Friedreich's ataxia: treatment within reach

Friedreich's ataxia (FA) is the most prevalent cerebellar ataxia in children and adults in Europe. FA is one of a growing number of diseases known to be caused by triplet-repeat expansions. The causative mutation is a GAA trinucleotide-repeat expansion in the first intron of the frataxin gene. The mitochondrial localisation of frataxin and decreased oxidation activity in vivo and in vitro show that FA is a mitochondrial disease. Frataxin is involved in iron metabolism and may protect mitochondria from oxidative damage. The understanding of the disease has only just begun and possible treatments are within reach. In this review I discuss the clinical knowledge of FA and recent developments that have helped to elucidate the pathogenesis of the disease and made the first therapeutic attempts possible.     

Iron metabolism in mice with partial frataxin deficiency

Friedreich ataxia (FRDA), the most common autosomal recessive inherited ataxic disorder, is the consequence of deficiency of the mitochondrial protein frataxin, typically caused by homozygous intronic GAA expansions in the corresponding gene. The yeast frataxin homologue (yfh1p) is required for cellular respiration. Yfh1p appears to regulate mitochondrial iron homeostasis and protect from free radical toxicity. Complete loss of frataxin in knockout mice leads to early embryonic lethality, indicating an important role for frataxin during development. Heterozygous littermates with partial frataxin deficiency are apparently healthy and have no obvious phenotype. Here we evaluate iron metabolism and sensitivity to dietary and parenteral iron loading in heterozygote frataxin knockout mice (Fx(+/-)). Iron concentrations in the liver, heart, pancreas and spleen, and cellular iron distribution patterns were compared between wild type and Fx(+/-) mice. Response to parenteral iron challenge was not different between Fx(+/-) mice and wild type littermates, while sporadic iron deposits were observed in the hearts of dietary iron-loaded Fx(+/-) mice. Finally, we evaluated the effect of partial frataxin deficiency on susceptibility to cardiac damage in the mouse model of hereditary hemochromatosis (HH), the Hfe knockout mice. HH, an iron overload disease, is one of the most frequent genetic diseases in populations of European origin. By breeding Hfe(-/-) with Fx(+/-) mice, we obtained compound mutant mice lacking both Hfe and one frataxin allele. Sparse iron deposits in areas of mild to moderate cardiac fibrosis were found in the majority of these mice. However, they did not develop any neurological symptoms. Our studies indicate an association between frataxin deficiency, iron deposits and cardiac fibrosis, but no obvious association between iron accumulation and neurodegeneration similar to FRDA could be detected in our model. In addition, these results suggest that frataxin mutations may have a modifier role in HH, that predisposes to cardiomyopathy.     

Friedreich ataxia

There has been rapid progress in the understanding of several aspects of Friedreich's ataxia (FA) since the gene mutation was identified in 1996. At the clinical level, now it is possible to confirm that the majority of patients fullfilling clinical criteria for classic FA have the FA gene mutation but some do not, indicating genetic heterogeneity. Also, the phenotype associated with the FA mutation is much wider than that defined by clinical criteria and includes ataxia with retained or brisk reflexes as well as late onset ataxia with or without retained reflexes. It is now clear that the unstable GAA expansion that underlies FA causes a deficiency of the mitochondrial protein frataxin, leading to potentially harmful oxidative injury associated with excessive iron deposits in mitochondria. In addition, pathogenesis may involve a primary defect in synthesis of iron-sulfur cluster containing enzymes. Therapeutic attempts are already using anti-oxidant strategies and such efforts are likely to be enhanced by the rapid availability of animal models of the disease.     

A case of Friedreich's ataxia having no abnormal gene

We report here a 25-year-old girl with Friedreich's ataxia (FA) who showed slowly progressive ataxia, deep sensory disturbance and loss of large myelinated fiber in the sural nerve. There was no evidence of cerebellar atrophy or abnormal values of vitamin E, albumin, CK, and gamma-globulin in the serum. Except for mild mental retardation, her clinical and laboratory findings were consistent with those of FA. However, she had no abnormal GAA trinucleotide repeat expansion on chromosome 9q13, unlike typical FA patients in Europe. Her cardiac muscle is not involved instead of 20 years have passed since her ataxia developed. She is considered to belong to a specific type of FA which lacks cardiac muscle involvement and abnormal gene encoding frataxin.     

