Diagnosis and management of glutaric aciduria type I – revised recommendations

Abstract

Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-011-9289-5) contains supplementary material, which is available to authorized users.

Rare Late-Onset Presentation of Glutaric Aciduria Type I in a 16-Year-Old Woman with a Novel GCDH Mutation

“…Glutaric aciduria type I is an autosomal recessive neurometabolic disease that is classified among the cerebral organic acid disorders, a subgroup of organic acid disorders, where the central nervous system (CNS) is predominantly and severely affected (Strauss et al 2003;K€ olker et al 2011, 2013. It is an inborn error of lysine, hydroxylysine, and tryptophan metabolism (Strauss et al 2003;K€ olker et al 2011).…”

“…It is an inborn error of lysine, hydroxylysine, and tryptophan metabolism (Strauss et al 2003;K€ olker et al 2011). Its pathophysiological basis is glutaryl-CoA dehydrogenase deficiency that results in accumulation of organic acids, such as GA and 3OHGA, that share structural and functional similarities with glutamate, in the CNS where they are believed to exert neurotoxic, gliotoxic, and myelinotoxic effects by several pathomechanisms, involving excitotoxic neuronal and oligodendroglial injury, dysregulation of mitochondrial energy production, and oxidative stress (Strauss et al 2003;K€ olker et al 2008.…”

“…GCDH is a homotetramer mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and carbon dioxide (Strauss et al 2003). Clinical presentation with acute encephalopathic crises in infancy or early childhood (typically between 6 and 18 months) often triggered by febrile illness resulting in striatal degeneration and severe dystonic-dyskinetic movement disorder is common, but insidious-onset, late-onset, or slowly progressive cases have also been described (Strauss et al 2003;K€ olker et al 2011;Kyllerman et al 1994). In presymptomatic patients, macrocephaly at birth or developing in the first months of life, wide Sylvian fissures and expansion of anterior frontotemporal CSF spaces are characteristic findings (Strauss et al 2003;K€ olker et al 2011;Kyllerman et al 1994;Gitiaux et al 2008;Oguz et al 2005).…”

“…Thus increased urinary concentrations of 3OHGA is the most sensitive and specific biochemical marker of GA-I (Al-Dirbashi et al 2011). The diagnosis is confirmed by GCDH enzyme assay in fibroblasts or leucocytes and molecular genetic analysis (Strauss et al 2003;K€ olker et al 2011). Prenatal or newborn screening and presymptomatic evaluation of asymptomatic siblings are essential for early diagnosis and treatment and prevention of striatal necrosis and permanent neurological sequelae (Strauss et al 2003;K€ olker et al 2011).…”

“…The diagnosis is confirmed by GCDH enzyme assay in fibroblasts or leucocytes and molecular genetic analysis (Strauss et al 2003;K€ olker et al 2011). Prenatal or newborn screening and presymptomatic evaluation of asymptomatic siblings are essential for early diagnosis and treatment and prevention of striatal necrosis and permanent neurological sequelae (Strauss et al 2003;K€ olker et al 2011). Currently, treatment consists of lysine-restricted diet and carnitine supplementation and prompt symptomatic and anticatabolic treatment of intercurrent illness (K€ olker et al 2006a, 2012).…”