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

Abstract

The pathogenic mutation in Friedreich’s ataxia (FRDA) is a homozygous guanine-adenine-adenine (GAA) trinucleotide repeat expansion on chromosome 9q13 that causes a transcriptional defect of the frataxin gene. Deficiency of frataxin, a small mitochondrial protein, is responsible for all clinical and morphological manifestations of FRDA. This autosomal recessive disease affects central and peripheral nervous systems, heart, skeleton, and endocrine pancreas. Long expansions lead to early onset, severe clinical illness, and death in young adult life. Patients with short expansions have a later onset and a more benign course. Some are not diagnosed during life. The neurological phenotype reflects lesions in dorsal root ganglia (DRG), sensory peripheral nerves, corticospinal tracts, and dentate nuclei (DN). Most patients succumb to cardiomyopathy, and many become diabetic during the course of their disease. This review seeks to reconcile the diverse clinical features with pathological and molecular data. In the pathogenesis of the lesion in DRG, dorsal spinal roots, and sensory peripheral nerves, developmental defects and atrophy occur in combination. The progressive lesion of the DN lacks a known developmental component. Destruction of the DN, optic atrophy, and degeneration of the corticospinal tracts are intrinsic central nervous system lesions. Fiber loss in dorsal columns and spinocerebellar tracts, and atrophy of the neurons in the dorsal nuclei of Clarke are secondary to the lesion in DRG. The role of frataxin deficiency in the pathogenesis of FRDA is still unclear because the protein has multiple functions in the normal state, including biogenesis of iron–sulfur clusters; iron chaperoning; iron storage; and control of iron-mediated oxidative tissue damage.

Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice

“…BMT in YG8R mice completely attenuated intracellular (nuclear and cytoplasmic) vacuolar degeneration of the large sensory neuronal cell bodies, and this change was associated with a reduced satellite cell‐to‐DRG neuron ratio, a likely consequence of improved large sensory neuronal cell survival (see Fig 3). 3 Within the cerebellar dentate nucleus, mean neuronal size was increased, indicating preservation of large neuronal cells. Alternatively, we found no significant preservation of neurons in spinal cord DNoC of transplanted mice.…”

“…Neuronal atrophy and dysfunctional glia are both thought to contribute to neuropathology in FA 3, 5, 6, 7. Despite advances in understanding of the disease, current therapeutics show little ability to protect nervous tissue and no capacity to promote repair.…”

Atypical Friedreich ataxia in patients with FXN p.R165P point mutation or comorbid hemochromatosis

“…The severity of clinical disease varies widely between patients. In GAA-TRE homozygotes, the number of repeats in the shorter GAA-TRE allele is inversely correlated with age of onset, likelihood for milder, late-onset FRDA as well as age of death, and directly correlated with symptom severity and risk for developing cardiomyopathy [5,6]. As pathogenic point mutations in FXN are rare, it has been difficult to associate a particular clinical phenotype with such mutations.…”

Serum versus Imaging Biomarkers in Friedreich Ataxia to Indicate Left Ventricular Remodeling and Outcomes

“…1,5,11 Cardiac involvement determines survival prospects. 1,4,12 Identifying early markers of cardiac involvement should enable the more aggressive institution of cardioprotective therapies to delay disease progression, although effective treatments remain in development. 5 Our group has previously shown that myocardial fibrosis can occur in FA patients who do not have overt cardiomyopathy.…”