Pathophysiogical and therapeutic progress in Friedreich ataxia

Friedreich ataxia (FRDA) is the most common hereditary autosomal recessive ataxia, but is also a multisystemic condition with frequent presence of cardiomyopathy or diabetes. It has been linked to expansion of a GAA-triplet repeat in the first intron of the FXN gene, leading to a reduced level of frataxin, a mitochondrial protein which, by controlling both iron entry and/or sulfide production, is essential to properly assemble and protect the Fe-S cluster during the initial stage of biogenesis. Several data emphasize the role of oxidative damage in FRDA, but better understanding of pathophysiological consequences of FXN mutations has led to develop animal models. Conditional knockout models recapitulate important features of the human disease but lack the genetic context, GAA repeat expansion-based knock-in and transgenic models carry a GAA repeat expansion but they only show a very mild phenotype. Cells derived from FRDA patients constitute the most relevant frataxin-deficient cell model as they carry the complete frataxin locus together with GAA repeat expansions and regulatory sequences. Induced pluripotent stem cell (iPSC)-derived neurons present a maturation delay and lower mitochondrial membrane potential, while cardiomyocytes exhibit progressive mitochondrial degeneration, with frequent dark mitochondria and proliferation/accumulation of normal mitochondria. Efforts in developing therapeutic strategies can be divided into three categories: iron chelators, antioxidants and/or stimulants of mitochondrial biogenesis, and frataxin level modifiers. A promising therapeutic strategy that is currently the subject of intense research is to directly target the heterochromatin state of the GAA repeat expansion with histone deacytelase inhibitors (HDACi) to restore frataxin levels.     

Friedreich's ataxia: past, present and future

Friedreich's ataxia (FRDA) is an autosomal recessive inherited disorder characterized by progressive gait and limb ataxia, dysarthria, areflexia, loss of vibratory and position sense, and a progressive motor weakness of central origin. Additional features include hypertrophic cardiomyopathy and diabetes. Large GAA repeat expansions in the first intron of the FXN gene are the most common mutation underlying FRDA. Patients show severely reduced levels of a FXN-encoded mitochondrial protein called frataxin. Frataxin deficiency is associated with abnormalities of iron metabolism: decreased iron-sulfur cluster (ISC) biogenesis, accumulation of iron in mitochondria and depletion in the cytosol, enhanced cellular iron uptake. Some models have also shown reduced heme synthesis. Evidence for oxidative stress has been reported. Respiratory chain dysfunction aggravates oxidative stress by increasing leakage of electrons and the formation of superoxide. In vitro studies have demonstrated that Frataxin deficient cells not only generate more free radicals, but also show a reduced capacity to mobilize antioxidant defenses. The search for experimental drugs increasing the amount of frataxin is a very active and timely area of investigation. In cellular and in animal model systems, the replacement of frataxin function seems to alleviate the symptoms or even completely reverse the phenotype. Therefore, drugs increasing the amount of frataxin are attractive candidates for novel therapies. This review will discuss recent findings on FRDA pathogenesis, frataxin function, new treatments, as well as recent animal and cellular models. Controversial aspects are also discussed.     

Friedreich's ataxia

Friedreich’s ataxia, the most common hereditary ataxia, is caused by expansion of a GAA triplet located within the first intron of the frataxin gene on chromosome 9q13. There is a clear correlation between size of the expanded repeat and severity of the phenotype. Frataxin is a mitochondrial protein that plays a role in iron homeostasis. Deficiency of frataxin results in mitochondrial iron accumulation, defects in specific mitochondrial enzymes, enhanced sensitivity to oxidative stress, and eventually free-radical mediated cell death. Friedreich’s ataxia is considered a nuclear encoded mitochondrial disease.

