Glutaric acidaemia type I

The phenotypic spectrum of GA1 ranges from infantile-onset to later-onset disease after the age of six years. If untreated, 80 to 90% of children with infantile-onset disease develop an acute encephalopathic crisis. In 95% of cases, this occurs within the first 24 months of life, typically precipitated by intercurrent febrile illness, vaccination-associated fever, or fasting and catabolic stress around anaesthesia and surgical procedures. These crises cause acute bilateral striatal injury, followed by progressive complex neurological movement disorders with high disability and mortality. Striatal injury typically manifests between three months and three years of age, and in rare cases between three and six years of age. Progressive macrocephaly, which may be present prenatally, is observed in 75% of affected individuals and is frequently the first clinical clue prompting evaluation. Late-onset presentations after the age of six years range from asymptomatic individuals, often identified through an affected child’s newborn screening (NBS) result, to varied neurological findings. Chronic kidney disease may occur as an extracerebral manifestation in adults, even with treatment adherence.

The estimated prevalence is approximately 1 in 100,000 newborns, with considerable variation between populations (reported estimates range from 1 in 30,000 to 1 in 110,000).

Biallelic pathogenic variants in the GCDH gene (19p13.2) cause GA1. GCDH encodes glutaryl-CoA dehydrogenase, a flavin adenine dinucleotide-dependent mitochondrial matrix enzyme. This enzyme oxidises and decarboxylates glutaryl-CoA in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan. Loss-of-function variants cause accumulation of glutaric acid, 3-hydroxyglutaric acid, C5DC, and glutaconic acid. Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids causes neurotoxicity with preferential bilateral striatal injury.

GA1 is inherited in an autosomal recessive manner. The parents of an affected individual are typically asymptomatic carriers. At conception, each sibling of an affected proband has a 25% chance of being affected, a 50% chance of being a heterozygous carrier, and a 25% chance of being unaffected and non-carrier. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis of GA1 is supported by biochemical, molecular, and imaging findings. Elevated glutarylcarnitine (C5DC) on NBS dried blood spots, measured by tandem mass spectrometry is the principal screening marker. It is confirmed by elevated glutaric and 3-hydroxyglutaric acids in urine, typically analysed by gas chromatography mass spectrometry (GC-MS; organic acids), and in plasma. Reduced glutaryl-CoA dehydrogenase activity in cultured fibroblasts supports the diagnosis when molecular results are equivocal. Characteristic brain MRI findings in symptomatic individuals include widened frontotemporal opercula, ventriculomegaly, attenuated basal ganglia signal, and white-matter abnormalities.

Main differential diagnoses include:

• Glutaric acidaemia type 2: elevated C5DC accompanied by additional elevated acylcarnitines on MS/MS, distinguishing it from the isolated C5DC elevation of GA1; clinically with hypotonia, hepatic dysfunction, and cardiomyopathy; ETFA, ETFB, ETFDH
• Glutaric acidaemia type 3: markedly elevated urinary glutaric acid on GC-MS but normal 3-hydroxyglutaric acid and normal C5DC, with no clinical phenotype; SUGCT
• Canavan disease: macrocephaly and leukodystrophy overlapping GA1, but distinguished biochemically by elevated urinary N-acetylaspartate on GC-MS rather than glutaric acid; ASPA

• Genetic testing supports establishing the diagnosis by identifying the underlying GCDH pathogenic variants, confirming the biochemical diagnosis of GA1 and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management, including emergency metabolic management during catabolic illness, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive and carrier testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

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• Boy N, Garbade SF, Heringer J, Seitz A, Kölker S, Harting I. Patterns, evolution, and severity of striatal injury in insidious- vs acute-onset glutaric aciduria type 1. J Inherit Metab Dis. 2019;42(1):117-127. doi: 10.1002/jimd.12033. PMID: .
• Boy N, Mühlhausen C, Maier EM, Ballhausen D, Baumgartner MR, Beblo S, et al. Recommendations for diagnosing and managing individuals with glutaric aciduria type 1: Third revision. J Inherit Metab Dis. 2023;46(3):482-519. doi: 10.1002/jimd.12566. PMID: .