Severity of Gene Mutation in Friedreich’s Ataxia Linked in Study to Glucose Tolerance

The severity of abnormal glucose regulation in people with Friedreich’s ataxia (FA) is linked to the extent of their genetic mutation, according to researchers at The Children’s Hospital of Philadelphia — a finding that might deepen understanding of disrupted glucose metabolism in FA patients.

The genetic mutation underlying Friedreich’s ataxia is composed of repeats of three DNA bases, GAA, in the starting sequence of the gene coding for the protein frataxin. The mutations cause low levels of the protein, and studies have shown that the extent of the repeats on the shorter of the two gene copies is mirrored by the person’s age at disease onset as well as disease severity.

In addition to classical symptoms, such as loss of reflexes, sensation, and coordination, as well as difficulties with walking, some 10 percent to 30 percent of Friedreich’s ataxia patients develop diabetes. This is a direct consequence of disrupted frataxin functions in insulin-producing pancreatic cells.

The study, “Effects of Genetic Severity on Glucose Homeostasis in Friedreich Ataxia,” explored if the number of GAA repeats had an impact on the severity of glucose intolerance in 42 people with Friedreich’s ataxia and 10 healthy controls.

Results revealed that 36 percent of FAA patients were pre-diabetic and, compared to controls, secreted more insulin even while displaying more resistance to its actions. The length of the GAA repeats could predict the severity of glucose metabolism disruption, assessed by the disposition index, a measure derived by multiplying insulin release with sensitivity.

Findings, published in the journal Muscle and Nerve, indicate that the genetic mutations affect glucose metabolism on a systemic level, altering cells’ sensitivity to insulin, producing resistance and glucose intolerance.

Researchers also compared measurements of insulin sensitivity and glucose tolerance in intravenous and oral assessments, and found that in many aspects, oral evaluation mirrored the intravenous results. This was, however, not true for all types of measurements, as the disposition index showed a poor agreement between intravenous and oral assessments.

While the findings show a link between glucose metabolism and genetic severity, other factors, such as hemoglobin or genetic modifiers of metabolic functions, likely impact glucose metabolism in patients with Friedreich’s ataxia.