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Glutaric Aciduria Type 1


Glutaryl-CoA dehydrogenase (GCDH) deficiency (GDD) is an autosomal recessive neurometabolic disorder clinically characterized by encephalopathic crises resulting in striatal injury and a severe dystonic dyskinetic movement disorder.

Worldwide prevalence is estimated at 1 in 100,000 births. GDD is more prevalent in the old order Amish community, Canadian Oji-Cree natives, Irish travelers and Lumbee Native Americans.

Neonates are mainly asymptomatic, although 75 % present with macrocephaly and possibly show hypotonia and irritability. If undiagnosed, the initial acute encephalopathic crisis occurs between 3-36 months, typically precipitated by an intercurrent febrile illness, vaccination or a surgical intervention, and characterized by hypotonia, loss of motor skills and convulsions resulting in bilateral striatal injury with severe secondary dystonia and occasionally subdural and retinal hemorrhage. GDD can exceptionally present with hypoglycemia or acidosis. With age (>6 years) and with appropriate treatment, the risk of encephalopathic crises subsides. In some patients, hypotonia and dystonia develop gradually with no encephalopathic crisis, which is known as late-onset or insidious-onset GDD.

GDD is caused by mutations in the GCDH gene, located to 19p13.2, and involved in L-lysine, L-hydroxylysine and L-tryptophane catabolic pathways. Over 200 GCDH mutations have been reported. GDD has a distinctive pathological appearance due to the accumulation of glutaric acid (GA), 3-hydroxyglutaric (3-OH-GA) and glutaconic acids and glutarylcarnitine in body fluids.

Presymptomatic detection can be offered through routine newborn screening programs implemented in some countries. If not available, diagnosis should be suspected on the basis of clinical findings and can be supported by neuroradiological findings including widely open opercula and basal ganglia injury. Diagnosis is confirmed by cytogenetic analysis or by measuring elevated levels of GA, 3-OH-GA, glutaconic acid and glutarylcarnitine by quantitative urinary organic acid analysis, gas chromatography-mass spectrometry and/or tandem mass spectrometry (acylcarnitines).

GDD is often misdiagnosed. Differential diagnosis includes encephalitis, Reye's syndrome, familial infantile bilateral striatal necrosis, familial megalencephaly, postencephalitic Parkinsonism (see these terms), dystonic cerebral palsy, battered child syndrome with chronic subdural effusions, sudden infant death syndrome and vaccine induced brain-injury.

Prenatal testing can be performed by genetic and GCDH enzyme analysis of chorionic villi sample or through measuring GA levels in amniotic fluid in at-risk families. Genetic testing is necessary to confirm antenatal diagnosis.

Genetic counseling is recommended and should be offered to affected families together with genetic testing, as inheritance is autosomal recessive.

Daily management comprises a low lysine diet, carnitine supplementation in association with prompt emergency treatment during intercurrent illness. During acute episodes, management includes, most importantly, increasing energy supply (20-100 % above RDI); omission of natural protein for 24-48 hours followed by a gradual reintroduction; L-carnitine supplementation doubling and close monitoring of glucose, electrolyte and fluid balance, as well as urea and liver status by an informed skilled interdisciplinary team. Adherence to emergency treatment recommendations is imperative in preventing neuronal damage and subsequent secondary dystonia.

Prognosis depends on a timely diagnosis and consequential management and treatment. GDD is now regarded as a treatable neurometabolic disorder.




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