Glutaric aciduria type I: From clinical, biochemical and molecular diversity to successful therapy

Abstract

The biochemical hallmark of glutaric aciduria type I (GA I) due to glutaryl-CoA dehydrogenase deficiency is the accumulation of glutaric acid, and to a lesser degree of 3-hydroxyglutaric and glutaconic acids. Abnormal metabolites vary from gross organic aciduria to only slightly or intermittently elevated or even normal excretion of glutaric acid, making the diagnosis sometimes difficult. Close to 100 pathogenic mutations have been identified in the gene encoding glutaryl-CoA dehydrogenase. Specific mutations correlate with low or no excretion of glutaric acid, but there appears to be no correlation between genotype and clinical phenotype. GA I causes unique age- and location-specific neuropathological sequelae. Starting in the second half of gestation, maturation of the frontal and temporal cortex is hindered, leading to the characteristic appearance of frontotemporal atrophy. Between 6 and 18 months of age, relatively mild neurological symptoms may become exacerbated by fever or a catabolic state in the course of common infections or routine immunizations, by fasts required for surgery, or by minor head injuries. Putamen and caudate are destroyed, resulting in a permanent movement disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Recently, the underlying pathophysiology could be delineated to an environmentally triggered age- and location-specific overstimulation of the NMDA 2B receptor subtype. Current therapy prevents brain degeneration in more than 90% of affected infants who are treated prospectively. Without treatment, more than 90% of affected children will develop severe neurological disabilities. Recognition of this disorder before the brain has been injured is essential to treatment. GA I may be recognized in routine neonatal screening performed with tandem mass spectrometry by an elevation of glutarylcarnitine. Where this is not done, timely diagnosis depends on the recognition of relatively nonspecific physical findings such as hypotonia, irritability, macrocephaly, on the detection of suggestive abnormalities in neuroimaging and on quantitative urinary organic acid analysis by gas chromatography--mass spectrometry.

A Treatable Neurometabolic Disorder: Glutaric Aciduria Type 1

“…GA-1 is inherited as an autosomal recessive trait and mutations of the GCDH gene on chromosome 19p13.2 [7]. Macrocephaly is a constant feature of GA-1 [1, 7].…”

“…Macrocephaly is a constant feature of GA-1 [1, 7]. The usual age of presentation for GA-1 is 6 months to 2 years of life [7, 8].…”

Glutaric aciduria type I: A rare metabolic disorder mimicking as choreoathetoid cerebral palsy

“…[7] Acute neuroregression following an initial phase of normal or almost normal development is a common mode of presentation, at times preceded by seizures. [5] The precipitating factors include febrile illness, immunization, mild head trauma, and starvation. [1] The other frequent presentation of GA I is a chronic encephalopathy associated with choreoathetosis or dystonia[4] often misdiagnosed as athetoid cerebral palsy.…”

“…[1] The other frequent presentation of GA I is a chronic encephalopathy associated with choreoathetosis or dystonia[4] often misdiagnosed as athetoid cerebral palsy. [5]…”

“…[3] This disorder is characterized by progressive extrapyramidal symptoms such as dystonia, dyskinesia, and choreoathetosis,[4] often misdiagnosed as athetoid cerebral palsy. [5]…”