A team of researchers at CFRI, CMMT, BC Children’s, and UBC have uncovered a genetic cause of excess ammonia in the blood of newborns, increasing the chances that children can be treated before suffering permanent brain damage.

Hyperammonemia, a medical emergency affecting between 1/8,000 to 1/44,000 infants, results from the body’s inability to detoxify by-products of converting proteins into energy. The treatment varies according to the cause, but determining the origin of each case is often a challenge — it could be a rare genetic condition, an infection, or an adverse reaction to other medication, each with its own particular remedy.

Dr. Clara van Karnebeek collaborated with colleagues to perform genomics studies on four children with hyperammonemia in B.C., the U.K. and Australia. Her team discovered a new cause of hyperammonemia: a mutation in a previously undescribed gene that encodes carbonic anhydrase VA, a liver enzyme that plays an essential role in energy production and detoxification.

Dr. van Karnebeek’s findings, published February 13 in the American Journal of Human Genetics, also demonstrated that this form of hyperammonemia – which manifests itself shortly after birth – can be treated effectively.

Carglumic acid, already used to treat other genetically-caused forms of hyperammonemia, is costly and difficult to obtain. So the standard response — until now — was to use it only when cheaper treatments failed or lab tests confirmed the cause through a genetic analysis or detection of a particular biomarker pattern in the infant’s blood. This process can take days, even weeks, during which irreversible brain damage can occur.

“Until now, deficiency of the carbonic anhydrase VA enzyme would not be recognized in a child with hyperammonemia, because this condition wasn’t known,” says Dr. van Karnebeek, an associate member of the Centre for Molecular Medicine and Therapeutics; CFRI associate clinician scientist; clinical assistant professor in the Division of Biochemical Diseases in the UBC Department of Pediatrics; medical director of the Complex Diagnostic Clinic at BC Children’s Hospital; and principal investigator for the gene discovery study in the Treatable Intellectual Disability Endeavor in BC (TIDE BC) initiative at BC Children’s Hospital.

“Now we can screen for it, and if we find the enzyme deficiency, we know what to do,” says Dr. van Karnebeek. “For the treatable forms of intellectual disability, time is ticking – the longer you wait, the more the brain is damaged. We want to identify it early and treat the patient to make a difference.”

“We’re hoping that with publication of this article, other provinces — and physicians around the world — will be quicker to think of this new genetic condition and try carglumic acid,” says Dr. van Karnebeek.

Individuals with this newly-discovered mutation are susceptible to hyperammonemia whenever they are in situations of high energy consumption, such as when they are battling infections or experiencing growth spurts. Whenever the condition threatens to recur, they must be put on a special diet; in case of hyperammonemia, carglumic acid must be administered to prevent brain damage.

Since identifying this enzyme deficiency and the corresponding treatment for this rare type of hyperammonemia, the Biochemical Diseases team at BC Children’s Hospital was able to arrange funding and shipment of carglumic acid to a small hospital in rural B.C. for a family whose siblings are affected by this newly-discovered genetic condition.

This study is part of the TIDE-BC (Treatable Intellectual Disability Endeavour in British Columbia) project at BC Children’s Hospital (Collaborative Area of Innovation initiative) supported with funding from BC Children’s Hospital Foundation, BC Clinical Genomics Network, the Rare Diseases Foundation, and the National Institutes of Health.

The TIDE-BC initiative is led by Dr. Sylvia Stockler, Head, Biochemical Diseases at BC Children’s Hospital and UBC and CFRI clinical investigator. The research team includes Dr. Wyeth Wasserman, CFRI Executive Director and UBC associate dean, research, CFRI: CMMT and CFRI scientist, and UBC Professor of Medical Genetics and Dr. Colin Ross, CFRI scientist and assistant professor; UBC Department of Pediatrics; and Genotyping Leader, BC Clinical Genomics Network. Dr. Ramona Salvarinova and Dr. Graham Sinclair of BC Children’s Hospital had key roles with this project, which included a collaboration with Dr. William Sly at St. Louis University.

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