Conservation of central nervous system glutaryl-coenzyme A dehydrogenase in fruit-eating bats with glutaric aciduria and deficient hepatic glutaryl-coenzyme A dehydrogenase.

McMillan, Tara; Gibson, K. Michael; Sweetman, Lawrence; Meyers, G. S.; Green, Ralph

doi:10.1016/s0021-9258(19)77829-6

Cited by 15 publications

(8 citation statements)

References 22 publications

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“…In a series of transplantation experiments, we demonstrated that hepatic lysine catabolism directly affects the accumulation of toxic catabolites in the brain in both directions (reduction or increase in catabolites) in the absence of functional lysine catabolism in the brain. These results are notable, given the previously described fruit bat ( 17 ) and liver-specific GA-1 mouse model ( 5 ), which both have GCDH deficiency in the liver but do not have any disease symptoms or accumulation of catabolites in the brain. We reproduced the same results when generating a liver-specific GA-1 mouse model with our TIRF strain.…”

Section: Discussionmentioning

confidence: 60%

Rescue of glutaric aciduria type I in mice by liver-directed therapies

et al. 2023

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Glutaric aciduria type I (GA-1) is an inborn error of metabolism with a severe neurological phenotype caused by the deficiency of glutaryl–coenzyme A dehydrogenase (GCDH), the last enzyme of lysine catabolism. Current literature suggests that toxic catabolites in the brain are produced locally and do not cross the blood-brain barrier. In a series of experiments using knockout mice of the lysine catabolic pathway and liver cell transplantation, we uncovered that toxic GA-1 catabolites in the brain originated from the liver. Moreover, the characteristic brain and lethal phenotype of the GA-1 mouse model was rescued by two different liver-directed gene therapy approaches: Using an adeno-associated virus, we replaced the defective Gcdh gene or we prevented flux through the lysine degradation pathway by CRISPR deletion of the aminoadipate-semialdehyde synthase ( Aass ) gene. Our findings question the current pathophysiological understanding of GA-1 and reveal a targeted therapy for this devastating disorder.

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Section: Discussionmentioning

confidence: 60%

Rescue of glutaric aciduria type I in mice by liver-directed therapies

et al. 2023

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“…These findings indicate a significant impact of the excretor phenotype on the progressive white matter changes and cognitive function of GA1 patients 140 . In contrast, postmortem studies showed the extensive accumulation of cerebral GA and 3‐OH‐GA to not differ between HE and LE individuals 23–27 . This can be explained by intracerebral entrapment due limited permeability of the blood–brain barrier and de novo synthesis of toxic metabolites, 28 which is in line with a similarly high a priori risk of developing an encephalopathic crisis and striatal damage with subsequent MD 6,11 .…”

Section: Discussionmentioning

confidence: 85%

“…Intriguingly, postmortem studies did not show differences in cerebral GA and 3‐OH‐GA concentrations between both biochemically defined groups 23–26 . Furthermore, naturally occurring animal models of hepatic GCDH deficiency lack a neurologic phenotype 27 . These findings suggest that the cerebral accumulation of these dicarboxylic acids is independent from the residual GCDH activity measured in fibroblasts, and from the concentration of GA and 3‐OH‐GA in blood and urine.…”

Section: Introductionmentioning

confidence: 81%

Exploring genotype–phenotype correlations in glutaric aciduria type 1

Schuurmans

Dimitrov

Schröter

et al. 2023

J of Inher Metab Disea

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Glutaric aciduria type 1 (GA1) is a rare neurometabolic disease caused by pathogenic variants in the gene encoding the enzyme glutaryl-CoA dehydrogenase (GCDH). We performed an extensive literature search to collect data on GA1 patients, together with unpublished cases, to provide an up-to-date genetic landscape of GCDH pathogenic variants and to investigate potential genotypephenotype correlation, as this is still poorly understood. From this search, 421 different GCDH pathogenic variants have been identified, including four novel variants; c.179T>C (p.Leu60Pro), c.214C>T (p.Arg72Cys), c.309G>C (p.Leu103Phe), and c.665T>C (p.Phe222Ser).The variants are mostly distributed across the entire gene; although variant frequency in GA1 patients is relatively high in the regions encoding for active domains of GCDH. To investigate potential genotype-phenotype correlations, phenotypic descriptions of 532 patients

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“…61 This notion has been supported by cerebral GA and 3-OH-GA concentrations in postmortem studies 62 and the lack of a neurologic phenotype in naturally occurring or transgenic animal models with hepatic GCDH deficiency. 61,63 Based on the knowledge derived from these observations in clinical prospective and preclinical studies, all GA1 patients should receive the same metabolic treatment, while therapeutic stratification according to the biochemical subtype is not recommended. 14 However, long-term observational studies have recently highlighted apparent differences between the two biochemical subgroups, but the clinical relevance remains to be elucidated: When compared with LE, HE patients show more frequent white matter abnormalities and increased intracerebral concentrations of neurotoxic metabolites, 64 pronounced extrastriatal abnormalities, 65 a larger head circumference, 66 less favorable cognitive outcome, 67 and increased risk of developing subdural effusion during the first 3 years of life, 68 despite early diagnosis and, in contrast to the risk for developing striatal injury, independent from adherence to dietary treatment recommendations.…”

Section: Glutaric Aciduria Typementioning

confidence: 99%

How guideline development has informed clinical research for organic acidurias (et vice versa)

Forny

Hörster

Baumgartner

et al. 2023

J of Inher Metab Disea

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Organic acidurias, such as glutaric aciduria type 1 (GA1), methylmalonic (MMA), and propionic aciduria (PA) are a prominent group of inherited metabolic diseases involving accumulation of eponymous metabolites causing endogenous intoxication. For all three conditions, guidelines for diagnosis and management have been developed and revised over the last years, resulting in three revisions for GA1 and one revision for MMA/PA. The process of clinical guideline development in rare metabolic disorders is challenged by the scarcity and limited quality of evidence available. The body of literature is often fragmentary and where information is present, it is usually derived from small sample sizes. Therefore, the development of guidelines for GA1 and MMA/PA was initially confronted with a poor evidence foundation that hindered formulation of concrete recommendations in certain contexts, triggering specific research projects and initiation of longitudinal, prospective observational studies using patient registries. Reversely, these observational studies contributed to evaluate the value of newborn screening, phenotypic diversities, and treatment effects, thus significantly improving the quality of evidence and directly influencing formulation and evidence levels of guideline recommendations. Here, we present insights into interactions between guideline development and (pre)clinical research for GA1 and MMA/PA, and demonstrate how guidelines gradually improved from revision to revision. We describe how clinical studies help to unravel the relative impact of therapeutic interventions on outcome and conclude that despite new and better quality of research data over the last decades, significant shortcomings of evidence regarding prognosis and treatment remain. It appears that development of clinical guidelines can directly help to guide research, and vice versa.

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Conservation of central nervous system glutaryl-coenzyme A dehydrogenase in fruit-eating bats with glutaric aciduria and deficient hepatic glutaryl-coenzyme A dehydrogenase.

Cited by 15 publications

References 22 publications

Rescue of glutaric aciduria type I in mice by liver-directed therapies

Rescue of glutaric aciduria type I in mice by liver-directed therapies

Exploring genotype–phenotype correlations in glutaric aciduria type 1

How guideline development has informed clinical research for organic acidurias (et vice versa)

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