Myopathic changes associated with psychomotor delay and seizures caused by a novel homozygous mutation in TBCK

Simona Saredi, Edmund S. Cauley, Alessandra Ruggieri, Tyler M. Spivey, Anna Ardissone, Marina Mora, Isabella Moroni, M. Chiara Manzini

Research output: Contribution to journalArticlepeer-review


Background: Biallelic mutations in TBC1-domain containing kinase (TBCK) lead to hypotonia, global developmental delay with severe cognitive and motor deficits, and variable presentation of dysmorphic facial features and brain malformations. It remains unclear whether hypotonia in these individuals is purely neurogenic, or also caused by progressive muscle disease. Methods: Whole exome sequencing was performed on a family diagnosed with nonspecific myopathic changes by means of histological analysis and immunohistochemistry of muscle biopsy samples. Results: A novel homozygous truncation in TBCK was found in two sisters diagnosed with muscle disease and severe psychomotor delay. TBCK was completely absent in these patients. Conclusions: Our findings identify a novel early truncating variant in TBCK associated with a severe presentation and add muscle disease to the variability of phenotypes associated with TBCK mutations. Inconsistent genotype/phenotype correlation could be ascribed to the multiple roles of TBCK in intracellular signaling and endolysosomal function in different tissues.

Original languageEnglish
Pages (from-to)266-271
Number of pages6
JournalMuscle and Nerve
Issue number2
Publication statusPublished - Aug 1 2020


  • encephalopathy
  • exome sequencing
  • hypotonia
  • mTOR signaling
  • muscle disease
  • TBCK

ASJC Scopus subject areas

  • Physiology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Physiology (medical)


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