Case Report Describes Early FA Onset in Boy with Rare Gene Mutation

A new case report describes a 7-year-old boy with Friedreich’s ataxia (FA) who has a particularly early age of disease onset and an extremely rare type of mutation in the FXN gene, which led to unsteady gait, tremor, and spine curvature, among other manifestations.

The study, “Friedreich’s Ataxia: Clinical Presentation of a Compound Heterozygote Child with a Rare Nonsense Mutation and Comparison with Previously Published Cases,” appeared in the journal Case Reports in Neurological Medicine.

The classic phenotype of Friedreich’s ataxia is caused by a homozygous (in both gene copies, or alleles) expansion of a GAA trinucleotide repeat in the FXN gene, and is associated with an age of disease onset before age 25,  wheelchair dependency within a decade, and often, mortality by age 40, usually due to heart complications.

Compound heterozygous individuals (2-5%) carry GAA expansions in just one gene copy and a point mutation — an alteration affecting only one nucleotide (the building blocks of DNA and RNA) — in the other.

Prior research in 111 compound heterozygotes reported 38 different types of mutations.

The main ones were of the splice site type — occurring at the boundary, or splice site, of an exon (the bits of DNA that contain the information to generate proteins) and an intron (normally spliced in protein production) — and in/del type, the insertion or deletion of a sequence of nucleotides.

Very few cases were nonsense point mutations, which alter the DNA sequence to prematurely stop gene expression.

Patients with null mutations, which may cause the complete loss of the encoded protein, have reported earlier onset and a higher incidence of diabetes than those with homozygous GAA expansions.

This earlier onset was attributed to the smaller size of the repeat expansion, and lower levels of frataxin, a key protein for the proper functioning of mitochondria (the energy-producing powerhouses in cells).

In turn, patients with homozygous alterations have a higher rate of cardiomyopathy, or diseases of the heart muscle, than any type of compound heterozygous mutations.

The 7-year-old boy described in the case study had progressive gait disturbance and falls. His medical history included no complications during pregnancy or delivery, and he had normal childhood milestones of sitting, walking, and speech development. A grandfather had a history of tremors.

The boy had first been seen by a pediatric neurologist at age 3 for toe walking and unsteady gait, which had started a year earlier. His falls and handwriting worsened by age 6. He started experiencing tremors in both hands sometime before his visit to the clinic.

Examinations revealed pes cavus, or high-arched feet, scoliosis (curvature of the spine) and no cardiac murmur. The patient also showed minimal to absent deep tendon reflexes (nerve reflexes that determine muscle contraction upon tapping), loss of position sense, lack of movement coordination, tremor, and unsteady gait. The boy also exhibited increased tone in lower extremities at the last exam.

Results of magnetic resonance imaging (MRI) of the brain, laboratory tests and ophthalmological exams were normal. Then, echocardiogram results revealed hypertrophy, or enlargement, of both ventricles.

A genetic analysis showed that one FXN gene copy had a GAA trinucleotide repeat expansion of approximately 1,000 and a very rare point mutation — c.464G>A, meaning a guanine (G) to adenine (A) nucleotide change in the DNA coding sequence — in the other copy.

This mutation would lead to the substitution of the amino acid tryptophan to a premature stop in gene activity.

According to the researchers, only three other cases of nonsense mutations have been reported in Freidriech’s ataxia patients. Including this new case, all four known patients are males and have the first disease manifestations before age 15.

All had gait ataxia, signs of lesion in upper motor neurons — cells that control muscle contraction — dysarthria (speech articulation problems), and decreased vibration perception, and scoliosis. Neither had diabetes and most did not present hearing loss.

However, the very limited number of FA patients with nonsense mutations precludes establishing a clinical pattern, the team cautioned.

Compared to the three previously reported patients, the boy had the earliest age of FA onset and the highest number of GAA repeats, the investigators noted.

“In conclusion, if the index of suspicion is high for [FA] then [FXN] sequencing should be performed if there is a repeat expansion detected only on one allele,” the scientists wrote.