Nonneurological Involvement in Late-Onset Friedreich Ataxia (LOFA): Exploring the Phenotypes

Abstract

Friedreich's ataxia (FDRA) is the most common inherited ataxia worldwide, caused by homozygous GAA expansions in the FXN gene. Patients usually have early onset ataxia, areflexia, Babinski sign, scoliosis and pes cavus, but at least 25 % of cases have atypical phenotypes. Disease begins after the age of 25 in occasional patients (late-onset Friedreich ataxia (LOFA)). Little is known about the frequency and clinical profile of LOFA patients. One hundred six patients with molecular confirmation of FDRA and followed in three Brazilian outpatient centers were enrolled. General demographics, GAA expansion size, age at onset, cardiac, endocrine, and skeletal manifestations were evaluated and compared between LOFA and classic FDRA (cFDRA) groups. We used Mann-Whitney and Fisher tests to compare means and proportions between groups; p values <0.05 were considered significant. LOFA accounted for 17 % (18/106) and cFDRA for 83 % (88/106) of the patients. There were 13 and 48 women in each group, respectively. LOFA patients were significantly older and had smaller GAA expansions. Clinically, LOFA group had a tendency toward lower frequency of diabetes/impaired glucose tolerance (5.8 vs. 17 %, p = 0.29) and cardiomyopathy (16.6 vs. 28.4 %, p = 0.38). Skeletal abnormalities were significantly less frequent in LOFA (scoliosis 22 vs. 61 %, p = 0.003, and pes cavus 22 vs.75 %, p < 0.001) as were spasticity and sustained reflexes, found in 22 % of LOFA patients but in none of the cFDRA patients (p = 0.001). LOFA accounts for 17 % of Brazilian FDRA patients evaluated herein. Clinically, orthopedic features and spasticity with retained reflexes are helpful tips to differentiate LOFA from cFDRA patients.

Nonataxia symptoms in Friedreich Ataxia

“…Although scoliosis has always been considered a typical feature of FRDA, its prevalence had been variably estimated to be from 33% to 100%. 1,[19][20][21][22][23] The 74% prevalence figure in our cohort is close to the average of the older studies, confirming that scoliosis is highly increased in FRDA compared to the normal population, where its prevalence in infantile and juvenile populations is between 0.19% and 18.7%, 24,25 and up to 13.4% in adults. 26 Foot deformities, mainly bilateral pes cavus, made the second most common nonneurologic feature in FRDA, occurring in 59% of cases.…”

Structural signature of classical versus late‐onset friedreich's ataxia by Multimodality brain MRI

“…However, diffusivity parameters (MD and RD) pointed to more severe microstructural damage in the LOFA group. A clinical correlate of this MRI feature are the pyramidal signs (spasticity, hyperreflexia, and Babinski sign), which were much more frequent and severe in our LOFA group as described by Martinez et al (). In terms of disease pathophysiology, this result looks counterintuitive at first, but we believe that it sheds some light in the basis of Frataxin‐related neuronal loss.…”

“…So, the exposure to the low levels of frataxin is longer in the LOFA group as they are older than the cFRDA group. In this sense, we hypothesize that corticospinal tracts are more resistant to the deleterious effects of frataxin loss in the short term, and therefore damage would only appear late in the disease course, what characterize a survivor effect as the LOFA patients experiment, on average, longer life span than cFRDA patients (Koeppen et al, ; Martinez et al, ). An alternative explanation would be that small and large (GAA) expansions lead to neurodegeneration through distinct biochemical mechanisms.…”

Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia

“…This shorter expansion enables residual Fxn expression 11 , thus modifying the classical FDRA phenotype, consistent with other data indicating that Fxn deficiency is directly related to the FRDA phenotype 12 . Extra-neurologic symptoms including metabolic dysfunction and insulin intolerance are observed in the majority and frank type I diabetes is observed in approximately 15% of patients, the severity of which is related to increasing repeat length [13][14][15] . The mechanisms by which Fxn reduction leads to clinical symptoms and signs remain to be elucidated, but molecular and cellular dysfunction mediated by a critical reduction in Fxn levels plays a central role 16 .…”