Novel Diagnostic Paradigms for Friedreich Ataxia

Friedreich ataxia is the most commonly inherited ataxia syndrome, accounting for half of the inherited progressive ataxias and three-quarters of those with onset before age 25.1 It is inherited in an autosomal recessive manner, and appears most prevalent among those of European, Middle Eastern, North African, and Indian descent.2 Since it was first characterized in 1863,3 its diagnosis historically depended on clinical findings using established criteria, namely onset before age 20, truncal and limb ataxia, and loss of deep tendon reflexes, followed by loss of proprioceptive and vibratory senses and dysarthria. The development of cardiomyopathy and scoliosis is not pathognomonic, but highly characteristic of the condition.4,5 Upon the discovery of FXN in 1996 and the introduction of confirmatory genetic testing,6 the wide phenotypic variability of the condition (discussed by Delatycki and colleagues in this issue) became more apparent, with up to 25% of individuals with homozygous GAA expansion mutations (approximately 95% to 98% of affected individuals) exhibiting clinical findings that do not perfectly match the classic clinical picture.7–10 For example, individuals of Acadian descent with Friedreich ataxia appear to have a milder disease course while exhibiting the classic expansion genotype.11 Molecular studies of the pathogenic GAA expansion have explained some of this phenotypic range, as they have shown the repeat expansion to be inversely related to age of onset and severity of disease, such that individuals with lower GAA repeat expansions often exhibit a later age of onset, sometimes well into adulthood, and often have a milder, variant phenotype.12 Compound heterozygotes (with a pathogenic GAA expansion on one allele and a point mutation on the second) make up a minority of those with Friedreich ataxia (2% to –5%) and often exhibit a nonclassical phenotype as well.13,14 Less severe phenotypes are associated with some of the missense mutations affecting the amino terminal portion of the protein, such as G130V, R165C, R165P, and D122Y. These individuals often exhibit spastic paraparesis with minimal ataxia, brisk reflexes, absence of scoliosis and cardiomyopathy, normal speech, and slower progression of disease.14,15 While no FXN point mutation homozygotes have been identified to date, this genetic combination seems theoretically possible. Either 2 loss-of-function alleles may be embryonically lethal or the phenotype of those individuals may lie so far outside the associated features of Friedreich ataxia that the condition is not even considered within the differential diagnoses. Two recent advances have changed the diagnostic landscape for Friedreich ataxia, and potentially further expanded an already broad spectrum of disease. The first is the introduction of an immunoassay-based test that measures the concentration of the frataxin protein in both whole blood and buccal cells, and readily identifies differences in frataxin levels between controls, carriers, and affected individuals.16–18 This test has multiple applications to clinical care and research.19,20 It is especially useful as an adjunct diagnostic test that can easily, noninvasively, and inexpensively help the clinician determine whether Friedreich ataxia should remain under diagnostic consideration, and further supports a diagnosis of Friedreich ataxia in those individuals without confirmatory genetic testing in the context of suggestive clinical findings and frataxin in the affected range. In addition, this assay holds promise as a biomarker for future clinical trials in which frataxin levels are increased following introduction of a potentially therapeutic agent, such as the proof-of-concept study of recombinant human erythropoietin recently undertaken in Austria,19 and may be useful in monitoring patients with Friedreich ataxia when exposed to other potentially hazardous agents, as discussed by Deutsch and colleagues in this issue. The second development is the identification of whole exon deletions within FXN via multiplex ligation-dependent probe analysis. This technique and the subsequent identification of affected individuals who are compound heterozygous with intragenic deletions and GAA expansions17,21 suggest a wider range of disease-causing mutation types than previously believed. This additional DNA-based diagnostic tool may provide definitive genetic diagnosis for a number of individuals previously characterized as “Friedreich-like” without confirmatory genetic testing by existing DNA-based testing. We discuss these novel diagnostic techniques for Friedreich ataxia in this paper, and a diagnostic testing algorithm for Friedreich ataxia incorporating them is proposed to guide the clinician when considering a diagnosis of Friedreich ataxia. In addition, the phenotype of the individuals who are compound heterozygotes for intragenic exon deletions is further characterized. The counseling implications of these new diagnostic tools are explored. Lastly, potential future approaches to diagnosis of this condition are considered.