Helped by artificial intelligence (AI) and advanced microscope technology, researchers at McMaster University have discovered a previously unknown neurodegenerative illness.

The findings were published in April in the journal Human Genome Variation, a forum for scientists researching important areas in human genetics.

The team, led by professors Mark Tarnopolsky and Ray Truant, examined the patient at the Neurometabolic and Neuromuscular Clinic of McMaster Children’s Hospital.

The study’s first author Siddharth Nath said the investigation took eight years. Tests conducted on a patient with a complex neurological disease first evaluated by Tarnopolsky in 2014 and enrolled in a “Care for Rare” whole exome sequencing research study that led to the discovery of a new type of ataxia, which affects ability to balance and move, triggered by mutations in two specific genes labelled TOP1MT and ATXN7, occurring at the same time.

The patient and the family kindly provided blood and skin samples and standard microscopy and biochemical tests were performed. Next, they ran a machine-learning algorithm on the microscopy images to detect cells with genetic mutations, which often cannot be picked up by the human eye using traditional scientific analysis.

Ataxia is a condition that impairs balance, co-ordination and muscle control and often worsens over time. The term covers a range of diseases that impair both muscle and nerve function.

“Our study provides the blueprint for other physicians to check for these specific genetic mutations, to determine if their difficult-to-diagnose patients may in fact have this novel spinocerebellar ataxia,” said Nath, currently an ophthalmology resident physician at McGill University, after completing his combined MD and PhD program at McMaster in 2020.

“Successful diagnosis is the first step towards developing a treatment and, eventually, a cure. Our study offers clinicians and researchers a way to help these vulnerable individuals,” he said.

“If you are a patient with a neurodegenerative condition, do not lose hope, as there are new discoveries being made every day and the pace of scientific research is unprecedented.”

Tarnopolsky, a professor of both medicine and pediatrics, said the study supports the value of genetic counselling that can not only lead to proper treatment but also end ‘diagnostic odysseys.’ This refers to patients who undergo multiple tests for illnesses that are difficult to detect through regular examinations, lab tests, or medical imaging.

Tarnopolsky said that a type of genetic analysis, called whole-exome sequencing, is increasingly common in tertiary care centres, such as Hamilton Health Sciences, in diagnosing genetic illnesses. Exomes are the coding region of the genes that make up the blueprints for proteins, important for normal functioning of the body’s cells.

He said the Care for Rare study has led to the Ontario Ministry of Health now offering exome sequencing as part of the genetic testing offered by provincial health-care providers.

“The human genome has many DNA variants, and we can find genetic variants in patients with complex neurological disorders, but we do not always know if they are causing the disease if new variants are found,” said Tarnopolsky.

“In this case, both the TOP1MT and the ATXN7 point mutations had not been seen together before and the project was to prove that these led to cell dysfunction and thus caused this novel cerebrospinal ataxia.”

Nath said other mutations in the ATXN7 gene can trigger the already-known spinocerebellar ataxia type 7.

Nath said AI and machine learning solutions can be successfully integrated into lab research, to investigate previously unknown neurodegenerative conditions.

Feeding images of cells into an AI algorithm sorted healthy and diseased cells into separate groups that allowed researchers to easily detect those with genetic defects.

However, Nath’s team also used traditional scientific methods to confirm their findings, by recreating the newly discovered genetic mutations in fruit flies.

“When melded with traditional science, AI presents clinicians and researchers with a methodology, unbiased and rooted in basic cell biology, which can be used across the spectrum of clinical medicine to reach diagnoses and translate findings from the clinic to the lab,” said Nath.

Ray Truant added: “It’s a modern example of how clinicians can reach out to basic university research labs for new technology when standard testing is not enough.

“This technology did not exist ten years ago. While this is a rare disease, it’s teaching us about more common neurodegenerative diseases, where we are also learning that DNA repair in old age is increasingly important.”

Nath said research projects like Care for Rare directly translate into better treatments for patients, adding that he felt privileged to see both these sides of the health sciences. As an ophthalmology resident, he often sees patients with diseases causing blindness.

“My biggest motivation in doing all of this is making a difference in the lives of my patients and finding ways to improve their quality of life,” said Nath.

“One must never lose sight of the human aspect.”



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