In the present work, we addressed the issue of diagnostic delay in FRDA for the first time. The median time to diagnosis was 3(IQR:1-7) years in this large European cohort, comprehending a mixed population of patients with onset before and after discovery of FXN mutations. This value resembles data from general surveys in the field of rare diseases (13), but is somewhat disappointing considering that FRDA is a “common rare disease” among Caucasians. Though, an in-depth look in the EFACTS registry reveals that marked variabilities concerning time to diagnosis are recorded within the FRDA collective.
First of all, the present data highlights the crucial contribution of the discovery of the GAA expansions in FXN gene to FRDA diagnosis. Indeed, in the whole cohort, as well in subgroup comparisons, a shorter time to diagnosis is invariably documented when disease presented after 1996. In particular, the increasing availability of genetic testing broke the paradigm of FRDA as a disease of the adolescence, enabling the diagnosis of FRDA with onset up to the mid-70s (18), as evident in our cohort (see fig. 1).
Despite substantial improvement in the diagnostic process, specific onset features still set a relevant challenge for the clinician and cause significant delay in the diagnosis of FRDA. Indeed, also in the era of genetic diagnosis 1) inaugural non-neurological symptoms and 2) adult onset symptoms go along with a significant diagnostic delay compared to the classical phenotype characterized by onset with gait unsteadiness around puberty. There are a number of reports of disease presentation with isolated cardiomyopathy or scoliosis (2, 15, 16). The present data shows instead that isolated non-neurological onset is not rare, accounting for ~10% of cases. Interestingly, two out of eight patients with pre-symptomatic diagnosis presented with isolated non-neurological symptoms. This suggest that, when transition to manifest disease is closely monitored, non-neurological features may precede clinical ataxia in an even higher percentage of cases. Of note, the EFACTS consortium consists mainly of adult neurological clinics and pediatric cases are underrepresented. Prevalence of non-neurological onset is likely to be higher in pediatric collectives.
Suspecting FRDA in the setting of isolated scoliosis is not reasonable given the prevalence of 1-2% among schoolchildren up to 15 years of age (22). On the contrary, isolated left ventricular hypertrophy in children is not a common finding. Therefore, testing for FRDA should be considered in individuals diagnosed with this finding (23).
Concerning late-onset FRDA, our results point out that awareness of an adult presentation is still limited. As highlighted by many reviews on the topic (24-26), FRDA testing should be always considered in the first line work-up in adult-onset ataxia after exclusion of secondary causes and in absence of an evident autosomal dominant inheritance.
Measuring the time to diagnosis in rare disease can be challenging, as the disease onset itself can be difficult to define. In the EFACTS registry, age and symptoms at onset are collected retrospectively and based on medical history. Collected information is subject to a recall bias and subclinical neurological signs may be missed. Though, in our experience, age at onset is often re-dated by patients or their parents at time of inclusion as, after becoming aware of FRDA, they can recall earlier abnormalities.
All clinical studies on FRDA consistently reported a significant correlation between the length of the shorter GAA repeat and age at onset. Interestingly in the siblings’ analysis difference in age at onset was not correlated with GAA repeats. This finding may reflect an observational and/or recall bias regarding the age at onset, since the siblings of a newly diagnosed patient are prone to be under higher awareness. More importantly, no correlation between GAA repeat length and age at onset was detected in the group with non-neurological onset. These findings contradict the established correlation between GAA repeat length and disease milestones and suggest that these associations may be valid only when neurological symptoms are considered. Interestingly, cumulative evidence showed that GAA repeat expansions are subjected to somatic instability with accumulation of further contractions/expansions, which can lead to marked differences in the affected tissue and possibly explain lack of correlation between the course non-neurological symptoms and GAA1-repeat length (27). Eventually, we cannot exclude that the smaller number cases in the siblings´ group and in group with non-neurological onset contributed to the lack of significant correlation between age at onset and GAA1-repeat length.
According to a currently leading hypothesis, FRDA neuropathology has considerable developmental aspects (28). Indeed, cumulative evidence shows that hypoplasia of the dorsal root ganglia and spinal cord is the dominant neuropathological feature, thus suggesting that anatomical changes predate birth and clinical symptoms (28, 29). It is not known which factors trigger disease progression and ultimately lead to overt clinical manifestations. Identifying and monitoring paucisymptomatic subjects, without overt ataxia, may offer a unique opportunity to address unanswered issues about the evolution of the disease.
In rare disorders, the interval elapsing between the moment of symptom awareness and definite diagnosis has been described as an “odyssey”(13), during which patients may not receive appropriate management and counseling. Misdiagnosis may also lead to over-testing and inappropriate interventions. In the worst-case scenario, the delay in diagnosis implies also a delay in the access to an available effective therapy. Increasing awareness about FRDA and its presentation represents the first step to address the issue of diagnostic delay. A timely diagnosis accelerates in turn the referral to specialized centers and may pave the way for a prompt access to therapies in the future (30).