Adenylosuccinate lyase deficiency in a Malaysian patient, with novel adenylosuccinate lyase gene mutations

Chen, Bee Chin; McGown, Ivan; Thong, Meow‐Keong; Pitt, James; Yunus, Zabedah Md; Khoo, Teck Beng; Ngu, Lock Hock; Duley, John A.

doi:10.1007/s10545-010-9056-z

Cited by 13 publications

(9 citation statements)

References 16 publications

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“…Another reported missense ADSL (c.71C > T, p.P24L) [58] mutation which was inherited from her unaffected father were scored as uncertain pathogenicity. ADSL has been reported to be related to adenylosuccinate lyase deficiency, which is an autosomal recessive defect of purine metabolism [59, 60]. The patient presented with spasms 2 months after birth.…”

Section: Resultsmentioning

confidence: 99%

Novel and de novo mutations in pediatric refractory epilepsy

et al. 2018

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Pediatric refractory epilepsy is a broad phenotypic spectrum with great genetic heterogeneity. Next-generation sequencing (NGS) combined with Sanger sequencing could help to understand the genetic diversity and underlying disease mechanisms in pediatric epilepsy. Here, we report sequencing results from a cohort of 172 refractory epilepsy patients aged 0–14 years. The pathogenicity of identified variants was evaluated in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria. We identified 43 pathogenic or likely pathogenic variants in 40 patients (23.3%). Among these variants, 74.4% mutations (32/43) were de novo and 60.5% mutations (26/43) were novel. Patients with onset age of seizures ≤12 months had higher yields of deleterious variants compared to those with onset age of seizures > 12 months (P = 0.006). Variants in ion channel genes accounted for the greatest functional gene category (55.8%), with SCN1A coming first (16/43). 81.25% (13/16) of SCN1A mutations were de novo and 68.8% (11/16) were novel in Dravet syndrome. Pathogenic or likely pathogenic variants were found in the KCNQ2, STXBP1, SCN2A genes in Ohtahara syndrome. Novel deleterious variants were also found in West syndrome, Doose syndrome and glucose transporter type 1 deficiency syndrome patients. One de novo MECP2 mutation were found in a Rett syndrome patient. TSC1/TSC2 variants were found in 60% patients with tuberous sclerosis complex patients. Other novel mutations detected in unclassified epilepsy patients involve the SCN8A, CACNA1A, GABRB3, GABRA1, IQSEC2, TSC1, VRK2, ATP1A2, PCDH19, SLC9A6 and CHD2 genes. Our study provides novel insights into the genetic origins of pediatric epilepsy and represents a starting-point for further investigations into the molecular pathophysiology of pediatric epilepsy that could eventually lead to better treatments.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0392-5) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Novel and de novo mutations in pediatric refractory epilepsy

et al. 2018

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“…Since this assay can result in false positives, the diagnosis must be confirmed, usually by high performance liquid chromatography (HPLC) [1, 3, 4, 5] followed by genomic and/or cDNA sequencing and characterization of the recombinant mutant proteins [6]. So far, 68 patients with 49 mutations leading to ADSL deficiency have been found (http://udmp.lf1.cuni.cz/adsl) [7, 8, 9, 10, 11, 12]. A majority of the identified mutations represent missense mutations, although in some cases, promoter mutations or splice site mutations leading to a truncated protein have been reported [2, 3, 13, 14].…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of the AdeI mutant of Chinese hamster ovary cells: A cellular model of adenylosuccinate lyase deficiency

Vliet

Wilkinson

Duval

et al. 2011

Molecular Genetics and Metabolism

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Adenylosuccinate lyase (ADSL, E. C. 4.3.2.2) carries out two non-sequential steps in de novo AMP synthesis, the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) to aminoimidazolecarboxamide ribotide (AICAR) and the conversion of succinyl AMP (AMPS) to AMP. In humans, mutations in ADSL lead to an inborn error of metabolism originally characterized by developmental delay, often with autistic features. There is no effective treatment for ADSL deficiency. Hypotheses regarding the pathogenesis include toxicity of high levels of SAICAR, AMPS, or their metabolites, deficiency of the de novo purine biosynthetic pathway, or lack of a completely functional purine cycle in muscle and brain. One important approach to understand ADSL deficiency is to develop cell culture models that allow investigation of the properties of ADSL mutants and the consequences of ADSL deficiency at the cellular level. We previously reported the isolation and initial characterization of mutants of Chinese hamster ovary (CHO-K1) cells (Ade I) that lack detectable ADSL activity, accumulate SAICAR and AMPS, and require adenine for growth. Here we report the cDNA sequences of ADSL from CHO-K1 and Ade I cells and describe a mutation resulting in an alanine to valine amino acid substitution at position 291 (A291V) in Ade I ADSL. This substitution lies in the "signature sequence" of ADSL, inactivates the enzyme, and validates Ade I as a cellular model of ADSL deficiency. Keywordsadenylosuccinate lyase deficiency; Chinese hamster ovary cells; inborn errors; cell culture models

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“…In 2010, Chen et al . firstly reported two novel ADSL mutations in a Malaysian patient 17 . Here, we firstly reported three novel ADSL mutations in Chinese, which will expand the spectrum of mutations in ADSL in Asian.…”

Section: Discussionmentioning

confidence: 97%

Novel mutations in ADSL for Adenylosuccinate Lyase Deficiency identified by the combination of Trio-WES and constantly updated guidelines

Mao

Tang

et al. 2017

Sci Rep

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Whole-exome sequencing (WES), one of the next-generation sequencing (NGS), has become a powerful tool to identify exonic variants. Investigating causality of the sequence variants in human disease becomes an important part in NGS for the research and clinical applications. Recently, important guidelines on them have been published and will keep on updating. In our study, two Chinese families, with the clinical diagnosis of “Epilepsy”, which presented with seizures, psychomotor retardation, hypotonia and etc. features, were sequenced by Trio-WES (including the proband and the unaffected parents), and a standard interpretation of the identified variants was performed referring to the recently updated guidelines. Finally, we identified three novel mutations (c.71 C > T, p.P24L; c.1387-1389delGAG, p.E463-; c.134 G > A, p.W45*; NM_000026) in ADSL in the two Chinese families, and confirmed them as the causal variants to the disease-Adenylosuccinate Lyase Deficiency. Previous reported specific therapy was also introduced to the patients after our refined molecular diagnosis, however, the effect was very limited success. In summary, our study demonstrated the power and advantages of WES in exploring the etiology of human disease. Using the constantly updated guidelines to conduct the WES study and to interpret the sequence variants are a necessary strategy to make the molecular diagnosis and to guide the individualized treatment of human disease.

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Adenylosuccinate lyase deficiency in a Malaysian patient, with novel adenylosuccinate lyase gene mutations

Cited by 13 publications

References 16 publications

Novel and de novo mutations in pediatric refractory epilepsy

Novel and de novo mutations in pediatric refractory epilepsy

Molecular characterization of the AdeI mutant of Chinese hamster ovary cells: A cellular model of adenylosuccinate lyase deficiency

Novel mutations in ADSL for Adenylosuccinate Lyase Deficiency identified by the combination of Trio-WES and constantly updated guidelines

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