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3-Methylglutaconic aciduria in two infants
Insights
Two children with a rare metabolic disorder showed developmental regression and organ damage. Their condition was not caused by a deficiency in hydroxymethylglutaryl-CoA lyase or methylglutaconyl CoA-hydratase.
Area of Science:
- Biochemistry
- Genetics
- Pediatric Neurology
Background:
- Investigating rare genetic metabolic disorders in children.
- Understanding the biochemical pathways of organic acidurias.
- Characterizing neurodegenerative syndromes with early-onset failure-to-thrive.
Observation:
- Two children presented with failure-to-thrive, psychomotor regression, hypotonia, liver damage, optic atrophy, and spastic paraparesis after normal early development.
- Elevated urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid was detected in both patients.
- Reduced activity of hydroxymethylglutaryl-CoA lyase was observed in leukocytes and fibroblasts of one child.
Findings:
- The syndrome was not attributed to a deficiency in hydroxymethylglutaryl-CoA lyase, as evidenced by normal ketone body formation during fasting.
- Deficiency in methylglutaconyl CoA-hydratase was also excluded based on normal metabolism of isovaleric acid and leucine.
- The specific enzyme deficiency underlying this organic aciduria remains unidentified.
Implications:
- This study highlights a distinct organic aciduria presenting with severe neurological and systemic manifestations.
- Further research is needed to identify the precise enzymatic defect in this rare metabolic disorder.
- Accurate diagnosis is crucial for potential future therapeutic interventions and genetic counseling.
Abstract:
We studied two children who developed normally for the first 3-4 months of life and then displayed a failure-to-thrive syndrome, regression in psychomotor development, pronounced muscular hypotonia, and liver damage. At the age of about 1-2 years, optic atrophy and spastic parapareses were evident. One child died at the age of 2.5 years the other at an age of 4 years. Both children excreted 3-methylglutaconic acid, 0.1-0.4 mol/mol creatinine and 3-methylglutaric acid, 0.02-0.05 mol/mol creatinine. The excretion of 3-hydroxy-3-methylglutaric acid was not increased. One of the children was available for further biochemical studies. The activity of hydroxymethylglutaryl-CoA lyase (EC 4.1.3.4) was moderately reduced in leucocytes and fibroblasts. During a 21-h fast there was a normal formation of ketone bodies and we conclude that the cause of the syndrome is not a deficiency of hydroxymethylglutaryl-CoA lyase. Normal formation of 14CO2 from [1-14C]isovaleric acid and [2-14C]leucine in fibroblasts and leucocytes apparently excludes a deficiency of methylglutaconyl CoA-hydratase (EC 4.2.1.18).