questionable benefit of the applied therapeutic intervention for them lead to doubts whether the inclusion of disease into the newborn screening programme is justified well enough (Tab. 1, Fig. 3, Ref. 41).

Topics: Amino Acid Metabolism, Inborn Errors; Base Sequence; Brain Diseases, Metabolic; Carnitine; Early Diagnosis; Female; Gas Chromatography-Mass Spectrometry; Genotype; Glutarates; Glutaryl-CoA Dehydrogenase; Humans; Infant, Newborn; Male; Mutation, Missense; Phenotype; Sequence Analysis; Slovakia

Glutaric aciduria type I (GA-I) is an autosomal recessive disease caused by a deficiency of the mitochondrial enzyme glutaryl CoA dehydrogenase (GCDH). This metabolic block causes increased urinary concentrations of glutaric and 3-hydroxyglutaric acids. The accumulation and excretion of glutarylcarnitine esters leads to secondary carnitine deficiency. GA-I has an incidence of 1:30,000. The clinical hallmark of GA-I is an acute encephalopathic crisis, with bilateral striatal necrosis presented by severe dystonic dyskinetic disorder. Most patients have their first symptoms during infancy, but some have a less severe form of the disease and some may even remain asymptomatic.

Topics: Age of Onset; Amino Acid Metabolism, Inborn Errors; Biological Transport; Brain Diseases, Metabolic; Carnitine; Glutarates; Glutaryl-CoA Dehydrogenase; Humans; Male; Middle Aged; Treatment Outcome

Glutaryl-CoA dehydrogenase (GCDH) deficiency causes glutaric academia type I (GA-I), an inborn error of metabolism that is characterized clinically by dystonia and dyskinesia and pathologically by neural degeneration of the caudate nucleus and putamen. We report a case of GA-I in a 4-year-old boy. Analysis of blood acylcarnitines by tandem mass spectrometry (MS/MS) revealed a high concentration of glutarylcarnitine in the blood (0.59 microM). Organic acid analysis of urine via gas chromatography mass spectrometry revealed glutaric acid and 3-hydroxyglutaric acids. In order to search for mutations, the GCDH gene of the patient and his parents were amplified by polymerase chain reaction and subjected to direct sequencing. Two mutations were detected in the patient's GCDH gene. One was located in exon 7 (T713C), which caused a codon 238 leucine to proline substitution; the other was located in intron 10 (IVS10-2 A-to-C), and caused a splicing variation in intron 10 and exon 11. Genetic amniocentesis was requested when the patient's mother became pregnant again, but the fetus did not carry any mutation. Tandem mass spectrometry was successfully used to make the diagnosis of GA-I in this case via identification of genetic mutation. If GA-I can be diagnosed in the early onset or presymptomatic stage, effective therapy would reduce sequelae.

Topics: Amino Acid Metabolism, Inborn Errors; Carnitine; Child, Preschool; Glutarates; Glutaryl-CoA Dehydrogenase; Humans; Male; Mutation; Oxidoreductases Acting on CH-CH Group Donors

The neurometabolic disorder glutaryl-CoA dehydrogenase (GCDH) deficiency is biochemically characterised by an accumulation of the marker metabolites 3-hydroxyglutaric acid, glutaric acid, and glutarylcarnitine. If untreated, the disease is complicated by acute encephalopathic crises, resulting in neurodegeneration of vulnerable brain regions, in particular the putamen. 3-hydroxyglutaric acid is considered the major neurotoxin in this disease. There are only preliminary data concerning glutaric acid concentrations in the brains of affected children and the distribution of 3-hydroxyglutaric acid and glutarylcarnitine has not been described. In the present study, we investigated post mortem the distribution of 3-hydroxyglutaric and glutaric acids as well as glutarylcarnitine in 14 different brain regions, internal organs, and body fluids (urine, plasma, cerebrospinal fluid) in a 14-year-old boy. 3-Hydroxyglutaric acid showed the highest concentration (62 nmol/g protein) in the putamen among all brain areas investigated. The glutarylcarnitine concentration was also highest in the putamen (7.1 nmol/g protein). We suggest that the regional-specific differences in the relative concentrations of 3-hydroxyglutaric acid contribute to the pattern of neuronal damage in this disease. These results provide an explanatory basis for the high vulnerability of the putamen in this disease, adding to the strong corticostriatal glutamatergic input into the putamen and the high excitotoxic susceptibility of neostriatal medium spiny neurons.

Topics: Acidosis; Acute Disease; Adolescent; Anticonvulsants; Atrophy; Brain; Carnitine; DNA Mutational Analysis; Fatal Outcome; Gas Chromatography-Mass Spectrometry; Gene Expression; Glutarates; Glutaryl-CoA Dehydrogenase; Humans; Male; Muscle Hypotonia; N-Methylaspartate; Oxidoreductases Acting on CH-CH Group Donors; Point Mutation; Putamen; Spasm; Vigabatrin