Pediatric researchers, using high-speed DNA sequencing tools, have identified a new syndrome that causes intellectual disability (ID). Drawing on knowledge of the causative gene mutation, the scientists’ cell studies suggest that an amino acid supplement may offer a targeted treatment for children with this condition.
“Intellectual disability is a common diagnosis, but it includes many different diseases, with multiple genetic causes, and few targeted therapies,” said first author Elizabeth Bhoj, M.D., Ph.D., a Genetics fellow in the Center for Applied Genomics (CAG) at The Children’s Hospital of Philadelphia (CHOP). “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.”
An international team of scientists from five countries collaborated on the study, published online March 31 in the American Journal of Human Genetics. The study’s senior author, Hakon Hakonarson, M.D., Ph.D., is director of the CAG at CHOP.
The study team analyzed DNA samples from 13 affected children from nine unrelated families, along with DNA from the children’s healthy parents. There were four pairs of affected siblings. All the children had developmental delays, ranging from moderate to severe, and all had hypotonia (low muscle tone). Five of the children had seizures.
Although the clinical symptoms varied among the children, all had mutations in one gene, TBCK (for TBC1-domain-containing kinase), found when the CAG performed whole-exome sequencing. The research built on a 2015 discovery by Saudi scientists who identified TBCK as playing a role in a family with ID.
The parents of all 13 children were healthy, but carried the same gene change found in their affected children, who inherited the recessive trait–one copy from each parent. The researchers propose naming the condition TBCK-related ID syndrome.
The TCBK gene codes for the TBCK protein, which in turn helps to regulate signals along a biological pathway called the mTOR pathway. Abnormal mTOR signaling is already known to play a role in brain abnormalities, epilepsy, autism and ID.
In the current research, the study team showed that cells from the affected children had lower levels of mTOR signaling and of the TCBK protein. However, when the researches added leucine, an amino acid that acts along the mTOR pathway, to cell cultures, they measured an increase mTOR signaling in the patients’ cells.
“This raises the possibility that treating affected children with leucine supplements could relieve some of their symptoms,” said Bhoj. She compared this to the clinical use of dietary modifications for patients with phenylketonuria (PKU), a long-recognized genetic condition identified in routine newborn screening. In that condition, protein-restricted diets and supplements prevent brain damage.
Pending further research, added Bhoj, a next step will be to perform a pilot study to test the effects of leucine supplements in children identified 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,” said Hakonarson, who added, “Such molecular phenotyping can help clarify disease relationships and inform future treatments, in keeping with our precision medicine focus.”
About this genetics research
Funding: Funds from the National Institutes of Health (grant TR000003), and the Institute for Translational Medicine and Therapeutics of the University of Pennsylvania partly supported this research.
Source: John Ascenzi – Children’s Hospital of Philadelphia Image Credit: The image is in the public domain. Original Research: Abstract for “Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia” by Elizabeth J. Bhoj, Dong Li, Margaret Harr, Shimon Edvardson, Orly Elpeleg, Elizabeth Chisholm, Jane Juusola, Ganka Douglas, Maria J. Guillen Sacoto, Karine Siquier-Pernet, Abdelkrim Saadi, Christine Bole-Feysot, Patrick Nitschke, Alekhya Narravula, Maria Walke, Michele B. Horner, Debra-Lynn Day-Salvatore, Parul Jayakar, Samantha A. Schrier Vergano, Mark A. Tarnopolsky, Madhuri Hegde, Laurence Colleaux, Peter Crino, and Hakon Hakonarson in American Journal of Human Genetics. Published online March 31 2016 doi:10.1016/j.ajhg.2016.03.016
Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia
Through an international multi-center collaboration, 13 individuals from nine unrelated families and affected by likely pathogenic biallelic variants in TBC1-domain-containing kinase (TBCK) were identified through whole-exome sequencing. All affected individuals were found to share a core phenotype of intellectual disability and hypotonia, and many had seizures and showed brain atrophy and white-matter changes on neuroimaging. Minor non-specific facial dysmorphism was also noted in some individuals, including multiple older children who developed coarse features similar to those of storage disorders. TBCK has been shown to regulate the mammalian target of rapamycin (mTOR) signaling pathway, which is also stimulated by exogenous leucine supplementation. TBCK was absent in cells from affected individuals, and decreased phosphorylation of phospho-ribosomal protein S6 was also observed, a finding suggestive of downregulation of mTOR signaling. Lastly, we demonstrated that activation of the mTOR pathway in response to L-leucine supplementation was retained, suggesting a possible avenue for directed therapies for this condition.
“Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia” by Elizabeth J. Bhoj, Dong Li, Margaret Harr, Shimon Edvardson, Orly Elpeleg, Elizabeth Chisholm, Jane Juusola, Ganka Douglas, Maria J. Guillen Sacoto, Karine Siquier-Pernet, Abdelkrim Saadi, Christine Bole-Feysot, Patrick Nitschke, Alekhya Narravula, Maria Walke, Michele B. Horner, Debra-Lynn Day-Salvatore, Parul Jayakar, Samantha A. Schrier Vergano, Mark A. Tarnopolsky, Madhuri Hegde, Laurence Colleaux, Peter Crino, and Hakon Hakonarson in American Journal of Human Genetics. Published online March 31 2016 doi:10.1016/j.ajhg.2016.03.016