This review discusses the major and rapid progress made in Friedreich’s ataxia from gene mapping and identification of the gene to pathogenesis and encouraging therapeutic implications.     

Therapeutic strategies in Friedreich's ataxia

Friedreich's ataxia is caused by a pronounced lack of frataxin, a mitochondrial protein of not fully understood function. Lack of frataxin homologues in yeast and mice leads to increased sensitivity to oxidative stress, depletion of proteins with iron-sulfur clusters like respiratory chain complexes I-III and aconitase, and to iron accumulation in mitochondria. Similar effects have been demonstrated in human disease with increased markers of oxidative DNA damage in urine and impaired oxidative phosphorylation in in vivo exercise studies using 31 Phosphorus magnetic resonance spectroscopy (31P-MRS). Therapeutical trials mainly focus on antioxidative treatment with coenzyme Q10 or its short-chain variant idebenone. Promising effects on cardiac hypertrophy in uncontrolled preliminary studies contrast with minor effects in controlled trials and no effect of antioxidants on neurological deficits has been established. Preliminary encouraging 31P-MRS data exist for the treatment with L-carnitine but not with creatine. However, all these interventions may take effect too late in the pathogenic process. Alternative strategies aiming at an enhancement of frataxin by stem cell transplantation, gene transfer or frataxin supplementation are desirable. Additionally, more efficient biomarkers are needed to monitor treatment effects.     

Molecular pathogenesis of Friedreich ataxia.

Friedreich ataxia, the most common type of inherited ataxia, is itself caused in most cases by a large expansion of an intronic GAA repeat, resulting in decreased expression of the target frataxin gene. The autosomal recessive inheritance of the disease gives this triplet repeat mutation some unique features of natural history and evolution. Frataxin is a mitochondrial protein that has homologues in yeast and even in gram-negative bacteria. Yeast organisms deficient in the frataxin homologue accumulate iron in mitochondria and show increased sensitivity to oxidative stress. This suggests that Friedreich ataxia is caused by mitochondrial dysfunction and free radical toxicity.     

Friedreich's ataxia associated with mitochondrial myopathy: clinicopathologic report

A 13-year-old boy with clinical and electrophysiologic findings of Friedreich's ataxia developed unusually prominent myopathy. Skeletal muscle biopsy showed mitochondrial proliferation and structural abnormalities. No mutation was found in skeletal muscle mitochondrial DNA to explain this finding. Molecular genetic and pathologic studies confirmed a diagnosis of Friedreich's ataxia in the proband and affected relatives. Although the Friedreich's ataxia phenotype results from decreased expression of a mitochondrially targeted protein, frataxin, mitochondrial myopathy has not been described as a feature of the disease. The association between the frataxin gene mutation and mitochondrial myopathy in this case suggests that severe or cumulative insults to mitochondrial function may produce myopathic changes in some cases of Friedreich's ataxia. The patient also responded clinically to carnitine supplementation, suggesting a potential palliative therapy for the disease.     

Iron–sulfur cluster synthesis,iron homeostasis and oxidative stress in Friedreich ataxia

Friedreich ataxia (FRDA) is an autosomal recessive, multi-systemic degenerative disease that results from reduced synthesis of the mitochondrial protein frataxin. Frataxin has been intensely studied since its deficiency was linked to FRDA in 1996. The defining properties of frataxin – (i) the ability to bind iron, (ii) the ability to interact with, and donate iron to, other iron-binding proteins, and (iii) the ability to oligomerize, store iron and control iron redox chemistry – have been extensively characterized with different frataxin orthologs and their interacting protein partners. This very large body of biochemical and structural data [reviewed in (Bencze et al., 2006)] supports equally extensive biological evidence that frataxin is critical for mitochondrial iron metabolism and overall cellular iron homeostasis and antioxidant protection [reviewed in (Wilson, 2006)]. However, the precise biological role of frataxin remains a matter of debate. Here, we review seminal and recent data that strongly link frataxin to the synthesis of iron–sulfur cluster cofactors (ISC), as well as controversial data that nevertheless link frataxin to additional iron-related processes. Finally, we discuss how defects in ISC synthesis could be a major (although likely not unique) contributor to the pathophysiology of FRDA via (i) loss of ISC-dependent enzymes, (ii) mitochondrial and cellular iron dysregulation, and (iii) enhanced iron-mediated oxidative stress. This article is part of a Special Issue entitled ‘Mitochondrial function and dysfunction in neurodegeneration’.     

