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Glutaric Acidemia Type 1: An Inherited Neurometabolic Disorder of Intoxication

  • Living reference work entry
  • First Online:
Handbook of Neurotoxicity

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Abstract

Glutaric acidemia type 1 (GA 1) is an inherited neurometabolic disease of intoxication caused by absent (high excretors) or deficient (low excretors) activity of glutaryl-CoA dehydrogenase, which is involved in lysine, hydroxylysine, and tryptophan degradation. The biochemical hallmark of this disease is the accumulation of the neurotoxic organic acids glutaric acid and 3-hydroxyglutaric acid in tissues, particularly in the brain, as well as in biological fluids. Disease presentation usually occurs acutely in most patients during infancy (early or infantile onset), although insidious- and late-onset variants manifest during childhood or adulthood. Infantile-onset untreated children predominantly manifest with acute life-threatening encephalopathy associated with irreversible striatum degeneration that is followed by a complex movement disorder. GA 1 is a treatable disease when diagnosed early by newborn screening, but in places without this facility, patients are identified after symptom onset, presenting irreversible basal ganglia lesions, motor disabilities, and high mortality. Otherwise, despite early diagnosis and immediate treatment, about 25% of affected individuals develop long-term irreversible cerebral complications, as well as kidney failure and other systemic disabilities, whose pathophysiology is not yet fully established. Therefore, further investigation on the mechanisms underlying brain and kidney damage is needed to enable the development of novel therapeutic strategies. This chapter focuses on the current knowledge of GA 1, including the molecular defect, epidemiology, clinical features, diagnosis, management, short-term and long-term neurological and systemic outcome, and recent advances in its pathophysiology. The major objective is to alert neurologists and neuroscientists to this disease.

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Abbreviations

3HGA :

3-Hydroxyglutaric acid

3-MGH:

3-Methylglutaconyl-CoA hydratase

C5DC :

Glutarylcarnitine

CAT:

L-Carnitine acyltransferase

CSF:

Cerebrospinal fluid

GA :

Glutaric acid

GA 1:

Glutaric acidemia type 1 or glutaric aciduria type 1

GC/MS:

Gas chromatography coupled to mass spectrometry

GCDH :

Glutaryl-CoA dehydrogenase

MCAD :

Medium-chain acyl-CoA dehydrogenase

MRI :

Magnetic resonance imaging

MS/MS :

Tandem mass spectrometry

NBS :

Newborn screening

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Authors and Affiliations

  1. Department of Biochemistry, Institute of Basic Sciences and Health, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil

    Moacir Wajner

  2. Medical Genetics Service, Clinical Hospital of Porto Alegre, Porto Alegre, RS, Brazil

    Moacir Wajner

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  1. Moacir Wajner
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  1. Department of Biomedical Sciences, East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Wajner, M. (2021). Glutaric Acidemia Type 1: An Inherited Neurometabolic Disorder of Intoxication. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-030-71519-9_202-1

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  • DOI: https://doi.org/10.1007/978-3-030-71519-9_202-1

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