The Neuropathology of Late-Onset Friedreich’s Ataxia

Abstract

Friedreich’s ataxia (FRDA) affects very young persons. In a large series, the mean ages of onset and death were 11 and 38 years, respectively. The clinical spectrum of FRDA has expanded after genetic confirmation of the mutation became a routine laboratory test. The main cause of death in juvenile-onset FRDA is cardiomyopathy whereas patients with late-onset are more likely to succumb to neurological disability or an intercurrent illness. Many patients with early onset now survive for 20 years or longer. This study made a systematic comparison of the neuropathology in 14 patients with juvenile onset and long survival, and five patients with late onset and long survival. Mean ages of onset (± standard deviation) were 10±5 and 28± 13 years, respectively. Disease durations were 33±11 and 47±11 years, respectively. Cross-sectional areas of the thoracic spinal cord were greatly reduced from the normal state but did not differ between the two groups. Similarly, the neurons of dorsal root ganglia were significantly reduced in size in both juvenile- and late-onset cases of FRDA. The dentate nucleus showed severe loss of neurons as well as modification and destruction of corticonuclear terminals in all FRDA patients. Delayed atrophy of the dentate nucleus is the likely cause of the ataxic phenotype of FRDA in late-onset cases, but the reason for the delay is unknown. Frataxin levels in the dentate nucleus of two patients with late onset were similar to those of seven patients with juvenile onset.

The cerebellar component of Friedreich’s ataxia

“…Details of the immunocytochemical protocol were published previously [14]. Optimal antigen retrieval for the visualization of NSE and GAD was incubation for 30 min at 95°C in a diluted de-cloaking solution termed “DIVA” by the supplier (Biocare Medical, Concord, CA, USA).…”

“…Frataxin levels in the DN of FRDA patients are low [14] but the pathogenesis of selective DN atrophy remains elusive. Evidence reported in the present study implicates interrupted transmission between Purkinje cells and large neurons of the DN.…”

Friedreich's ataxia: Pathology, pathogenesis, and molecular genetics

“…Systematic measurements of cross-sectional areas have confirmed this overall reduction: The mean cross-sectional area of 12 typical juvenile-onset FRDA cases was 20.5±5.3 mm 2 (mean±standard deviation). In 6 normal spinal cords, the comparable measurement was 30.4±5.6 mm 2 [49]. Transverse slices of the spinal cord also reveal smallness and gray discoloration of the dorsal columns.…”

“…The author and his collaborators previously summarized the evidence for a combined process in DRG [53] and sensory peripheral nerves [55]. In DRG, the reduction in average neuronal size [49,54] is probably not the result of selective atrophy of larger neurons. Satellite cells invade nerve cells of large and small size (Fig.…”

Autologous stem cell transplant with gene therapy for Friedreich ataxia

“…Demonstration of differentiation into neurons and cardiomyocytes, arguably the two major cell populations necessary for gene- and cell-based therapy, will establish the relevance of an autologous transplantation regimen for the treatment of FRDA. As noted above, FRDA is accompanied by neurodegeneration and cardiomyopathy [3], with progressive cell death in the spinal cord, peripheral nerves, and the cerebellum associated with the early clinical symptom of gait ataxia [17,18], and heart diseases, such as hypertrophic cardiomyopathy, myocardial fibrosis, and cardiac failure, as the major underlying cause of death [19,20]. With this in mind, treatment of FRDA should be approached by abrogating both neurodegeneration and cardiomyopathy.…”