The molecular pathogenesis of Friedreich ataxia

Friedreich ataxia, the most frequent cause of recessive ataxia is due in most cases to a homozygous intronic expansion resulting in the loss of function of frataxin. Frataxin is a mitochondrial protein conserved through evolution. Yeast knock-out models and histological data from patients heart autopsies have shown that frataxin defect causes mitochondrial iron accumulation. Biochemical data from patients heart biopsies or autopsies have revealed a specific deficiency in the activities of aconitases and of mitochondrial iron–sulfur proteins. These results suggest that frataxin may play a role either in mitochondrial iron transport or in iron–sulfur cluster assembly or transport. Iron abnormalities suggest a pathogenic mechanism involving free radicals production and oxidative stress, a process that might be sensitive to anti-oxidant therapies.     

Clinical monitoring in a patient with friedreich ataxia and osteogenic sarcoma

Friedreich ataxia is an autosomal recessive neurodegenerative disorder caused by mutations in the FXN gene that result in abnormally low levels of the mitochondrial protein frataxin. The authors recently used a lateral flow immunoassay to measure frataxin levels in a large cohort of controls, carriers, and patients with the condition. The findings show that frataxin levels do not appreciably change over time and correlate well with GAA(1) repeat length and age of onset; thus, frataxin is a reliable and stable marker for severity of disease. In this article, the authors present a patient diagnosed as having Friedreich ataxia and osteosarcoma who received combined methotrexate, doxorubicin (Adriamycin), and cisplatin (MAP) chemotherapy over 8 months. The authors assessed the effect of treatment on frataxin levels, blood cell counts, and clinical markers of cardiomyopathy. Results of the regimen and the use of MAP chemotherapy for treatment of neoplasms in individuals with Friedreich ataxia are discussed.     

Therapeutic developments in friedreich ataxia

Friedreich ataxia is an inherited, severe, progressive neuro- and cardiodegenerative disorder for which there currently is no approved therapy. Friedreich ataxia is caused by the decreased expression and/or function of frataxin, a mitochondrial matrix protein that binds iron and is involved in the formation of iron-sulfur clusters. Decreased frataxin function leads to decreased iron-sulfur cluster formation, mitochondrial iron accumulation, cytosolic iron depletion, oxidative stress, and mitochondrial dysfunction. Cloning of the disease gene for Friedreich ataxia and elucidation of many aspects of the biochemical defects underlying the disorder have led to several major therapeutic initiatives aimed at increasing frataxin expression, reversing mitochondrial iron accumulation, and alleviating oxidative stress. These initiatives are in preclinical and clinical development and are reviewed herein.     

A novel deletion–insertion mutation identified in exon 3 of <Emphasis Type="Italic">FXN</Emphasis> in two siblings with a severe Friedreich ataxia phenotype

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease most commonly caused by a GAA trinucleotide repeat expansion in the first intron of FXN, which reduces expression of the mitochondrial protein frataxin. Approximately 98% of individuals with FRDA are homozygous for GAA expansions, with the remaining 2% compound heterozygotes for a GAA expansion and a point mutation within FXN. Two siblings with early onset of symptoms experienced rapid loss of ambulation by 8 and 10 years. Diagnostic testing for FRDA demonstrated one GAA repeat expansion of 1010 repeats and one non-expanded allele. Sequencing all five exons of FXN identified a novel deletion-insertion mutation in exon 3 (c.371_376del6ins15), which results in a modified frataxin protein sequence at amino acid positions 124–127. Specifically, the amino acid sequence changes from DVSF to VHLEDT, increasing frataxin from 211 residues to 214. Using the known structure of human frataxin, a theoretical 3D model of the mutant protein was developed. In the event that the modified protein is expressed and stable, it is predicted that the acidic interface of frataxin, known to be involved in iron binding and interactions with the iron–sulphur cluster assembly factor IscU, would be impaired.     

