What began as a clinical mystery in two child patients ended up connecting the metabolism of an important neurotransmitter with the metabolism of nucleosides (building blocks of genetic material) as well as maintenance of the mitochondrial genome in a single gene called ABAT, said researchers led by those at Baylor College of Medicine in a report that appears online in the journal Cell Metabolism.

“We found a novel function for this gene in the cell,” said Dr. Penelope Bonnen, assistant professor of molecular and human genetics at Baylor and corresponding author of the report.

The revelation began when Dr. Seema Lalani, associate professor of molecular and human genetics at Baylor and a clinical geneticist at Texas Children’s Hospital, sequenced the genome of a child with intractable seizures and muscle dysfunction and found a mutation in the ABAT gene. While this was the not the first time disease was associated with ABAT, it took a team to understand how this gene mutation caused the full range of clinical problems in this child and her similarly affected brother. The children had severe neurological dysfunction, seizures that did not improve in response to medication, and poor muscle tone and twitches or over responsive reflexes.

Bonnen and her colleagues took an interdisciplinary approach involving cutting edge functional genomics and molecular genetics to find that ABAT is not only responsible for the metabolism of GABA, a critical neurotransmitter, but it is essential also in maintaining the integrity of the mitochondrial genome.

“It has two independent functions, and both are necessary for the cell,” said Bonnen. “This discovery gives us a fuller understanding of the clinical problems of the children.”

Many drugs used to treat seizures target the GABAergic system, and one used in the most serious syndromes is called Vigabatrin. It is a drug of last resort because it can adversely affect the eye and vision, but there are some individuals whose seizures do not improve with any other medication.

 “We feel strongly that the action of this gene in maintenance of the mitochondrial genome is a compelling candidate to evaluate as a cause of this side effect,” said Bonnen.  If it is a cause, the side effect might be alleviated by giving patients nucleoside supplements. This study lays the groundwork for future animal or human experiments, she said.

Others who took part in this work include Arnaud Besse; Ping Wu; Taraka Donti; Brett H. Graham; William J. Craigen; Paolo Moretti; Seema Lalani and Kenneth L. Scott, all of Baylor and Francesco Bruni, Robert McFarland and Robert W. Taylor, all of the Medical School, Newcastle University at Newcastle upon Tyne in the United Kingdom.

Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (R01NS083726.) Funding for this work also came from the Texas Norman Hackerman Advanced Research Program (THECB 19 02006; NHARP proposal number 0049-0041-2009); Wellcome Trust Strategic Award (096919/Z/11/Z); the MRC Centre for Neuromuscular Diseases (G0601943); the Lily Foundation and the UK NHS Highly Specialized “Rare Mitochondrial Disorders of Adults and Children” Service and the Cytometry and Cell Sorting Core at Baylor with funding from the NIH (AI036211, CA125123, and RR024574).