Unreported deletion mutation linked to man’s FA symptoms

Mutation involved loss of large part of FXN gene

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A yet unreported mutation that involves the loss of a large piece of the FXN gene, which is linked to Friedreich’s ataxia (FA), was identified in a man with typical symptoms of the disease, according to a report from Spain.

“With this case, we want to raise awareness about the potentially higher prevalence of [within-the-gene] deletions and underline the essential role of parental sample testing in providing accurate genetic counseling,” the reseachers wrote in “Novel intragenic deletion within the FXN gene in a patient with typical phenotype of Friedreich ataxia: may be more prevalent than we think?” which was published in BMC Medical Genomics.

FA is caused by mutations in the FXN gene, which provides instructions for making the protein frataxin. Without enough frataxin, mitochondria, the cells’ powerhouses, fail to produce enough energy, leading to symptoms.

The FXN gene contains a sequence of three building blocks, called GAA, that gets repeated a number of times. In healthy people, this happens from 5 to 33 times. In FA, it can be repeated more than 1,000 times.

In rare cases, FA is caused by a deletion that involves the loss of any number of a gene’s building blocks — from a single building block to an entire piece of a gene, which consists of exons that code for proteins, and noncoding regions called introns.

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An unreported mutation

A 32-year-old man who was diagnosed with FA when he was 23 is the subject of the report by researchers. Over five years, the man experienced difficulty walking and a progressive loss in balance and coordination, along with mild speaking issues. A loss of muscle tone and an inability to estimate the amount of time that had passed, a condition called dyschronometry, were noted on a neurological examination, as were muscle weakness, difficulty with coordination and timing, abnormal reflexes, and sensory impairment.

A physical exam showed the man had a spine that curved sideways, called scoliosis, and high arches in his feet — two bone abnormalities often seen in FA.

The disease develops when a person inherits two mutated copies of FXN, one from the father and one from the mother. Genetic testing revealed the man carried one copy with an expanded GAA repeat of unknown size. In the other copy, a large piece of the gene, including exons 1 and 2, was deleted.

“This unreported deletion is predicted to eliminate the start codon [the initiation signal to start producing a protein] and consequently no protein will be produced,” the researchers wrote.

The two mutations were confirmed by genetic testing of the man’s parents. According to the scientists, it’s important to be aware of less common disease-causing mutations and testing the parents may help provide better genetic counseling.

“In conclusion, we describe a patient presenting with novel intragenic [within the gene] deletion and an expansion on the FXN gene who shows the typical progression and clinical features of [FA],” the researchers wrote.