MONTRÉAL, June 4, 2018 – Primary dystonia, a neurological disorder involving painful, involuntary muscle contractions diagnosed in children, affects approximately 300,000 people in North America and, unfortunately, treatment options are limited. The cause of the muscle contractions remains poorly understood, but an international team of researchers has discovered a new gene responsible for the complex disorder. A recessive mutation in the VPS13D gene is thought to be involved. The findings were published in the Annals of Neurology in March 2018. Though causal mutations have already been associated with a variety of movement disorders, many patients still remain without a clear genetic diagnosis. This discovery paves the way to new avenues for treatment and a better understanding of the underlying disease mechanisms.

In order to achieve these results, the research team started by comparing the genetic data from two members of the same Québec family affected by primary dystonia who were under the care of Dr. Guy Rouleau at the Montreal Neurological Hospital and Dr. Inge Meijer at CHU Sainte-Justine. This led them to identify the VPS13D gene as a potential culprit. “We initially hypothesized that both patients had the same genetic defect in an area that plays an important role in the development of motor control. We wanted to show that a recessive mutation in the VPS13D gene, which has never been associated with a disease in humans, was involved,” says the study’s first author, Julie Gauthier, PhD. “The VPS13D gene intervenes in mitochondrial function. The role of mitochondria is to supply the body with energy. If this function is compromised in any way, it will impact energy-intensive systems, such as the neurones and muscles, says Dr. Philippe Campeau, the study’s senior author. Primary dystonia is a neurological disorder causing involuntary contractions that “freeze up” certain parts of the body or the body as a whole into a dystonic position.

With the support of an international network of clinicians and researchers who share an interest in the same gene(s) and conditions, the research team was able to identify four other families whose children were affected by muscle dystonia and mutations in the VPS13D gene. “These similar observations in five unrelated families supported our starting hypothesis,” says Julie Gauthier. “We were also able to observe other movement disorders in these same patients and a slow neurological deterioration before age 12, suggesting involvement of the VPS13D gene.” This clinical and genetic evidence led the researchers to consider mutations in the VPS13D gene to be the cause of a progressive neurological disorder characterized by a delay in motor development and movement disorder.

From now on, clinicians and health care professionals will be able to consider this gene when diagnosing not only primary dystonia but also other childhood-onset movement disorders, such as Leigh syndrome, spastic paraparesis and spastic ataxia. “The ability to confirm a diagnosis with a genetic screening test is very important when it comes to providing patients with the best possible care. We can modify or change a treatment based on the genetic diagnosis and better inform families on the disease prognosis,” says Dr. Inge Meijer. “Knowing that the disorder is genetic will make parents aware of the risk of passing it down should they wish to have other children.” 

“We now want to understand the role of this gene and defective protein in movement disorders in order to test drugs currently used to treat mitochondrial dysfunction,” says Dr. Inge Meijer.

From left to right: Dr. Philippe Campeau, Dr. Inge Meijer, Julie Gauthier, PhD, Nicole Richard, Jacques Richard, Jean-François Richard and Louis-Philippe Richard.

About the study

The article entitled “Recessive mutations in VPS13D cause childhood onset movement disorders” was published in the Annals of Neurology in March 2018. The study’s first author is Julie Gauthier, M.Sc., Ph.D., clinical specialist in molecular biology at the Molecular Diagnostic Laboratory, CHU Sainte-Justine. The study’s senior author is Philippe Campeau, M.D., medical geneticist, researcher and deputy head of the Musculoskeletal Diseases and Rehabilitation Department, CHU Sainte-Justine, and assistant clinical professor at the Department of Pediatrics, Université de Montréal.

Authors: Julie Gauthier, MSc, PhD, Inge A. Meijer, MD, PhD, Davor Lessel, MD, Niccolò E. Mencacci, MD, PhD, Dimitri Krainc, MD, PhD, Maja Hempel, MD, Konstantinos Tsiakas, MD, Holger Prokisch, PhD, Elsa Rossignol, MD, MSc, Margaret H. Helm, MSc, CGC, Lance H. Rodan, MD, Jason Karamchandani, MD, Miryam Carecchio, MD, PhD,  Steven J. Lubbe, MSc, PhD,  Aida Telegrafi, MS, CGC, Lindsay B. Henderson, PhD, FACMG, Kerry Lorenzo, MSc, CGC, Stephanie E Wallace, MD, Ian A Glass, MD, MB ChB, Fadi F. Hamdan, MSc, PhD, Jacques L. Michaud, MD, Guy A. Rouleau, MD, PhD, Philippe M. Campeau, MD

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