Genetic Screening of Selected Disease-Causing Mutations in Glutaryl-CoA Dehydrogenase Gene among Indian Patients with Glutaric Aciduria Type I

Tp, Kruthika-Vinod; Shaik, Muntaj; Devaraju, K. S.; Kamate, Mahesh; Vedamurthy, A. B.

doi:10.1055/s-0037-1599202

Cited by 6 publications

(6 citation statements)

References 22 publications

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“…A systematic literature search was performed by the authors and conducted in PubMed for publications between January 2000 up to May 2022, that report GCDH variants in GA1 patients. For this search the following MeSH terms were used: “glutaric aciduria type 1,” “glutaric acidemia type 1,” “glutaric aciduria type I,” “glutaric acidemia type I,” “glutaryl‐CoA dehydrogenase deficiency,” and “GCDH” 30–107 . References from selected articles from before the year 2000 with complete description of GA1 patients were also included.…”

Section: Methodsmentioning

confidence: 99%

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 We performed an extensive literature search to collect data on GA1 patients, together with unpublished cases, to provide an up-to-date genetic landscape of GCDH pathogenic variants and to investigate potential genotypephenotype correlation, as this is still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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Section: Methodsmentioning

confidence: 99%

Exploring genotype–phenotype correlations in glutaric aciduria type 1

Schuurmans

Dimitrov

Schröter

et al. 2023

J of Inher Metab Disea

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“…V400M and R402W are both found in homozygous [17,35] and heterozygous [25] patients and represent the most common GCDH variants in the αDC domain [9,25]. V400M is strongly associated with a LE phenotype and high residual activity in heterozygotes [36,37], while R402W is one of the most severe common variants of GCDH [15,22]. GCDH activities as high as for M263V homozygotes (30% of control activity) have been reported for compound heterozygotes V400M and R227P [15,30].…”

Section: Selection and Mapping Of Gcdh Variants On The Crystallograph...mentioning

confidence: 99%

“…R402W is the most common variant in people from a Caucasian background, accounting for 10-20% of alleles [20,21]. Variants such as R227P (c.680G > C) and V400M (c.1198G > A) are associated with LE and are also prevalent in closed communities [22,23].…”

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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“…17 The other most commonly reported low excretor associated mutations are p.Arg227Pro and p. Val400Met. [17][18][19][20] Other variants have been noted in the context of low excretor patients; however, the strength of this association is less certain. In one paper showing 30 novel mutations, it was noted that p.Ala293Thr may potentially be associated with the low excretor phenotype as well as p.Gly178Arg and p.Arg88Ser; however, these have since been observed in a high excretor phenotype.…”

Section: Pathophysiologymentioning

confidence: 99%

“…7 This finding suggests that, for many variants, genotype is indicative rather than definitive of excretor type. Other variants which have been reported in the presence of a low excretor phenotype include p. Pro286Ser, 19 p.Leu221Pro, 1 p.Arg313Trp, p.Arg234Trp, 22 p.Arg88Cys, p.Phe236Leu, p.Ser259Pro, 23 p.Ser119Leu, p. Ala195Thr, and p.Tyr155His. 4 The literature currently supports the assertion that p.Arg227Pro and p.Val400Met and p.Met405Val are strongly associated with the low excretor phenotype, for many other variants, further data are needed.…”

Section: Pathophysiologymentioning

confidence: 99%

Low excretor glutaric aciduria type 1 of insidious onset with dystonia and atypical clinical features, a diagnostic dilemma

et al. 2020

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A 4‐year‐old girl was referred for reassessment of dyskinetic cerebral palsy. Initial investigations in her country of birth, India, had not yielded a diagnosis. MRI brain in infancy revealed bilateral putamen hyperintensity. She had generalized dyskinesia predominantly bulbar and limbs. Motor and speech development were most affected with preservation of cognitive development. There was no history of acute encephalopathic crisis or status dystonicus. Initial urine organic acids and amino acids and acylcarnitine profile (ACP) were normal. A dystonia genetic panel showed compound heterozygosity with a pathogenic variant and a variant of uncertain significance in the GCDH gene. The latter is hitherto undescribed and is indicative of a potential diagnosis of glutaric aciduria type 1 (alternatively glutaric acidemia type 1) (GA‐1), an autosomal recessive disorder of mitochondrial lysine/hydroxylysine and tryptophan metabolism. Repeat urine organic acids showed isolated slightly increased 3‐hydroxy glutarate excretion consistent with GA‐1 and characterizing the patient as a “low excretor,” a diagnostic sub‐group where diagnosis is more challenging but prognosis is similar. Repeat MRI Brain at age 4 showed volume loss and symmetric T2 hyperintensity in the posterior putamina bilaterally. This case highlights the diagnostic dilemma of GA‐1 where differing clinical courses, genetic variants, neuroradiological findings, and biochemical excretion patterns may lead to a later diagnosis. The presence of newborn screening for GA‐1 should not dull the clinician's suspicion of the possibility that GA‐1 may present with a complex movement disorder. Timely diagnosis and treatment is essential, as neurological sequelae are largely irreversible.

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Genetic Screening of Selected Disease-Causing Mutations in Glutaryl-CoA Dehydrogenase Gene among Indian Patients with Glutaric Aciduria Type I

Cited by 6 publications

References 22 publications

Exploring genotype–phenotype correlations in glutaric aciduria type 1

Exploring genotype–phenotype correlations in glutaric aciduria type 1

Glutaryl-CoA Dehydrogenase Misfolding in Glutaric Acidemia Type 1

Low excretor glutaric aciduria type 1 of insidious onset with dystonia and atypical clinical features, a diagnostic dilemma

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