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HEREDITARY MONOGENIC DISEASES

           

Glutaryl-CoA type 1

Glutaryl-CoA dehydrogenase deficiency (GDD) is an autosomal recessive neurometabolic disorder which is characterized by encephalopathic crisis that lead to striatal lesions and severe dystonic dyskinetic movement disorders.

The global prevalence is estimated to be 1/100,000 live births. GDD is more prevalent in some communities: the old Amish order, the Oji-Cree Canadian natives, the Irish travelers and the Lumbee Native Americans.
Neonates are mostly asymptomatic, although 75% have macrocephaly, hypotonia and irritability. Presymptomatic diagnosis can be reached via neonatal screening of metabolic diseases.

Those neonates who are not diagnosed can manifest symptoms by 3 to 36 months. These symptoms usually are hypotonia, loss of motor skills and seizures, which lead to striatal lesions with secondary dystonia and subdural and retinal hemorrhage.

At older ages (with the appropriate treatment) the risk of encephalopathic crisis decreases.

The diagnosis should be based on the clinic and it is usually supported by neuro-radiological findings, including very open operculums and lesions in the basal ganglia. The diagnosis is confirmed by a cytogenetic analysis or by measuring the high levels of GA, 3-OH-GA, glutaconic acid and glutarylcarnitine by means of a quantitative analysis of organic acids in urine, gas chromatography-mass spectrometry and/or tandem mass spectrometry (acylcarnitines).

GDD is caused by mutations in the GCDH gene, located in 19p13.2, which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. More than 200 GCDH mutations have been described. GDD is pathogenic because of the accumulation of glutaric acid (GA), 3-hydroxyglutaric acids (3-OH-GA), glutaconic acids and glutarylcarnitine in body fluids.

Genetic counseling is recommended. It should be offered to affected families along with the genetic tests, since the inheritance pattern is autosomal recessive.

The prognosis relies on a timely diagnosis and proper management and treatment, since it is considered a treatable neurometabolic disorder.
Daily management includes a low lysine diet, carnitine supplements along with an emergency treatment early during any intercurrent process.

Following up on recommendations for emergency treatment is essential to prevent neuronal damage and subsequent secondary dystonia.

GENE OR REGION STUDIED


  • GCDH