Glutaric Acidaemia Type 1

Glutaric acidaemia type 1 is an autosomal recessive disorder of lysine, hydroxylysine and tryptophan breakdown caused by deficiency of glutaryl-CoA dehydrogenase. Untreated, most infants develop an acute encephalopathic crisis with permanent striatal injury and a severe dystonic movement disorder.

Incidence is about 1 in 100 000 live births, with higher rates in some populations. Many infants have macrocephaly at birth or in the first months of life. Diagnosis by newborn screening before the first crisis, with early treatment, greatly lowers the risk of neurological damage.

Patients are classified as high or low excretors by urine glutaric acid, but both have the same risk of neurological injury. Low excretors can be missed on screening.

Pathophysiology.

Glutaryl-CoA accumulates and converts to glutaric acid, 3-hydroxyglutaric acid and glutarylcarnitine. These dicarboxylic acids cross the blood brain barrier poorly and become trapped in the brain.

The striatum is most vulnerable between 3 and 36 months of age. Catabolic stress from fever, vaccination or surgery during this window triggers neuronal energy failure and injury to the putamen and caudate.

• Macrocephaly, irritability and hypotonia in early infancy, often before any crisis.
• Acute encephalopathic crisis, usually between 6 and 36 months, after fever, vomiting or diarrhoea: lethargy, seizures, then dystonia, dyskinesia and bulbar dysfunction.
• Chronic: dystonia and choreoathetosis with preserved intellect, and later complications including dysphagia, scoliosis and contractures.
• Subdural haematoma and retinal haemorrhage can occur with minor trauma.

Red flags.

• Acute encephalopathy or loss of motor skills during a febrile illness in an infant with macrocephaly.
• Subdural haematoma with no clear mechanism: a metabolic screen is needed before concluding non-accidental injury.

• Newborn screening: raised glutarylcarnitine (C5DC) in dried blood spots.
• Urine organic acids: raised glutaric acid and 3-hydroxyglutaric acid. Low excretors can have normal urine glutaric acid, so measure 3-hydroxyglutaric acid and plasma or blood glutarylcarnitine.
• Molecular testing of GCDH confirms the diagnosis. Enzyme assay in fibroblasts is rarely needed.
• MRI brain: widened frontotemporal (Sylvian) fissures, frontotemporal atrophy, subdural collections and, after a crisis, T2 hyperintensity in the putamen and caudate.
• Blood glucose, ammonia, gas and lactate in acute illness.

Differential diagnosis. Other organic acidaemias, glutaric acidaemia type 2, mitochondrial disease (Leigh syndrome), infective encephalitis, non-accidental injury and hydrocephalus or other causes of macrocephaly.

Maintenance.

• Lysine restricted diet with a lysine free and tryptophan reduced amino acid supplement. Natural protein supplies lysine of about 100 mg/kg/day in the first 6 months, falling to about 60 to 80 mg/kg/day by 3 years. Restriction is relaxed after 6 years, but a protein controlled diet continues.
• L-carnitine 50 to 100 mg/kg/day orally in 3 divided doses.
• Avoid fasting. Treat fever early with paracetamol 15 mg/kg every 6 hours, maximum 60 mg/kg/day.

Emergency regimen during illness or fever.

• Start at the first sign of illness. Stop natural protein for no more than 24 hours.
• Glucose polymer solution (10% under 1 year, 15% at 1 to 2 years, 20% at 2 to 9 years, 25% from 10 years) every 2 to 3 hours day and night, with L-carnitine continued.
• Admit at once if vomiting, drowsiness or poor intake. Give IV glucose 10% with electrolytes at 8 to 10 mg/kg/min in infants, L-carnitine 100 to 200 mg/kg/day IV in divided doses and treatment for the underlying infection.
• Restart natural protein stepwise within 24 to 48 hours.

Movement disorder.

• Baclofen initially 0.3 mg/kg/day orally in 3 divided doses, increased gradually to a maximum of 2 mg/kg/day (maximum 40 mg daily under 8 years, 60 mg daily from 8 years). Do not stop abruptly.
• Trihexyphenidyl, benzodiazepines such as clonazepam, and botulinum toxin injections for focal dystonia, directed by neurology. Consider gastrostomy for dysphagia.

Monitoring. Growth, head circumference, development, movement disorder, MRI when clinically indicated, plasma carnitine and amino acids.

Referral and escalation. Refer to a metabolic centre at diagnosis and a paediatric neurologist for dystonia. Provide an emergency regimen letter.