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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 79-80

Role of glutaric aciduria type 1 in movement disorders

Medicine Department, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil

Date of Submission23-Aug-2021
Date of Decision06-Sep-2021
Date of Acceptance15-Nov-2021
Date of Web Publication11-Feb-2022

Correspondence Address:
Dr. Jamir P Rissardo
Medicine Department, Federal University of Santa Maria, Rua Roraima, Santa Maria, Rio Grande do Sul
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/AOMD.AOMD_39_21

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How to cite this article:
Rissardo JP, Fornari Caprara AL. Role of glutaric aciduria type 1 in movement disorders. Ann Mov Disord 2022;5:79-80

How to cite this URL:
Rissardo JP, Fornari Caprara AL. Role of glutaric aciduria type 1 in movement disorders. Ann Mov Disord [serial online] 2022 [cited 2023 Mar 23];5:79-80. Available from: https://www.aomd.in/text.asp?2022/5/1/79/337584

Dear Editor,

We read the article entitled “Microencephaly in macrocephaly: Rare report of two siblings with glutaric aciduria type 1” by Agarwal et al., published in your esteemed journal Annals of Movement Disorders with great interest. The authors report the case of a 9-month-old individual presenting with dystonia and macrocephaly. Laboratory analysis revealed increased excretion of glutarylcarnitine and hydroxyglutaric acid (OHGA), which, along with the neuroimaging findings, suggested glutaryl-CoA dehydrogenase deficiency.[1] Their study was compelling because they described clinical features suggestive of glutaric aciduria type 1 with microencephalic macrocephaly that has rarely been reported in the literature.

In 2016, a task force by the International Parkinson and Movement Disorder Society reported recommendations for the nomenclature of genetic movement disorders. Among the genetic diseases listed, glutaric aciduria type 1 (OMIM#231670) was characterized as complex dystonia (predominant dystonia in a complex phenotypic presentation). The new designation/abbreviation for this genetic disease was DYT/CHOR-GCDH. In addition, the task force provided clinical clues to this disorder. For example, dystonia and chorea usually occur after acute metabolic crises, while  Parkinsonism More Details presents later in the disease course.[2]

Here, we wish to further discuss the pathophysiological mechanism of this organic aciduria. [Figure 1] presents a summary of the pathogenesis of the increased concentration of glutaric acid (GA) associated with high levels of lysine, hydroxylysine, and tryptophan.[3],[4]
Figure 1: Pathological mechanism of glutaric acidemia type 1. Blockage of Lys catabolism due to GCDH deficiency (1) leading to accumulation of GA and 3OHGA (2). GA inhibits the Krebs cycle and mitochondrial function (3) causing increased ROS (4). In the synaptic cleft, the high concentrations of GA and 3OHGA inhibit glutamate uptake (5). increasing glutamate availability. 3OHGA overstimulates AMPA and NMDA (6). This excitotoxic environment associated with changes in astrocyte function and astrogliosis leads to neuronal damage
Abbreviations: 3-OHGA, 3-hydroxyglutaric acid; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; GA, glutaric acid; GCDH, glutaryl-CoA dehydrogenase; GLUT, glutamate transporter; H-Lys, hydroxylysine; Lys, lysine; NMDA, N-methyl-d-aspartate; ROS, reactive oxygen species; Trp, tryptophan

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We believe that glutaric acidemia type 1 may be the most extensively studied organic aciduria, when regarding brain pathogenesis. A study by Wajner uses a well-known knockout mouse model that develops diffuse spongiform lesions when exposed to GA; lysine is subsequently given in high concentrations.[4] These procedures are performed to simulate the biochemical conditions of the human brain when glutaryl-CoA dehydrogenase is deficient. Furthermore, it is noteworthy that even before the development of this knockout model for glutaric acidemia type 1, protocols for experimental studies of epilepsy in rats, based on GA causing neuronal damage and consequently epilepsy, were already widely studied.[5]

Glutaryl-CoA dehydrogenase is encountered in presynaptic neuronal mitochondria, and its deficiency causes the accumulation of GA and 3-OHGA (GA-3OHGA). These two compounds get trapped inside the cerebral tissue due to low dicarboxylate transport efflux.[4] They can cause mitochondrial dysfunction, inhibiting the Krebs cycle and blocking the respiratory chain; this contributes to the production of reactive oxygen species. Moreover, GA-3OHGA can increase glutamate release in the synaptic membrane, stimulate glutamate receptors, and decrease glutamate uptake.[3] This excitotoxic environment activates microglia and astrocytes, leading to a pro-inflammatory state and damaging the neural tissue.

An interesting fact about this disease is that the lesions occur in specific areas of the brain. Garbade et al. reported the neuroradiological patterns of patients with glutaric aciduria type 1 using statistical models. They showed that individuals with movement disorders more frequently had abnormalities in the putamen, caudate, cortex, ventricles, and external cerebrospinal fluid spaces compared to individuals without or with minor neurological symptoms. Putaminal changes (r2 = 0.75) and strongly dilated ventricles (r2 = 0.79) were identified as the most reliable predictors of a movement disorder.[6] It is noteworthy that the location of the lesions could be explained by the abnormal movements reported among patients with specific stroke lesions.



Author contribution

JPR and ALFC contributed equally to this work. JPR contributed to research project: conception, organization, execution; Statistical analysis: design, execution, review, and critique; Manuscript preparation: writing of the first draft, review, and critique. ALFC contributed to research project: conception, organization, execution; Statistical analysis: design, execution, review, and critique; Manuscript preparation: writing of the first draft, review, and critique.

Ethical compliance statement

The authors confirm that neither informed patient consent nor the approval of an Institutional Review Board was necessary for this work. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

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Conflicts of interest

There authors have no conflicts of interest to declare.

  References Top

Agarwal A, Garg D, Agarwal S Microencephaly in macrocephaly: Rare report of two siblings with glutaric aciduria type 1. Ann Mov Disord 2021;4:42-45.  Back to cited text no. 1
Marras C, Lang A, van de Warrenburg BP, Sue CM, Tabrizi SJ, Bertram L, et al. Nomenclature of genetic movement disorders: Recommendations of the international Parkinson and movement disorder society task force. Mov Disord 2016;31:436-457.  Back to cited text no. 2
Singer HS, Mink JW, Gilbert DL, Jankovic J Inherited metabolic disorders with associated movement abnormalities. Movement Disorders in Childhood. 2nd ed. Philadelphia, PA: Saunders Elsevier. 2016, pp. 337-407.  Back to cited text no. 3
Wajner M Neurological manifestations of organic acidurias. Nat Rev Neurol 2019;15:253-271.  Back to cited text no. 4
Magni DV, Souza MA, Oliveira AP, Furian AF, Oliveira MS, Ferreira J, et al. Lipopolysaccharide enhances glutaric ­acid-induced seizure susceptibility in rat pups: behavioral and electroencephalographic approach. Epilepsy Res 2011;93:138-148.  Back to cited text no. 5
Garbade SF, Greenberg CR, Demirkol M, Gökçay G, Ribes A, Campistol J, et al. Unravelling the complex MRI pattern in glutaric aciduria type I using statistical models-a cohort study in 180 patients. J Inherit Metab Dis 2014;37:763-773.  Back to cited text no. 6


  [Figure 1]


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