- Email: [email protected]
IN72-FR-01 Ayurvedic medicine in neurology
19th World Congress of Neurology, Invited Abstracts / Journal of the Neurological Sciences 285 S1 (2009) S5–S56
gastrointestinal effects and a descending paralysis that rapidly progresses to respiratory failure in severe cases, with a high fatality rate. In all marine poisoning the diagnosis is based on the circumstances of ingestion (type of fish and location) and the clinical effects. Neurophysiological investigations may be useful in confirming the diagnosis. Findings from recent patient studies using novel excitability techniques established unique changes in human nerve and also confirmed that the neurotoxic effects in cases of puffer fish poisoning can be explained by TTX blockade of Na+ channels. Supportive care is the mainstay of therapy, including mechanical ventilation with severe paralysis. IN70-FR-02 Botulism R. Witoonpanich. Division of Neurology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Purpose: To study the patient characteristics, neurological symptoms and signs, clinical neurophysiology, predictive factors associated with respiratory failure and outcome of food-borne botulism patients from a large outbreak in Thailand. Method: A prospective observational cohort study was conducted. Neurological symptoms and signs were recorded. Pre- and postexercise single supramaximal stimulation (SSS) was performed and the best cut-off value of percentage increment for the diagnosis of botulism was estimated. Predictive factors associated with respiratory failure and weaning off ventilator were determined. Results: A total of 91 in-patients with baseline clinical characteristics were included. Most cases first presented with gastrointestinal symptoms followed by neurological symptoms, the most striking of which being difficulty in swallowing. Common clinical features included ptosis, ophthalmoplegia, proximal muscle weakness, pupillary abnormality and respiratory failure. Pre- and postexercise SSS showed incremental response in all the patients studied. A percentage increment of 25% showed a sensitivity of 95.2% and a specificity of 100%. All patients had antitoxin injection and there was no mortality in this outbreak. The median duration on ventilator was 14 days and median length of hospital stay was 13.5 days. Difficulty in breathing, moderate to severe ptosis and dilated and fixed pupils were associated with respiratory failure whereas intubated patients who had long incubation time to onset of GI symptoms (≥25 hours) and reactive pupils had better prognosis with shorter period of mechanical ventilation. Conclusion: These patients provided us with information on the clinical presentation and natural history of this disease. SSS is a simple and reliable diagnostic test for botulism. The good outcome must have been attributable to good intensive care but antitoxin, although given rather late, might have also increased the chances of survival and recovery. IN70-FR-03 Congenital myasthenic syndromes – from molecule to pathophysiology and therapy H.K.M. Lochmuller. Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom Purpose: Congenital myasthenic syndromes (CMS) are a genetically and phenotypically heterogeneous group of rare hereditary disorders affecting neuromuscular transmission. Method: The understanding of the molecular basis of the different types of CMSs has evolved rapidly in recent years. After the identification of mutations in the subunits of the nicotinic acetylcholine receptor (AChR), other genes encoding post-, pre- or synaptic proteins were determined as candidate genes for CMS, to date, mutations in ten different genes have been shown to cause CMS. Results: Pathogenic mechanisms leading to an impaired neuromuscular transmission modify AChRs or endplate structure or lead to decreased acetylcholine synthesis and release. However, the genetic background of many CMS forms is still unresolved.
S51
Conclusion: A precise molecular classification of CMS type is of paramount importance for the diagnosis, counselling and therapy of a patient, as different drugs may be beneficial or deleterious depending on the molecular background of the particular CMS.
IN71 – Neuropathy 2 IN71-FR-01 Multifocal motor neuropathy D. Cornblath. Department of Neurology, Johns Hopkins Hospital, Baltimore, United States IN71-FR-02 Vasculitic neuropathy G. Said. Neurology Service, Bicˆetre University Hospital, Le Kremlin Bicˆetre, France IN71-FR-03 Dyslipidemia and diabetic neuropathy E.L. Feldman, A. Vincent. University of Michigan, Ann Arbor, United States Emerging results from our clinical and basic studies strongly support the idea that dyslipidemia, in association with hyperglycemia, plays a role in the pathogenesis of diabetic neuropathy (DN). Progression of diabetic neuropathy was assessed in 427 participants with diabetes and known DN by comparing sural nerve myelinated fiber density at study onset and one year later. DN progression, as measured by a decrease in sural nerve myelinated fiber density, is more closely associated with elevated triglyceride levels than measures of glycated hemoglobin or insulin therapy. Similar results are present in experimental murine models of DN, where neuropathy parallels dyslipidemia and preceeds frank diabetes. In these animals, increased plasma oxidized low density lipoproteins (oxLDL), containing elevated triglycerides, correlate with systemic and nervous system measures of oxidative stress and injury. In tissue culture models of DN where sensory neurons are exposed to high glucose media, oxLDLs activate intracellular oxidative stress pathways leading to neural injury and eventual neuronal apoptosis. Microarray analysis of human sural nerve biopsies from the 427 participants with DN identify lipid and metabolism pathways as instrumental in the pathogenesis and progression of DN. Two different lipid lowering drugs (rosiglitazone and fenofibrate) ameliorate experimental DN in murine models of diabetes. Collectively, our clinical and basic studies suggest that dyslipidemia is a new therapeutic target in the treatment of DN and argue for new clinical trials aimed at controlling dyslipidemia in concert with hyperglycemia for the treatment of DN.