Friedreich ataxia: effects of genetic understanding on clinical evaluation and therapy

The discovery of the genetic cause of Friedreich ataxia has significantly affected our understanding of the disorder at both the clinical and basic science levels. Friedreich ataxia results from a deficiency of functional frataxin, a protein that appears to be involved in mitochondrial iron homeostasis. This leads to iron accumulation and mitochondrial abnormalities with consequent oxidant damage. The clinical spectrum of Friedreich ataxia has also expanded with the recognition of broader phenotypic features, including the absence of classical Friedreich ataxia features, later age at onset, and spasticity instead of ataxia. Although no proven therapy is yet available, antioxidants are a potential method for therapeutic intervention.     

Friedreich's ataxia and iron metabolism

The possible causes of abnormal iron metabolism in patients with Friedreich's ataxia are considered. Reduced expression of a frataxin homologue in yeast is associated with mitochondrial iron accumulation at the expense of cytosolic iron, and the same phenomenon can be demonstrated in these patients. A decrease in cytosolic iron causes the expression of a high-affinity iron-uptake protein, and therefore Friedreich's ataxia can be considered to be a disease of abnormal intracellular iron distribution. Friedreich's ataxia is of autosomal recessive inheritance, and the gene associated with it has been mapped to chromosome 9. This encodes the protein frataxin which regulates mitochondrial iron transport. The commonest mutation causing this disorder is an expanded GAA repeat in the gene for this protein. Different point mutations may account for some of the variations in the phenotypic features that are often found, and these variations are discussed. These findings have raised therapeutic possibilities in a condition for which previously there was no specific treatment. There are intracellular enzymes which are very sensitive to injury by oxygen-free radicals. Treatment has therefore been tried with ibebenone which acts as a free-radical scavenger, with some evidence of improvement. Iron chelating agents, such as deferoxamine, have also been given, but the finding of normal serum iron and ferritin casts doubt on the rationale of this. However the finding that the accumulation of iron in the mitochondria of the cells in patients with this form of ataxia will cause oxidative stress and cell death, gives hope for more effective treatment in the future, possibly with gene therapy.     

Multicellular models of Friedreich ataxia

Journal of Neurology - Patients with Friedreich ataxia (FRDA) have severely reduced levels of the mitochondrial protein frataxin, which results from a large GAA triplet-repeat expansion within the...     

Childhood ataxia: clinical features, pathogenesis, key unanswered questions, and future directions

Childhood ataxia is characterized by impaired balance and coordination primarily because of cerebellar dysfunction. Friedreich ataxia, a form of childhood ataxia, is the most common multisystem autosomal recessive disease. Most of these patients are homozygous for the GAA repeat expansion located on the first intron of the frataxin gene on chromosome 9. Mutations in the frataxin gene impair mitochondrial function, increase reactive oxygen species, and trigger redistribution of iron in the mitochondria and cytosol. Targeted therapies for Friedreich ataxia are undergoing testing. In addition, a centralized database, patient registry, and natural history study have been launched to support clinical trials in Friedreich ataxia. The 2011 Neurobiology of Disease in Children symposium, held in conjunction with the 40th annual Child Neurology Society meeting, aimed to (1) describe clinical features surrounding Friedreich ataxia, including cardiomyopathy and genetics; (2) discuss recent advances in the understanding of the pathogenesis of Friedreich ataxia and developments of clinical trials; (3) review new investigations of characteristic symptoms; and (4) establish clinical and biochemical overlaps in neurodegenerative diseases and possible directions for future basic, translational, and clinical studies.