Mutation Analysis of the GCDH Gene in Italian and Portuguese Patients with Glutaric Aciduria Type I

Busquets, Concepció Gotzens; Soriano, María de la Vieja; Almeida, Isabel Tavares de; Garavaglia, Barbara; Rimoldi, M.; Rivera, Isabel; Uziel, Graziella; Cabral, Aguinaldo; Coll, MJ; Ribes, Antònia

doi:10.1006/mgme.2000.3082

Cited by 21 publications

(16 citation statements)

References 6 publications

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“…Exceptions are P18S (all residues in MCAD numbering) in very long chain acyl-CoA dehydrogenase (32); F27S in GCDH that packs against residues at positions 61 and 83 (33); and G70S and Gl4C in short chain acyl-CoA dehydrogenase that are essential for local folding and therefore shape of the Leu␤ 195 binding pocket (34,35). Mutation of the stop codon to Trp in GCDH (36) leads to an extended C terminus. This is expected to obstruct ETF binding, because additional polypeptide would occupy the space normally populated by the FAD domain.…”

Section: Resultsmentioning

confidence: 99%

Extensive Domain Motion and Electron Transfer in the Human Electron Transferring Flavoprotein·Medium Chain Acyl-CoA Dehydrogenase Complex

Toogood

Thiel

Basran

et al. 2004

Journal of Biological Chemistry

137

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The crystal structure of the human electron transferring flavoprotein (ETF)⅐medium chain acyl-CoA dehydrogenase (MCAD) complex reveals a dual mode of protein-protein interaction, imparting both specificity and promiscuity in the interaction of ETF with a range of structurally distinct primary dehydrogenases. ETF partitions the functions of partner binding and electron transfer between (i) the recognition loop, which acts as a static anchor at the ETF⅐MCAD interface, and (ii) the highly mobile redox active FAD domain. Together, these enable the FAD domain of ETF to sample a range of conformations, some compatible with fast interprotein electron transfer. Disorders in amino acid or fatty acid catabolism can be attributed to mutations at the protein-protein interface. Crucially, complex formation triggers mobility of the FAD domain, an induced disorder that contrasts with general models of protein-protein interaction by induced fit mechanisms. The subsequent interfacial motion in the MCAD⅐ETF complex is the basis for the interaction of ETF with structurally diverse protein partners. Solution studies using ETF and MCAD with mutations at the protein-protein interface support this dynamic model and indicate ionic interactions between MCAD Glu 212 and ETF Arg␣ 249 are likely to transiently stabilize productive conformations of the FAD domain leading to enhanced electron transfer rates between both partners.

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Section: Resultsmentioning

confidence: 99%

Extensive Domain Motion and Electron Transfer in the Human Electron Transferring Flavoprotein·Medium Chain Acyl-CoA Dehydrogenase Complex

Toogood

Thiel

Basran

et al. 2004

Journal of Biological Chemistry

137

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“…A correlation of genotype with biochemical phenotype has been reported in GA1, whereas as yet no correlation of either genotype or biochemical phenotype with clinical phenotype is known [2, 38, 39]. High excretors show a complete loss of GCDH activity in contrast to up to 30% residual enzyme capacity in low excretors who predominantly carry missense mutations on at least one GCDH allele [5, 39]. Without treatment high- and low-excretors have a similar risk of developing striatal damage and dystonia which determine clinical outcome [2].…”

Section: Discussionmentioning

confidence: 99%

Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

Boy

Heringer

Brackmann

et al. 2017

Orphanet J Rare Dis

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BackgroundWithout neonatal initiation of treatment, 80–90% of patients with glutaric aciduria type 1 (GA1) develop striatal injury during the first six years of life resulting in a complex, predominantly dystonic movement disorder. Onset of motor symptoms may be acute following encephalopathic crisis or insidious without apparent crisis. Additionally, so-called late-onset GA1 has been described in single patients diagnosed after the age of 6 years. With the aim of better characterizing and understanding late-onset GA1 we analyzed clinical findings, biochemical phenotype, and MRI changes of eight late-onset patients and compared these to eight control patients over the age of 6 years with early diagnosis and start of treatment.ResultsNo late-onset or control patient had either dystonia or striatal lesions on MRI. All late-onset (8/8) patients were high excretors, but only four of eight control patients. Two of eight late-onset patients were diagnosed after the age of 60 years, presenting with dementia, tremor, and epilepsy, while six were diagnosed before the age of 30 years: Three were asymptomatic mothers identified by following a positive screening result in their newborns and three had non-specific general symptoms, one with additional mild neurological deficits. Frontotemporal hypoplasia and white matter changes were present in all eight and subependymal lesions in six late-onset patients. At comparable age a greater proportion of late-onset patients had (non-specific) clinical symptoms and possibly subependymal nodules compared to control patients, in particular in comparison to the four clinically and MR-wise asymptomatic low-excreting control patients.ConclusionsWhile clinical findings are non-specific, frontotemporal hypoplasia and subependymal nodules are characteristic MRI findings of late-onset GA1 and should trigger diagnostic investigation for this rare disease. Apart from their apparent non-susceptibility for striatal injury despite lack of treatment, patients with late-onset GA1 are not categorically different from early treated control patients. Differences between late-onset patients and early treated control patients most likely reflect greater cumulative neurotoxicity in individuals remaining undiagnosed and untreated for years, even decades as well as the higher long-term risk of high excretors for intracerebral accumulation of neurotoxic metabolites compared to low excretors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-017-0612-6) contains supplementary material, which is available to authorized users.

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“…Molecular analyses of the GCDH gene in peripheral blood DNA from the patients and their children were performed as described [4].…”

Section: Methodsmentioning

confidence: 99%

Outcome of three cases of untreated maternal glutaric aciduria type I

Garcia¹,

Martins

Diogo³

et al. 2007

Eur J Pediatr

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We report, for the first time, the outcome of three children born to two women with untreated glutaric aciduria type I (GA I). Isolated hypocarnitinemia in neonatal screening in one baby allowed the identification of the disease in his mother, who was undiagnosed so far and had had a previous daughter. The other baby was born to an already diagnosed mother who was not treated; newborn screening in the child reflected the metabolic state of the mother. Biochemical abnormalities returned to normal within one week. At the age of 4 months, neuroimaging showed Sylvian enlargement in both infants and bilateral temporal arachnoid cysts in one. Physical and neurological developments were normal for the three patients at ages 2 and 5 years. We conclude that long-term follow up will determine the true impact of GA I in such children.

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Mutation Analysis of the GCDH Gene in Italian and Portuguese Patients with Glutaric Aciduria Type I

Cited by 21 publications

References 6 publications

Extensive Domain Motion and Electron Transfer in the Human Electron Transferring Flavoprotein·Medium Chain Acyl-CoA Dehydrogenase Complex

Extensive Domain Motion and Electron Transfer in the Human Electron Transferring Flavoprotein·Medium Chain Acyl-CoA Dehydrogenase Complex

Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity

Outcome of three cases of untreated maternal glutaric aciduria type I

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