IN72 – Alternative medicine: neurological aspects IN72-FR-01 Ayurvedic medicine in neurology S. Prabhakar, J.S. Chopra. Department of Neurology, Postgraduate Inst. of Medical Education & Research, Chandigarh, India Ayurveda is a system of traditional medicine native to India and is considered a form of complementary alternative medicine in West. Ayurveda focuses on exercise, yoga, meditation, massage in addition to medication. There is comprehensive treatment of neurological disorders in Ayurveda. Details will be discussed. Few of the commonly used Ayurvedic medicines are described. Brahmi (Bacopa monnieri) is creeping herb commonly found throughout India. Its constituents include Alkaloids resembling strychnine in therapeutic action but less toxic. Bacopa extract contains Bacoside
S52
19th World Congress of Neurology, Invited Abstracts / Journal of the Neurological Sciences 285 S1 (2009) S5–S56
A and B known since 5000 BC. It is used in Neurology as nerve tonic, for treatment of insanity and epilepsy. It has been mentioned to improve process of learning, restoring memory, enhancing power of speech and imagination. Bacopa was documented to exert antiamnesic effect on diazepam induced anterograde amnesia in mice by the author. Brahmi has anti-oxidant effect, improving activities of defense enzymes. It has anti-stress activity in rat. Bacopa protects against electric shock seizures and chemoconvulsion. Tulsi (Occimum sanctum) called Holy Basil in West is known for its religious / spiritual sanctity. Included in Rigveda – 5000 BC. It is known to protect and reduce stress, enhance stamina, boost immune system and lessen aging factor. It has antibiotic, antioxidant and antiepileptic properties. Guggulipid (Commiphora mukul) is used in stroke to treat hyperlipidaemia. It reduces cholesterol production in liver. Sarapgandha (Rauwolfia sarpantina), Dashmool and Ashwagandha are also used in management of stroke. Ashwagandha is also used in Epilepsy. Mucuna pruriens and Vicia fava beans (English dwarf beans) have long been used in Parkinson’s disease, as natural source of L-dopa. IN72-FR-02 Traditional medicine for neurological diseases C.Z. Lu. Department of Neurology, Hua Shan Hospital, Shanghai, China China is well known for its long history of using traditional medicine (TCM) to treating the patients with various disease including neurological disorders. Traditional Medicine used in Neurological disorders includes Chinese Herbs, acupuncture and meditations. 1. Chinese herbs’ under present conditions, a new wave of modernization of TCM isoccuring along with a trend of exploring TCM as a source for discover of newtherapeutic compounds. Now a days, we have several compounds which extracted and isolated from herbs, such as Huperizine-A isolated from a Chinese herb called Qian Ceng Ta has been widely used in treating Alzheimer’s disease and cognitive disease, Egb extracted from the leaf of Gingo Biloba used in stroke, both have intravenous agent and tables: DinsengRg1,g3 and Re are used as a neuroprotectives for neurodegenerative disoders. 2. Accpuncture has been widely used in stroke, bells palsy, Sciatica and against pain. The mechanisms of pain treatment is continuely on going. 3. Meditations, we have several report that meditation can improve the epilepsy, delay the progressive of parkinsonism. IN72-FR-03 Brain and metabolic system: a holistic view on migraine from the aspect of polarity O. Koob. General Practitioner, Berlin, Germany The basis of western orientated medicine is quantity and analysis. The traditional medicine of the East and the West is more based on quality and synthesis: the inner relation of the different organs (“organ families”). One of the leading ideas for diagnosis and therapy is polarity and the connection of rhythm as a guarantee for health. In Chinese thinking it is yin and yang, in Anthroposophical medicine (a spirituell based view on the human being and nature) it is the relation of the threefold human organism in nerve and sense, rhythmical and metabolic/limb system. It has to be shown how in evolution there is an inner connection between the evolution of brain and the colon system. In migraine we have in a way a kind of over accentuation of the metabolic process. In Anthroposophical medicine there are remedies – like Kephalodoron and remedies for liver and bile- to counterbalance the tendency of migraine. Especially Kephalodoron which is a special preparation of quartz (silica), iron and sulphur helps in long terms to harmonize the brain and metabolic system.
