Last Updated: August 25, 2022
Introduction to Friedreich Ataxia
Friedreich ataxia (FRDA) is an autosomal recessive disease named for Nicholas Friedreich who, in 1863, described a degenerative atrophy of the posterior columns of the spinal cord that resulted in a progressive ataxia, sensory loss, and muscle weakness. Distinctive neuropathological findings in FRDA are loss of the large primary sensory neurons of the dorsal root ganglia (DRG). Unlike the majority of trinucleotide repeat expansion diseases, FRDA is inherited as an autosomal recessive disorder.
Molecular Biology of Friedreich Ataxia
FRDA is the result of trinucleotide expansion in the frataxin (FXN) gene. The FXN gene is located on chromosome 9q21.11 spanning 80 kb and composed of 5 exons that generate two alternatively spliced mRNAs each of which encode a distinct protein isoform. Exons 5b and 6 are only found in a minor alternative transcript. The largest frataxin protein (mitochondrial isoform 1) is composed of 210 amino acids and shows no homology to other mammalian proteins. Homologues have been found in yeast and the worm C. elegans.
The most common FRDA mutations are expansion of a GAA trinucleotide repeat in the intron between the first and second exons of the FXN gene. Normal individuals have 5 to 30 GAA repeats whereas affected individuals have from 70 to >1000 repeats. Repeats in the range of 34–200 are considered premutation alleles due to their highly unstable nature leading to expansion to over 300 in a single generation. The expansion of the GAA repeat results in interference with transcription of the gene leading to reduced levels of frataxin.
Although point mutations in the frataxin gene are also observed in typical FRDA patients (constituting less than 5% of individuals), detection of GAA expansion is the most sensitive diagnostic test for Friedreich ataxia.
Expression of the frataxin gene is highest in the dorsal root ganglia (DRG) with significant levels seen also in the granular layer of the cerebellum. Non-neuronal sites of expression include the heart and pancreas which likely accounts for the cardiac symptoms and increased incidence of diabetes observed in FRDA patients.
The frataxin protein localizes to the mitochondrial membrane. Mutation studies in yeast indicated that the frataxin protein is involved in iron homeostasis in the mitochondria. The frataxin protein can bind approximately 10 iron atoms and loss of frataxin protein is correlated with iron-sulfur (Fe-S) deficiency and consequent mitochondrial dysfunction. Although the precise role of frataxin in mitochondrial function is still not certain it is accepted that the protein serves a role as an iron donor in Fe-S cluster (ISC) biogenesis both in the mitochondria and in the cytosol. The latter function involves a mitochondrial process and is not due to frataxin function in the cytosol as the protein is strictly localized to the mitochondria.
Clinical Features of FRDA
Friedreich ataxia is the most common form of autosomal recessive ataxia occurring with a frequency of approximately 1 in 50,000. The clinical hallmarks of FRDA is a progressive mixed cerebellar-sensory ataxia. Frequent falls due to clumsy gait is the most commonly observed symptom. Symptoms of FRDA are most commonly observed beginning in puberty with the “typical” age of onset being 20 years of age. As the disease progresses, limb incoordination, dysmetria (lack of coordination of movements characterized by under- or over-shooting intended position) and intention tremor (a tremor that is triggered by aiming for a particular location) follow.
Within five years of the onset of symptoms patients will exhibit speech abnormalities that included dysarthria and slowed ability to speak. Loss of tendon reflexes and extensor plantar response (extension of the big toe and fanning of the other toes in response to stimulation of the bottom of the foot) have been considered as obligatory signs in a definitive diagnosis of FRDA. Muscle weakness is progressive particularly in the lower limbs.
Unlike other ataxias where ocular defects such as nystagmus are common, this symptom is rare in FRDA. The most common ocular defect in FRDA is fixation instability. In the latter stages of the disease patients often develop optic atrophy. FRDA is a progressive lethal disease and patients usually succumb to the disorder in the fourth or fifth decade.
Cardiomyopathy is the most common non-neurological symptom in FRDA and is most often seen in patients with the earliest onset of disease. Approximately 10% of FRDA patients develop diabetes mellitus. Detailed studies demonstrated that the diabetes results from a loss of pancreatic β-cells without autoimmune inflammation.