Expanding the phenotype of children presenting with hypoventilation with biallelic TBCK pathogenic variants and literature review

Saraswathy Sabanathan; Deepti Gulhane; Kshitij Mankad; James Davison; Min Tsui Ong; Rahul Phadke; Robert Robinson; Michael Spiller; Emma Wakeling; Sithara Ramdas; Angela F Brady; Meena Balasubramanian; Pinki Munot

doi:10.1016/j.nmd.2022.10.004

Expanding the phenotype of children presenting with hypoventilation with biallelic TBCK pathogenic variants and literature review

Neuromuscul Disord. 2023 Jan;33(1):50-57. doi: 10.1016/j.nmd.2022.10.004. Epub 2022 Oct 25.

Authors

Affiliations

¹ Department of Neurosciences, Evelina Children's Hospital, London, UK.
² Department of Neurology, Great Ormond Street Hospital NHS Trust, London, UK.
³ Department of neuroradiology, Great Ormond Street Hospital NHS Trust, London, UK.
⁴ Department of Metabolic Medicine, Great Ormond Street Hospital NHS Trust, London, UK.
⁵ Department of Neurology, Sheffield Children's Hospital NHS Foundation Trust, London, UK.
⁶ Department of Neuropathology, Institute of Neurology, Queen Square, London, UK.
⁷ Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
⁸ North East Thames Regional Genetic Service, Great Ormond Street Hospital NHS Trust, London, UK.
⁹ MDUK neuromuscular centre, Department of Paediatrics, University of Oxford, UK; Department of Paediatric Neurology, John Radcliffe Hospital, Oxford, UK.
¹⁰ North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Middlesex, HA1 3UJ, UK.
¹¹ Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK; Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK. Electronic address: m.balasubramanian@sheffield.ac.uk.
¹² Department of Neurology, Great Ormond Street Hospital NHS Trust, London, UK. Electronic address: Pinki.Munot@gosh.nhs.uk.

PMID: 36522252
DOI: 10.1016/j.nmd.2022.10.004

Abstract

Individuals with biallelic TBCK pathogenic variants present in infancy with distinctive facial features, profound hypotonia, severe intellectual impairment and epilepsy. Although rare, it may mimic other neurogenetic disorders leading to extensive investigations. Improved understanding of the clinical phenotype can support early monitoring of complications due to respiratory insufficiency. We present six individuals who were found to have pathogenic biallelic TBCK variants. The clinico-radiological and diagnostic records were reviewed. Five individuals were diagnosed with hypoventilation, requiring respiratory support, highlighting the need for early respiratory surveillance. Characteristic brain imaging in our cohort included periventricular leukomalacia-like changes. We recommend screening for TBCK in hypotonic children with periventricular leukomalacia-like changes, particularly in the absence of prematurity.

Keywords: Hypotonia; Hypoventilation; Neurodevelopmental disorder; TBCK.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Brain
Child
Humans
Hypoventilation / diagnosis
Hypoventilation / genetics
Leukomalacia, Periventricular*
Phenotype
Protein Serine-Threonine Kinases* / genetics

Substances

Protein Serine-Threonine Kinases
TBCK protein, human