IN73 – Neurodegeneration 2 IN73-FR-01 Ion channels in degenerative ataxias: causative mutations, genetic modifiers and targets for treatment S.M.P. Pulst. Neurology, University of Utah, Salt Lake City, United States Spinocerebellar ataxias are neurodegenerative diseases with autosomal dominant inheritance affecting the cerebellum and its connections. In this presentation, we will examine the functional interactions between polyglutamine (polyQ) proteins, voltage-gated ion channels, and intracellular Ca++ release. The CACNA1A channel subunit is important for cerebellar functioning. It is essential for generation of P/Q currents and the complex spike in Purkinje cells (PCs). CACNA1A is mutated in SCA6 by polyQ expansion in the cytoplasmic tail. Both Ca++ and Na+ currents in PCs are modulated by different classes of K+ channels. We recently mapped an ataxia mutation to CHR19 into the region containing KCNC3 (Kv3.3). Indeed, KCNC3 was mutated in a number of families now collectively referred to as SCA13. The importance of intracellular calcium levels also extends to spinocerebellar ataxia type 2 (SCA2), a polyQ disease. Although CAG length is highly correlated with age of onset (AO), the CAG repeat explains less than two-thirds of AO variance. We found that variation in the CACNA1A polyQ tract modified AO in that longer normal alleles predisposed to earlier onset. We have also explored the effects of mutant ataxin-2 on intracellular calcium release. The inositol 1,4,5-triphosphate receptor type 1 (IP3R1) has a greatly enhanced physical interaction with mutant ataxin-2. This abnormal interaction results in enhanced calcium release and exaggerated cell death upon glutamate receptor activation. Cellular toxicity was ameliorated by dantrolene, an inhibitor of the ryanodine receptor. In initial tests in an SCA2 mouse model, dantrolene treatment delayed onset of motor and morphologic abnormalities. IN73-FR-02 Friedreich’s ataxia update M. Pandolfo. Universit´e Libre de Bruxelles, Hˆ opital Erasme, Brussels, Belgium Friedreich’s ataxia (FRDA) is neuropathologically characterized by a sensory neuronopathy associated with pyramidal tract and cerebellar deep nuclei degeneration that gives rise to a very characteristic clinical picture of progressive ataxia, weakness, arefelexia, and extensor plantar responses. Visual and auditory loss, hypertrophic cardiomyopathy, skeletal abnormalities and diabetes are common complicating features. We made remarkable progress in understanding FRDA since the discovery in 1996 of the mutated gene, encoding the mitochondrial protein frataxin, and of its most common mutation, the unstable hyperexpansion of an intronic GAA triplet repeats sequence that suppresses the expression of the gene. The epigenetic mechanisms of frataxin gene silencing by the GAA repeat expansion, the structure of frataxin, its function and role in iron metabolism and antioxidant defenses and the downstream consequences of a lack of frataxin on cellular homeostasis are rapidly being elucidated. As a result, a number of therapeutic targets have been identified for this so far incurable genetic disorder. The development of cellular and animal models that recapitulate essential aspects of the disease has been key for this progress and it remains essential also to develop and pre-clinically test therapeutics. Recent clinical studies has provided a better picture of the clinical features of FRDA and generated tools to asses disease severity, its progression and the resulting functional impairment, that are essential to conduct clinical trials. There are, however, still major challenges. Several spects of pathogenesis are still undefined, the function of frataxin is incompletely understood and controversial, treatments are not yet able to stop disease progression, let alone restore lost functionality. Our current models are also
gastrointestinal effects and a descending paralysis that rapidly progresses to respiratory failure in severe cases, with a high fatality rate. In all marine poisoning the diagnosis is based on the circumstances of ingestion (type of fish and location) and the clinical effects. Neurophysiological investigations may be useful in confirming the diagnosis. Findings from recent patient studies using novel excitability techniques established unique changes in human nerve and also confirmed that the neurotoxic effects in cases of puffer fish poisoning can be explained by TTX blockade of Na+ channels. Supportive care is the mainstay of therapy, including mechanical ventilation with severe paralysis. IN70-FR-02 Botulism R. Witoonpanich. Division of Neurology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Purpose: To study the patient characteristics, neurological symptoms and signs, clinical neurophysiology, predictive factors associated with respiratory failure and outcome of food-borne botulism patients from a large outbreak in Thailand. Method: A prospective observational cohort study was conducted. Neurological symptoms and signs were recorded. Pre- and postexercise single supramaximal stimulation (SSS) was performed and the best cut-off value of percentage increment for the diagnosis of botulism was estimated. Predictive factors associated with respiratory failure and weaning off ventilator were determined. Results: A total of 91 in-patients with baseline clinical characteristics were included. Most cases first presented with gastrointestinal