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

Published:October 25, 2022DOI:https://doi.org/10.1016/j.nmd.2022.10.004

      Highlights

      • Hypoventilation has been reported in 46-83% of infants presenting with TBCK-related disorders.
      • Respiratory surveillance should be considered in the management of TBCK-related disorders.
      • TBCK-related disorders should be considered in infants with hypotonia, hypoventilation and white matter abnormalities on brain imaging.

      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

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      References

        • Liu Y
        • Yan X
        • Zhou T.
        TBCK influences cell proliferation, cell size and mTOR signaling pathway.
        PLoS One. 2013; 8: e71349
        • Ortiz-González XR
        • Tintos-Hernández JA
        • Keller K
        • Li X
        • Foley AR
        • Bharucha-Goebel DX
        • et al.
        Homozygous boricua TBCK mutation causes neurodegeneration and aberrant autophagy.
        Ann Neurol. 2018; 83: 153-165
      1. Tintos-Hernandez JA, Santana A, Keller KN, Ortiz-Gonzalez XR. Lysosomal dysfunction impairs mitochondrial quality control and predicts neurodegeneration in TBCKE. bioRxiv. 2020.

        • Chong JX
        • Caputo V
        • Phelps IG
        • Stella L
        • Worgan L
        • Dempsey JC
        • et al.
        Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy.
        Am J Hum Genet. 2016; 98: 772-781
        • Zapata-Aldana E
        • Kim DD
        • Remtulla S
        • Prasad C
        • Nguyen CT
        • Campbell C.
        Further delineation of TBCK - Infantile hypotonia with psychomotor retardation and characteristic facies type 3.
        Eur J Med Genet. 2019; 62: 273-277
        • Panitch HB.
        The pathophysiology of respiratory impairment in pediatric neuromuscular diseases.
        Pediatrics. 2009; 123: S215-S218
        • Beck-Wödl S
        • Harzer K
        • Sturm M
        • Buchert R
        • Rieß O
        • Mennel HD
        • et al.
        Homozygous TBC1 domain-containing kinase (TBCK) mutation causes a novel lysosomal storage disease - a new type of neuronal ceroid lipofuscinosis (CLN15)?.
        Acta Neuropathol Commun. 2018; 6: 145
        • Saredi S
        • Cauley ES
        • Ruggieri A
        • Spivey TM
        • Ardissone A
        • Mora M
        • et al.
        Myopathic changes associated with psychomotor delay and seizures caused by a novel homozygous mutation in TBCK.
        Muscle Nerve. 2020; 62: 266-271
        • Rahikkala E
        • Myllykoski M
        • Hinttala R
        • Vieira P
        • Nayebzadeh N
        • Weiss S
        • et al.
        Biallelic loss-of-function P4HTM gene variants cause hypotonia, hypoventilation, intellectual disability, dysautonomia, epilepsy, and eye abnormalities (HIDEA syndrome).
        Genet Med. 2019; 21: 2355-2363
        • Tesson C
        • Koht J
        • Stevanin G.
        Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology.
        Hum Genet. 2015; 134: 511-538
        • Di Lascio S
        • Benfante R
        • Di Zanni E
        • Cardani S
        • Adamo A
        • Fornasari D
        • et al.
        Structural and functional differences in PHOX2B frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome.
        Human mutation. 2018; 39: 219-236
        • AL-Buali M
        • Al Ramadhan S
        • Al Buali H
        • Al-Faraj J
        • Al Mohanna M.
        Progressive Encephalopathy and Central Hypoventilation Related to Homozygosity of NDUFV1 Nuclear Gene, a Rare Mitochondrial Disease.
        J Pediatr Child Care. 2019; 5: 05
        • Bhoj EJ
        • Li D
        • Harr M
        • Edvardson S
        • Elpeleg O
        • Chisholm E
        • et al.
        Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia.
        Am J Hum Genet. 2016; 98: 782-788
        • Saneto RP
        • Friedman SD
        • Shaw DW.
        Neuroimaging of mitochondrial disease.
        Mitochondrion. 2008; 8: 396-413
        • de la Cruz
        • López KG
        • Toledo Guzmán ME
        • Sánchez EO
        García Carrancá A. mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer.
        Front Oncol. 2019; 9: 1373
        • Aboussouan LS.
        Sleep-disordered Breathing in Neuromuscular Disease.
        Am J Respir Crit Care Med. 2015; 191: 979-989
        • Caruana-Montaldo B
        • Gleeson K
        • Zwillich CW
        The control of breathing in clinical practice.
        Chest. 2000; 117: 205-225