Genetic discovery helps prevent brain damage in newborns with hyperammonemia


Dr. Clara van Karnebeek

Dr. Clara van Karnebeek, Clinical Assistant Professor in the Division of Biochemical Diseases in the Department of Pediatrics, has 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 one in 1,000 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. 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 in the American Journal of Human Genetics, (van Karnebeek et al.,  Mitochondrial Carbonic Anhydrase VA Deficiency Resulting from CA5A Alterations Presents with Hyperammonemia in Early Childhood, The American Journal of Human Genetics (2014), demonstrate that this form of hyperammonemia, manifesting shortly after birth, can be treated effectively.

Carglumic acid, costly and difficult to obtain, is used to treat other genetically-caused forms of hyperammonemia.  Until now, the standard response was to use carglumic acid only when less expensive treatments failed or lab tests confirmed the cause through a genetic analysis or detection of a particular biomarker pattern in the infant’s blood. As this process can take days, even weeks, irreversible brain damage can occur.

“Until now, deficiency of the carbonic anhydrase VA enzyme would not be recognized in a child with hyerpammonemia, because this condition wasn’t known,” said Dr. van Karnebeek, an Associate Member of the Centre for Molecular Medicine and Therapeutics, Associate Clinician Scientist at the Child and Family Research Institute, and Principal Investigator for the gene discovery study in the Treatable Intellectual Disability Endeavor in BC (TIDE BC) at BC Children’s Hospital. “Now we can screen for it, and if we find the enzyme deficiency, we know what to do. These children no longer have to languish in neo-natal intensive care units without proper treatment.”

“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,” said Dr. van Karnebeek, who collaborated with Wyeth Wasserman, a UBC Professor of Medical Genetics, and William Sly, a Professor of Biochemistry and Molecular Biology at St. Louis University.

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.