Milestones in Friedreich ataxia: more than a century and still learning

Abstract

Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia worldwide. This review highlights the main clinical features, pathophysiological mechanisms, and therapeutic approaches for FRDA patients. The disease is characterized by a combination of neurological involvement (ataxia and neuropathy), cardiomyopathy, skeletal abnormalities, and glucose metabolism disturbances. FRDA is caused by expanded guanine-adenine-adenine (GAA) triplet repeats in the first intron of the frataxin gene (FXN), resulting in reduction of messenger RNA and protein levels of frataxin in different tissues. The molecular and metabolic disturbances, including iron accumulation, lead to pathological changes characterized by spinal cord and dorsal root ganglia atrophy, dentate nucleus atrophy without global cerebellar volume reduction, and hypertrophic cardiomyopathy. DNA analysis is the hallmark for the diagnosis of FRDA. There is no specific treatment to stop the disease progression in FRDA patients. However, a number of drugs are under investigation. Therapeutic approaches intend to improve mitochondrial functioning and to increase FXN expression.

Regional Cerebral Disease Progression in Friedreich's Ataxia: A Longitudinal Diffusion Tensor Imaging Study

“…FRDA is a progressive disease affecting the central nervous system (CNS), skeleton, heart, and pancreas . CNS involvement is responsible for debilitative ataxia and neuropathy, constraining patients to a wheelchair for 2/3 of their life.…”

“…CNS involvement is responsible for debilitative ataxia and neuropathy, constraining patients to a wheelchair for 2/3 of their life. Median age of death is 40 years due to heart failure secondary to hypertrophic cardiomyopathy . There is no cure …”

The Structure of the Complex between Yeast Frataxin and Ferrochelatase

“…Low levels of frataxin in humans are responsible for the progressive neurodegenerative disease Friedreich's ataxia, caused by trinucleotide repeat expansions in the first intron of the frataxin gene and the consequent gene silencing. Frataxin deficiency results in aberrations in cellular iron homeostasis, progressive accumulation of iron in mitochondria, high levels of oxidative stress, and deficiency in heme and ISC biosynthesis (4,(7)(8)(9).…”

Current concepts in the treatment of hereditary ataxias

“…Therefore, several mechanism-based therapies are available to correct the underlying defective metabolic pathways. Friedreich’s ataxia (FRDA) is the most common autosomal recessive cerebellar ataxia and therapy this condition has been extensively reviewed 4 .…”