Neurology Central

Newly-discovered syndrome causing intellectual disability identified

The findings of an international, multi-center study, published recently in the American Journal of Human Genetics, have provided evidence that a syndrome resulting from a mutation in the TBCK gene may cause intellectual disability (ID) in children. The study also points to a potential targeted therapy for the newly-discovered syndrome.

“ID is a common diagnosis, but it includes many different diseases, with multiple genetic causes, and few targeted therapies,” remarked Elizabeth Bhoj from the Center for Applied Genomics (CAG) at The Children’s Hospital of Philadelphia (CHOP, PA, USA). “This study may represent an early step toward the types of precision medicine treatment that may become more common as we draw on genomic research.”

The current study comprised a cohort of 13 ID-affected children from nine unrelated families. DNA of all ID-affected study participants, as well as their parents (all unaffected by ID), was examined.

Although variation in clinical symptoms was observed amongst the ID-affected children – for example, developmental delays (ranging from moderate to severe), hypotonia and seizures, as well as brain atrophy and white-matter changes on neuroimaging – whole-exome sequencing determined that all possessed mutations in one key gene – termed TBCK. Researchers have nominated TBCK-related ID syndrome as a potential name for the disorder.

TBCK was first identified by a research group in Saudi Arabia in 2015, where they discovered its role in a single family with ID. In the current study, all parents were found to be carriers of the gene mutation, which is inherited as a recessive trait  by the affected children.

The TBCK protein regulates signaling in the highly important cellular mTOR pathway. Disruptions in mTOR signaling are already known to be a contributing factor to brain abnormalities, autism, epilepsy and ID.

TBCK was observed to be absent from the cells of ID-affected individuals within the cohort in the current study,.  Phosphorylation of phosphoribosomal protein S6 was also decreased, suggesting downregulation of mTOR signaling.

The mTOR pathway is known to be stimulated by exogenous leucine supplementation. Following this line of investigation, researchers demonstrated that the mTOR pathway in ID-affected individuals was stimulated and retained following L-leucine supplementation.

These findings offer the potential for focused therapies, directly impacting the pathogenic effects of the TBCK gene mutation.

“This raises the possibility that treating affected children with leucine supplements could relieve some of their symptoms,” commented Bhoj.

Further work is envisaged in the form of a pilot study to investigate the effects of taking leucine supplements on children with TBCK-related ID syndrome.

“This work highlights how modern genetic approaches can uncover disease-causing variants in phenotypically heterogeneous samples that involve the same gene and molecular pathway,” remarked senior author Hakon Hakonarson (CHOP), adding, “Such molecular phenotyping can help clarify disease relationships and inform future treatments, inkeeping with our precision medicine focus.”

Sources: The Children’s Hospital of America press release; Bhoj EJ, Li D, Harr M 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; doi:10.1016/j.ajhg.2016.03.016 (2016) (Epub ahead of print).