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[Macrocephaly and dystonic cerebral palsy in a child with type I glutaric aciduria]
E Plöchl1, E Christensen, J P Colombo
1Kinderspital Landeskrankenanstalten Salzburg.
Insights
Glutaric aciduria type I, a rare metabolic disorder, was diagnosed in an infant with macrocephaly and cerebral palsy. Dietary restriction of lysine and tryptophan helped manage urinary excretion, but neurological symptoms persisted.
Area of Science:
- Biochemistry and Genetics
- Metabolic Disorders
- Neuroscience
Background:
- Glutaric aciduria type I (GA-I) is an inherited metabolic disorder caused by a defect in glutaryl-CoA-dehydrogenase.
- This enzyme defect disrupts lysine and tryptophan degradation, leading to abnormal accumulation of organic acids.
- Key urinary markers include elevated glutaric acid and 3-hydroxy-glutaric acid.
Observation:
- A male infant presented with macrocephaly and dystonic cerebral palsy.
- Diagnosis of GA-I was confirmed through urine organic acid analysis and fibroblast enzyme assays.
- Cerebral CT revealed significant frontotemporal atrophy.
Findings:
- Dietary protein, lysine, and tryptophan restriction reduced urinary glutarate excretion.
- Carnitine supplementation improved carnitine levels but did not alter neurological status.
- Riboflavin supplementation showed no clinical benefit or effect on glutarate excretion.
- Baclofen improved dystonia but did not impact organic aciduria.
Implications:
- Early diagnosis of GA-I is crucial for initiating dietary management to mitigate neurological damage.
- While dietary interventions can control metabolite levels, established neurological deficits like dystonia may be irreversible.
- Understanding the mechanism of neurotoxicity, potentially via glutamate decarboxylase inhibition, is vital for future therapeutic strategies.
Abstract:
In a male infant with macrocephaly and dystonic cerebral palsy glutaric aciduria type I was detected by analysis of urine for organic acids. Glutaric aciduria type I is an inherited metabolic disorder of organic acids due to a defect of glutaryl-CoA-dehydrogenase in the intermediate metabolic step of lysine and tryptophan degradation. In the urine glutaric acid is usually accompanied by 3-hydroxy-glutaric acid in abnormal quantities. The enzyme defect in our patient was proved in cultured fibroblasts. In the cerebral computer tomography marked atrophy of bilateral frontotemporal regions could be demonstrated. The amount of urinary glutarat excretion decreased after protein but especially after lysine and tryptophan restriction in the diet. The administration of carnitine improved carnitine levels in blood and urine. Although the progression of neurological impairment could be stopped, dystonia and dyskinesis remained nearly unaltered. In spite of severe motor retardation, recognition and vocalisation were established. In the two year old patient mental retardation is relatively mild comparing with motor retardation. The administration of 100 or 200 mg Riboflavin/day was stopped, as it did not alter clinical symptoms or excretion of glutarat. Baclofen, an analogue of gamma-amino-butyric acid, was orally given (2 mg/kg/day) and improved dystonia, but did not influence organic aciduria. The neurological manifestations may be due in part to inhibition of neuronal glutamat decarboxylase by glutaric acid with decreased gamma-amino-butyric acid biosynthesis. The characteristic clinical symptoms with macrocephaly and dystonia and the very typical pattern of organic acids in urine are a challenge for rapid diagnosis and therapy.