Phenotypic prediction in glutaric aciduria type 1 combining in silico and in vitro modeling with real‐world data

Yuan, Yuheng; Dimitrov, Bianca; Boy, Nikolas; Gleich, Florian; Zielonka, Matthias; Kölker, Stefan

doi:10.1002/jimd.12618

Cited by 5 publications

(5 citation statements)

References 83 publications

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“…Pathogenic variants tend to cluster around important structural domains of GCDH protein, such as the FAD and substrate binding domain, with amino acid changes in their vicinity correlating with HE and symptomatic clinical phenotypes (Schuurmans et al 2023). Previous studies had discovered a shared characteristic among variants with residual activities exceeding 10% that they were not located at the binding sites of FAD or the alternative substrate NBC (Yuan et al 2023). This distribution is similar to that observed in adult-onset GA-1.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and genotypic characteristics of adult-onset glutaric aciduria type 1: report of two cases and a literature review

Li,

Xie,

Zhu

et al. 2023

Preprint

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Glutaric aciduria type 1 (GA-1) is an autosomal recessive inherited disorder caused by GCDH variations. GA-1 is a rare disease that typically manifests in infancy and early childhood, with adult-onset cases being even rarer. Currently, data on the clinical and genetic characteristics of adult-onset GA-1 remains limited. We hereby reported two new cases of adult-onset GA-1 and systematically summarized reported studies to investigate its genotypic and phenotypic features. Patient 1 presented with seizures as the onset symptom. Patient 2 exhibited recurrent stroke-like episodes. Brain magnetic resonance imaging showed subependymal lesions. Urine organic acid analyses were performed since both patients had hyperhomocysteinemia (HHcy) and found significantly elevated glutaric acid and 3-hydroxyglutaric acid. Genetic analysis further identified four missense variants in the GCDH gene (c.937C > T, c.383G > A, c.533G > A, c.1205G > A). A literature review found seven cases and 12 variants in adult-onset GA-1. Most of them showed nonspecific neurological manifestations. The most common symptoms were cognitive impairment and headache. Subependymal lesions have been reported in 5/7 cases. One of them also had HHcy. All adult-onset GA-1 cases were high excretors. A common feature of the 12 variants was that they spared the binding site of flavin adenine dinucleotide or 4-nitrobutyryl-CoA. This study characterized the phenotype of adult-onset GA-1 emphasizing subependymal lesions and the coexistence of HHcy. The latter might suggest the influence of environmental factors on the age of onset. No clear phenotype-genotype correlation was found. However, the variants in adult-onset GA-1 mainly affect the non-active binding regions.

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Section: Discussionmentioning

confidence: 99%

Phenotypic and genotypic characteristics of adult-onset glutaric aciduria type 1: report of two cases and a literature review

Li,

Xie,

Zhu

et al. 2023

Preprint

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“…Several functional studies were reviewed in order to obtain an overview of functional assays used. Multiple investigators performed in vitro GCDH enzyme activity analysis in heterologous cells (E. coli or COS-7) [9,11,27]. Furthermore, a considerable number of studies addressed the additional potential impact of missense variants on GCDH function [28][29][30][31][32].…”

Section: Functional Datamentioning

confidence: 99%

“…A GA-1 diagnosis can then be confirmed by molecular genetic analysis of the GCDH gene. However, a correlation between genotype and clinical course of the disease has not been established so far [3,5,[9][10][11][12]. If the patient does not want genetic analysis or if the analysis fails to detect two biallelic pathogenic GCDH variants, GCDH enzyme activity in leukocytes or fibroblasts can be analyzed to confirm the diagnosis [13].…”

Section: Introductionmentioning

confidence: 99%

Compilation of Genotype and Phenotype Data in GCDH-LOVD for Variant Classification and Further Application

Tibelius,

Evers,

Oeser

et al. 2023

Genes

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Glutaric aciduria type 1 (GA-1) is a rare but treatable autosomal-recessive neurometabolic disorder of lysin metabolism caused by biallelic pathogenic variants in glutaryl-CoA dehydrogenase gene (GCDH) that lead to deficiency of GCDH protein. Without treatment, this enzyme defect causes a neurological phenotype characterized by movement disorder and cognitive impairment. Based on a comprehensive literature search, we established a large dataset of GCDH variants using the Leiden Open Variation Database (LOVD) to summarize the known genotypes and the clinical and biochemical phenotypes associated with GA-1. With these data, we developed a GCDH-specific variation classification framework based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. We used this framework to reclassify published variants and to describe their geographic distribution, both of which have practical implications for the molecular genetic diagnosis of GA-1. The freely available GCDH-specific LOVD dataset provides a basis for diagnostic laboratories and researchers to further optimize their knowledge and molecular diagnosis of this rare disease.

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“…Moreover, it was demonstrated by in silico score modeling that highly pathogenic variants are significantly correlated with lower residual enzyme activity [7]. Despite these associations, no clear correlation between the clinical phenotype and genotype has been established [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1

Barroso,

Gertzen,

Puchwein-Schwepcke

et al. 2023

IJMS

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Glutaric acidemia type 1 (GA1) is a neurotoxic metabolic disorder due to glutaryl-CoA dehydrogenase (GCDH) deficiency. The high number of missense variants associated with the disease and their impact on GCDH activity suggest that disturbed protein conformation can affect the biochemical phenotype. We aimed to elucidate the molecular basis of protein loss of function in GA1 by performing a parallel analysis in a large panel of GCDH missense variants using different biochemical and biophysical methodologies. Thirteen GCDH variants were investigated in regard to protein stability, hydrophobicity, oligomerization, aggregation, and activity. An altered oligomerization, loss of protein stability and solubility, as well as an augmented susceptibility to aggregation were observed. GA1 variants led to a loss of enzymatic activity, particularly when present at the N-terminal domain. The reduced cellular activity was associated with loss of tetramerization. Our results also suggest a correlation between variant sequence location and cellular protein stability (p < 0.05), with a more pronounced loss of protein observed with variant proximity to the N-terminus. The broad panel of variant-mediated conformational changes of the GCDH protein supports the classification of GA1 as a protein-misfolding disorder. This work supports research toward new therapeutic strategies that target this molecular disease phenotype.

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Phenotypic prediction in glutaric aciduria type 1 combining in silico and in vitro modeling with real‐world data

Cited by 5 publications

References 83 publications

Phenotypic and genotypic characteristics of adult-onset glutaric aciduria type 1: report of two cases and a literature review

Phenotypic and genotypic characteristics of adult-onset glutaric aciduria type 1: report of two cases and a literature review

Compilation of Genotype and Phenotype Data in GCDH-LOVD for Variant Classification and Further Application

Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1

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