Somatic mosaicism for a novel PDHA1 mutation in a male with severe pyruvate dehydrogenase complex deficiency

Deeb, Kristin K.; Bedoyan, Jirair K.; Wang, Raymond; Sremba, Leighann; Schroeder, Molly C.; Grahame, George; Boyer, Monica; McCandless, Shawn E.; Kerr, Douglas S.; Zhang, Shulin

doi:10.1016/j.ymgmr.2014.08.001

Cited by 6 publications

(3 citation statements)

References 16 publications

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“…Mosaicism is increasingly recognized within pediatric neurology as a pathogenic mechanism in monogenic disorders (∼3% in neurodevelopmental disorders) (175,176). In PxMDs, mosaic variants have been reported in ATP1A3, ADCY5, SLC2A1 and PDHA1, (98,(177)(178)(179). In ADCY5, mosaicism is reported in 25-50% of cases, associated with a milder phenotype and symptoms may not be recognized (96,98).…”

Section: Mosaicismmentioning

confidence: 99%

Paroxysmal Movement Disorders

2021

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Paroxysmal movement disorders (PxMDs) are a clinical and genetically heterogeneous group of movement disorders characterized by episodic involuntary movements (dystonia, dyskinesia, chorea and/or ataxia). Historically, PxMDs were classified clinically (triggers and characteristics of the movements) and this directed single-gene testing. With the advent of next-generation sequencing (NGS), how we classify and investigate PxMDs has been transformed. Next-generation sequencing has enabled new gene discovery (RHOBTB2, TBC1D24), expansion of phenotypes in known PxMDs genes and a better understanding of disease mechanisms. However, PxMDs exhibit phenotypic pleiotropy and genetic heterogeneity, making it challenging to predict genotype based on the clinical phenotype. For example, paroxysmal kinesigenic dyskinesia is most commonly associated with variants in PRRT2 but also variants identified in PNKD, SCN8A, and SCL2A1. There are no radiological or biochemical biomarkers to differentiate genetic causes. Even with NGS, diagnosis rates are variable, ranging from 11 to 51% depending on the cohort studied and technology employed. Thus, a large proportion of patients remain undiagnosed compared to other neurological disorders such as epilepsy, highlighting the need for further genomic research in PxMDs. Whole-genome sequencing, deep-sequencing, copy number variant analysis, detection of deep-intronic variants, mosaicism and repeat expansions, will improve diagnostic rates. Identifying the underlying genetic cause has a significant impact on patient care, modification of treatment, long-term prognostication and genetic counseling. This paper provides an update on the genetics of PxMDs, description of PxMDs classified according to causative gene rather than clinical phenotype, highlighting key clinical features and providing an algorithm for genetic testing of PxMDs.

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Section: Mosaicismmentioning

confidence: 99%

Paroxysmal Movement Disorders

2021

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“…However, the use of supplemental techniques varies widely by laboratory and specific panel and is not typically evident to the ordering clinician; 3. Mosaicism has been described for ATP1A3 , ADCY5, SLC2A1, PDHA1, SCN1A and SCN2A gene mutations and is likely to be associated with other conditions in the future. Low‐level mosaicism may not be identified by Sanger and though mosaicism may be detected by WES or WGS, low‐level mosaicism may be excluded by filtering protocols.…”

Section: Resultsmentioning

confidence: 99%

Paroxysmal motor disorders: expanding phenotypes lead to coalescing genotypes

Zima

Ceulemans

Reiner

et al. 2018

Ann Clin Transl Neurol

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Paroxysmal movement disorders encompass varied motor phenomena. Less recognized features and wide phenotypic and genotypic heterogeneity are impediments to straightforward molecular diagnosis. We describe a family with episodic ataxia type 1, initially mis‐characterized as paroxysmal dystonia to illustrate this diagnostic challenge. We summarize clinical features in affected individuals to highlight underappreciated aspects and provide comprehensive phenotypic description of the rare familial KCNA1 mutation. Delayed diagnosis in this family is emblematic of the broader challenge of diagnosing other paroxysmal motor disorders. We summarize genotypic and phenotypic overlap and provide a suggested diagnostic algorithm for approaching patients with these conditions.

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“…The random X chromosome inactivation will lead to the selective expression of mutant genes and normal genes in different tissues. Therefore, the clinical manifestations of women are mainly determined by the lack of PDHc activity and the random X chromosome inactivation pattern (Deeb et al, 2014; Horga et al, 2019; Willemsen et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Clinical exome sequencing reveals a mutation in PDHA1 in Leigh syndrome: A case of a Chinese boy with lethal neuropathy

Gong

Xie

et al. 2021

Molec Gen & Gen Med

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Background Leigh syndrome, the most common mitochondrial syndrome in pediatrics, has diverse clinical manifestations and is genetically heterogeneous. Pathogenic mutations in more than 75 genes of two genomes (mitochondrial and nuclear) have been identified. PDHA1 encoding the E1 alpha subunit is an X‐chromosome gene whose mutations cause pyruvate dehydrogenase complex deficiency. Methods Here, we have described a 12‐year‐old boy with lethal neuropathy who almost died of a sudden loss of breathing and successive cardiac arrest. Extracorporeal membrane oxygenation rescued his life. His diagnosis was corrected from Guillain–Barré syndrome to Leigh syndrome 1 month later by clinical exome sequencing. Furthermore, we used software to predict the protein structure caused by frameshift mutations. We treated the boy with vitamin B1, coenzyme Q10, and a ketogenic diet. Results A PDHA1 mutation (NM_000284.4:c.1167_1170del) was identified as the underlying cause. The amino acid mutation was p.Ser390LysfsTer33. Moreover, the protein structure prediction results suggested that the protein structure has changed. The parents of the child were negative, so the mutation was de novo. The comprehensive assessment of the mutation was pathogenic. His condition gradually improved after receiving treatment. Conclusion This case suggests that gene detection should be popularized to improve diagnosis accuracy, especially in developing countries such as China.

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Somatic mosaicism for a novel PDHA1 mutation in a male with severe pyruvate dehydrogenase complex deficiency

Cited by 6 publications

References 16 publications

Paroxysmal Movement Disorders

Paroxysmal Movement Disorders

Paroxysmal motor disorders: expanding phenotypes lead to coalescing genotypes

Clinical exome sequencing reveals a mutation in PDHA1 in Leigh syndrome: A case of a Chinese boy with lethal neuropathy

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