Assistant Professor of Neurology,Weill Cornell Medical College
Dr. Vo reports she is an advisory board member for CSL Behring, is a consultant and advisory board member for Alexion Pharmaceuticals, and receives grant/research support from Takeda Pharmaceuticals.
SYNOPSIS: Friedreich’s ataxia (FRDA) is characterized by progressive weakness, sensory loss, ataxia, and dysarthria starting in childhood. The authors of this MRI-based study demonstrated that structural damage is limited to the spinal cord, red nucleus, and cerebellar peduncles in young FRDA patients, but progresses to widespread cerebral damage in adult FRDA patients.
SOURCE: Rezende TJR, Martinez ARM, Faber I, et al. Developmental and neurodegenerative damage in Friedreich’s ataxia. Eur J Neurol 2019;26:483-489.
The most common autosomal recessive ataxia, Friedreich’s ataxia (FRDA) is caused by a GAA expansion in intron 1 of the FXN gene, resulting in a reduced amount of frataxin protein. Frataxin is essential in the assembly of iron and sulfur cluster molecules needed for energy production and cellular response to oxidative stress. Cells of the central nervous system are particularly vulnerable to the effects of frataxin depletion. FRDA results in progressive weakness, ataxia, speech disturbance, and sensory loss.
The classical form of FRDA manifests prior to age 25 years, and most patients rely on wheelchairs for mobility within 15 years of diagnosis. The neurodegenerative nature of FRDA has been demonstrated by imaging studies showing progressive atrophy of multiple areas of the brain, especially cerebellar dentate nuclei and white and grey matter atrophy of the brainstem, motor cortex, and cerebellum in affected adults. However, there are scarce data describing imaging abnormalities in the pediatric population.
Between 2009 and 2017, 37 patients with confirmed FRDA and 38 healthy controls were recruited from University of Campinas neurogenetics clinic in Brazil. All 37 FRDA patients had the classical form of disease, with onset prior to age 25 years. Of the 37 FRDA patients, 12 were grouped into young FRDA (yFRDA), mean age 14 ± 2.7 years, and 25 were in the adult FRDA (aFRDA) group, mean age 28.4 ± 12.2 years. Disease onset occurred at age 9.2 ± 2.6 years in the yFRDA group and 13.5 ± 4.5 years in the aFRDA group. Older FRDA patients tended to have more severe disease, with Friedreich’s Ataxia Rating Scale (FARS) III subscore 66.0 ± 18.0 relative to 53.3 ± 15.1 in the yFRDA group. There were no significant differences between GAA1 or GAA2 repeat lengths.
All underwent 3T high-resolution magnetic resonance imaging (MRI) scan of the brain and cervical spinal cord. Multimodal MRI analysis was performed. Investigators also collected detailed clinical and molecular data, including disease onset, duration, GAA repeat length, and FARS score for all subjects. The focus of the study was to explore neuroanatomical differences between yFRDA and aFRDA subjects. Among the yFRDA group, volumetric reduction was limited to the red nuclei compared to controls. In contrast, aFRDA patients had more widespread atrophy in the hippocampi, thalami, red nuclei, and brainstem structures. White matter analysis in the yFRDA group showed increased radial diffusivity in the cerebellar peduncle and volume loss in superior cerebellar white matter tracts compared to healthy controls. The finding of increased cerebellar radial diffusivity directly correlated with disease severity.
Overall, yFRDA patients had limited infratentorial structural damage, whereas supratentorial involvement was found in aFRDA patients. The yFRDA group did not show evidence of supratentorial grey matter atrophy, cortical thinning that has been described in affected adults. Further, the yFRDA group did not demonstrate evidence of white matter injury, including abnormal axial diffusivity and fractional anisotropy, seen in the aFRDA group.
Spinal cord imaging showed reduced spinal cord area among all FRDA subjects compared to healthy controls, consistent with prior neuropathological observations showing that the spinal cord in FRDA patients fails to reach normal size. In contrast to the positive correlation between cord area and age in controls, the yFRDA group showed a progressive decline in cord area with aging. Moreover, there were no significant differences in spinal cord area between the yFRDA and aFRDA groups despite wide differences in mean ages. These findings suggest that the spinal cord involvement seen in FRDA is the result of both impaired development and neurodegeneration.
The current study offers a unique insight into early structural damage in FRDA patients, suggesting that frataxin deficiency can cause impaired brain and spinal cord development, leading to a distinctive neuroanatomical signature where the cervical spinal cord, medulla, inferior cerebellar peduncle, and red nucleus are affected preferentially.
FRDA is a progressive neurological disease resulting in severe disability and early death. Rezende et al defined a unique neuroanatomical pattern seen in children with early disease and offered valuable insight into the pathophysiology of FRDA. This work underscores the critical need for imaging biomarkers to predict disease progression and serves as an outcome measure for clinical trials.