Novel <i>CHKB</i> mutation expands the megaconial muscular dystrophy phenotype

Cabrera‐Serrano, Macarena; Junckerstorff, Reimar; Atkinson, Vanessa; Sivadorai, Padma; Allcock, Richard J. N.; Lamont, Phillipa; Laing, Nigel G.

doi:10.1002/mus.24446

Cited by 18 publications

(7 citation statements)

References 13 publications

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“…In congenital megaconial muscular dystrophy associated with CHKB variants, reports have suggested the possibility that inter-current vaccinations or anaesthesia can lead to deterioration in muscle or cardiac function; thus, extra caution is advised. 17 Lifestyle changes were advised in 6/43 (14%) cases, including sun protection against the potential complication of squamous cell carcinoma in a patient with a mutation in GJB2 or keratitis-ichthyosis-deafness syndrome. …”

Section: Resultsmentioning

confidence: 99%

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Exome sequencing for paediatric-onset diseases: impact of the extensive involvement of medical geneticists in the diagnostic odyssey

et al. 2018

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Currently, offering whole-exome sequencing (WES) via collaboration with an external laboratory is increasingly common. However, the receipt of a WES report can be merely the beginning of a continuing exploration process rather than the end of the diagnostic odyssey. The laboratory often does not have the information the physician has, and any discrepancies in variant interpretation must be addressed by a medical geneticist. In this study, we performed diagnostic WES of 104 patients with paediatric-onset genetic diseases. The post-exome review of WES reports by the clinical geneticist led to a more comprehensive assessment of variant pathogenicity in 16 cases. The overall diagnostic yield was 41% (n = 43). Among these 43 diagnoses, 51% (22/43) of the pathogenic variants were nucleotide changes that have not been previously reported. The time required for the post-exome review of the WES reports varied, and 26% (n = 27) of the reports required an extensive amount of time (>3 h) for the geneticist to review. In this predominantly Chinese cohort, we highlight the importance of discrepancies between global and ethnic-specific frequencies of a genetic variant that complicate variant interpretation and the significance of post-exome diagnostic modalities in genetic diagnosis using WES. The challenges faced by geneticists in interpreting WES reports are also discussed.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Exome sequencing for paediatric-onset diseases: impact of the extensive involvement of medical geneticists in the diagnostic odyssey

et al. 2018

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“…CHKB mediated muscular dystrophy presents as a rostral-to-caudal gradient and is often accompanied by neonatal hypotonia, global developmental delays without brain malformation, ichthyosis-like changes of skin, and dilated cardiomyopathy. In affected muscle, there are mitochondrial structural changes including enlarged mitochondria at the periphery of muscle fibers and loss of mitochondria at the center [8,[11][12][13][14][15][16][17][18].…”

Section: Mutations In the First Step Of The Cdpcholine Pathway For Pcmentioning

confidence: 99%

Genetic diseases of the Kennedy pathways for membrane synthesis

Tavasoli

Lahire

Reid

et al. 2020

Journal of Biological Chemistry

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The two branches of the Kennedy pathways (CDP-choline and CDP-ethanolamine) are the predominant pathways responsible for the synthesis of the most abundant phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively, in mammalian membranes. Recently, hereditary diseases associated with single gene mutations in the Kennedy pathways have been identified. Interestingly, genetic diseases within the same pathway vary greatly, ranging from muscular dystrophy to spastic paraplegia to a childhood blinding disorder to bone deformations. Indeed, different point mutations in the same gene (PCYT1; CCTα) result in at least three distinct diseases. In this review article, we will summarize and review the genetic diseases associated with mutations in genes of the Kennedy pathway for phospholipid synthesis. These single gene disorders provide insight, indeed direct genotype-phenotype relationships, into the biological functions of specific enzymes of the Kennedy pathway. We discuss potential mechanisms of how mutations within the same pathway can cause disparate disease.

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“…Differential expression patterns [116,117], mitochondrial activity [118], and neuromuscular junctions [119] are all effects of ChoKβ deficiency in mice. Inactivating mutations in the CHKB gene have been linked to human muscular dystrophy and myopathy in several recent studies [11,[120][121][122][123][124][125][126][127][128]. Since a lack of ChoKβ activity causes muscular dystrophy, any intervention that restores ChoKβ activity can help to restore normal muscle development in this pathological situation.…”

Section: Choks More Than Metabolism Enzymes?mentioning

confidence: 99%

Choline Kinase: An Unexpected Journey for a Precision Medicine Strategy in Human Diseases

Lacal

Zimmerman²,

Campos

2021

Pharmaceutics

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Choline kinase (ChoK) is a cytosolic enzyme that catalyzes the phosphorylation of choline to form phosphorylcholine (PCho) in the presence of ATP and magnesium. ChoK is required for the synthesis of key membrane phospholipids and is involved in malignant transformation in a large variety of human tumours. Active compounds against ChoK have been identified and proposed as antitumor agents. The ChoK inhibitory and antiproliferative activities of symmetrical bispyridinium and bisquinolinium compounds have been defined using quantitative structure–activity relationships (QSARs) and structural parameters. The design strategy followed in the development of the most active molecules is presented. The selective anticancer activity of these structures is also described. One promising anticancer compound has even entered clinical trials. Recently, ChoKα inhibitors have also been proposed as a novel therapeutic approach against parasites, rheumatoid arthritis, inflammatory processes, and pathogenic bacteria. The evidence for ChoKα as a novel drug target for approaches in precision medicine is discussed.

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Novel CHKB mutation expands the megaconial muscular dystrophy phenotype

Abstract: Pathological features broaden the description of the entity and provide new insight in the pathogenic mechanisms. This case highlights the usefulness of next-generation sequencing in the diagnosis of rare and incompletely understood conditions.

Cited by 18 publications

References 13 publications

Exome sequencing for paediatric-onset diseases: impact of the extensive involvement of medical geneticists in the diagnostic odyssey

Exome sequencing for paediatric-onset diseases: impact of the extensive involvement of medical geneticists in the diagnostic odyssey

Genetic diseases of the Kennedy pathways for membrane synthesis

Choline Kinase: An Unexpected Journey for a Precision Medicine Strategy in Human Diseases

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