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Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome

Journal of Human Genetics volume 66, pages 813–823 (2021)Cite this article

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A Correction to this article was published on 26 March 2021

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Abstract

Megaconial congenital muscular dystrophy (CMD)(OMIM #602541), related to CHKB mutation, is a rare autosomal recessive disorder. To date, only 35 confirmed patients are recorded. We present a detailed description of the clinical, histopathological, imaging, and genetic findings of five children from four Indian families. The children had moderate-to-severe autistic behavior, hand stereotypies, and global developmental delay mimicking atypical Rett syndrome. In addition, generalized hypotonia was a common initial finding. The progression of muscle weakness was variable, with two patients having a milder phenotype and three having a severe form. Interestingly, the majority did not attain sphincter control. Only patient 1 had classical ichthyotic skin changes. Muscle biopsy in two patients showed a myopathic pattern with characteristic peripherally placed enlarged mitochondria on modified Gomori trichrome stain and electron microscopy. Genetic analysis in these patients identified three novel null mutations in CHKB [c.1027dupA (p.Ser343LysfsTer86);c.224 + 1G > T (5′ splice site); c.1123C > T (p.Gln375Ter)] and one reported missense mutation, c.581G > A (p.Arg194Gln), all in the homozygous state. Megaconial CMD, although rare, forms an important group with a complex phenotypic presentation and accounted for 5.5% of our genetically confirmed CMD patients. Atypical Rett syndrome-like presentation may be a clue towards CHKB-related disorder.

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Acknowledgements

We thank the patients and their families in this study.

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Author notes

  1. These authors contributed equally: Mainak Bardhan, Kiran Polavarapu.

Authors and Affiliations

  1. Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India

    Mainak Bardhan, Kiran Polavarapu, Preethish-Kumar Veeramani, Ram Murthy Anjanappa, Leena Shingavi, Seena Vengalil, Saraswati Nashi, Tanushree Chawla, Divya Nagabushana, Dhaarini Mohan & Atchayaram Nalini

  2. Children’s Hospital of Eastern Ontario Research Institute; Division of Neurology, Department of Medicine, The Ottawa Hospital; Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada

    Kiran Polavarapu

  3. Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru, India

    Nandeesh N. Bevinahalli

  4. Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bengaluru, India

    Gautham Arunachal

  5. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

    Rita Horvath MD,PhD

  6. Department of Neuromuscular Research, National Institute of Neuroscience, Tokyo, Japan

    Ichizo Nishino MD,PhD

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  1. Mainak Bardhan
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Correspondence to Atchayaram Nalini.

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Bardhan, M., Polavarapu, K., Bevinahalli, N.N. et al. Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome. J Hum Genet 66, 813–823 (2021). https://doi.org/10.1038/s10038-021-00913-1

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