Shorter tips on chromosomes linked with cardiomyopathy in FA patients
These telomeres are protective stretches of DNA at the ends of chromosomes
Cardiomyopathy in people with Friedreich’s ataxia (FA) significantly associated with a shortening of chromosomal telomeres —  the “tips” of chromosomes — in immune cells, a study reported.
Telomere length is known to decrease with age, and younger FA patients, up to around the mid-30s, had longer telomeres than did healthy individuals of a similar age. But patients’ telomeres shortened much faster than others as they continued to age.
No associations were found between telomere length and diabetes, a possible disease symptom, or a dependence on wheelchairs.
“The present study indicates that telomere length analysis in [FA] may be a relevant biomarker for following the stages of the disease,” the researchers wrote in the study, “Unusual Age-Dependent Behavior of Leukocytes Telomere Length in Friedreich’s Ataxia,” published in Movement Disorders.
Telomeres shorten slightly each time a cell divides
FA is caused by defects in both copies of the FXN gene, each inherited from one biological parent. The most common type of defect is called a GAA trinucleotide repeat expansion, where three DNA building blocks — GAA — are repeated too many times in the FXN gene. Such expansions reduce the levels of frataxin, a protein essential to the healthy function of mitochondria, structures that provide energy in cells.
Mitochondria dysfunction primarily affects cells with high energy demands, like nerves and muscles, leading to a loss of muscle control and coordination, or ataxia. Other symptoms include cardiomyopathy (heart muscle damage), speech difficulties, and skeletal abnormalities.
Telomeres are stretches of DNA found at the ends of chromosomes, like tips or caps, that help to protect the free DNA ends, maintain their integrity, and facilitate proper genome replication. As people age, the ends of telomeres shorten with each cell division, and this shortening has been linked with age-related illnesses, including cardiovascular disease and type 2 diabetes.
Because FA is associated with cardiomyopathy and diabetes, researchers in Italy and the U.K. sought to investigate a relationship between telomere length and FA progression.
Scientists collected white blood cells (leukocytes, part of the immune system) from 61 FA patients who carried two identical GAA expansions (homozygous group) and five patients with two different GAA expansions (compound heterozygous). A group of 29 unaffected individuals with one FXN expansion (heterozygous), known as carriers, and 87 healthy adults (controls) were included. DNA was extracted from cells, and leukocyte telomere length, or LTL, was measured.
At the time of blood sample collection, about half of the FA patients (51.7%) were wheelchair dependent, 33.9% were affected by cardiomyopathy, and 11.9% had diabetes. Patients’ mean age was 31.9, carriers’ mean age was 38.21, and the control group’s was 35.66.
Steepest loss of telomere length seen in FA patients after age 35
Overall, there were no significant differences in LTL between patients and controls, with a slight trend toward longer LTL in FA patients than controls. Telomere length in carriers was significantly longer than in controls, while the five compound heterozygous patients showed a similar LTL with homozygous patients. LTL was similar in males and females across all groups.
Experiments confirmed leukocyte telomere length shortening with increasing age, but the decline in LTL was steepest in FA patients compared with carriers and controls. Generally, before the age of 35, LTL was longer in patients than in controls, but after age 35, LTL was shorter in patients than in controls.
Researchers then divided the number of GAA expansions in patients into four classes: 67-467 GAA repeats, 468-680 repeats, 681-834 repeats, and 835-1,200 repeats. After adjusting for age, LTL significantly increased with more homozygous and compound heterozygous GAA expansions, whereas no relationship was observed between GAA repeat number and telomere length in carriers.
Shorter LTL was significantly associated with a longer disease duration, but this link lost statistical significance after adjusting for age.
Shorter lengths significantly linked with the presence of cardiomyopathy
In clinical measures, shorter LTL values significantly associated with the presence of cardiomyopathy after age adjustment, but not with diabetes or wheelchair dependence. “The presence of cardiomyopathy showed a significant shortening effect on LTL, in agreement with previous studies where LTL reduction was frequently found to be a common hallmark of cardiovascular disease,” the researchers wrote.
“We believe that the LTL is a biomarker capturing oxidative stress and inflammatory processes” in this disease, they added. Oxidative stress refers to the imbalance between the production of damaging free radicals (reactive oxygen-containing molecules) and the body’s ability to eliminate them.
No relationship was observed among evaluable patients between LTL values and disease severity, as measured using the Scale for the Assessment and Rating of Ataxia.
“The present study indicates that telomere length analysis in [Friedreich’s ataxia] may provide a relevant tool to follow, at the molecular level, the stages of the disease,” the researchers wrote. “Further studies in this field could make LTL measurement a useful biomarker of [FA] progression, supporting clinical trial design and further insights into disease mechanisms.”
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