symptoms followed by neurological symptoms, the most striking of which being difficulty in swallowing. Common clinical features included ptosis, ophthalmoplegia, proximal muscle weakness, pupillary abnormality and respiratory failure. Pre- and postexercise SSS showed incremental response in all the patients studied. A percentage increment of 25% showed a sensitivity of 95.2% and a specificity of 100%. All patients had antitoxin injection and there was no mortality in this outbreak. The median duration on ventilator was 14 days and median length of hospital stay was 13.5 days. Difficulty in breathing, moderate to severe ptosis and dilated and fixed pupils were associated with respiratory failure whereas intubated patients who had long incubation time to onset of GI symptoms (≥25 hours) and reactive pupils had better prognosis with shorter period of mechanical ventilation. Conclusion: These patients provided us with information on the clinical presentation and natural history of this disease. SSS is a simple and reliable diagnostic test for botulism. The good outcome must have been attributable to good intensive care but antitoxin, although given rather late, might have also increased the chances of survival and recovery. IN70-FR-03 Congenital myasthenic syndromes – from molecule to pathophysiology and therapy H.K.M. Lochmuller. Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom Purpose: Congenital myasthenic syndromes (CMS) are a genetically and phenotypically heterogeneous group of rare hereditary disorders affecting neuromuscular transmission. Method: The understanding of the molecular basis of the different types of CMSs has evolved rapidly in recent years. After the identification of mutations in the subunits of the nicotinic acetylcholine receptor (AChR), other genes encoding post-, pre- or synaptic proteins were determined as candidate genes for CMS, to date, mutations in ten different genes have been shown to cause CMS. Results: Pathogenic mechanisms leading to an impaired neuromuscular transmission modify AChRs or endplate structure or lead to decreased acetylcholine synthesis and release. However, the genetic background of many CMS forms is still unresolved.
S51
Conclusion: A precise molecular classification of CMS type is of paramount importance for the diagnosis, counselling and therapy of a patient, as different drugs may be beneficial or deleterious depending on the molecular background of the particular CMS.
IN71 – Neuropathy 2 IN71-FR-01 Multifocal motor neuropathy D. Cornblath. Department of Neurology, Johns Hopkins Hospital, Baltimore, United States IN71-FR-02 Vasculitic neuropathy G. Said. Neurology Service, Bicˆetre University Hospital, Le Kremlin Bicˆetre, France IN71-FR-03 Dyslipidemia and diabetic neuropathy E.L. Feldman, A. Vincent. University of Michigan, Ann Arbor, United States Emerging results from our clinical and basic studies strongly support the idea that dyslipidemia, in association with hyperglycemia, plays a role in the pathogenesis of diabetic neuropathy (DN). Progression of diabetic neuropathy was assessed in 427 participants with diabetes and known DN by comparing sural nerve myelinated fiber density at study onset and one year later. DN progression, as measured by a decrease in sural nerve myelinated fiber density, is more closely associated with elevated triglyceride levels than measures of glycated hemoglobin or insulin therapy. Similar results are present in experimental murine models of DN, where neuropathy parallels dyslipidemia and preceeds frank diabetes. In these animals, increased plasma oxidized low density lipoproteins (oxLDL), containing elevated triglycerides, correlate with systemic and nervous system measures of oxidative stress and injury. In tissue culture models of DN where sensory neurons are exposed to high glucose media, oxLDLs activate intracellular oxidative stress pathways leading to neural injury and eventual neuronal apoptosis. Microarray analysis of human sural nerve biopsies from the 427 participants with DN identify lipid and metabolism pathways as instrumental in the pathogenesis and progression of DN. Two different lipid lowering drugs (rosiglitazone and fenofibrate) ameliorate experimental DN in murine models of diabetes. Collectively, our clinical and basic studies suggest that dyslipidemia is a new therapeutic target in the treatment of DN and argue for new clinical trials aimed at controlling dyslipidemia in concert with hyperglycemia for the treatment of DN.
IN72 – Alternative medicine: neurological aspects IN72-FR-01 Ayurvedic medicine in neurology S. Prabhakar, J.S. Chopra. Department of Neurology, Postgraduate Inst. of Medical Education & Research, Chandigarh, India Ayurveda is a system of traditional medicine native to India and is considered a form of complementary alternative medicine in West. Ayurveda focuses on exercise, yoga, meditation, massage in addition to medication. There is comprehensive treatment of neurological disorders in Ayurveda. Details will be discussed. Few of the commonly used Ayurvedic medicines are described. Brahmi (Bacopa monnieri) is creeping herb commonly found throughout India. Its constituents include Alkaloids resembling strychnine in therapeutic action but less toxic. Bacopa extract contains Bacoside
S52
19th World Congress of Neurology, Invited Abstracts / Journal of the Neurological Sciences 285 S1 (2009) S5–S56
A and B known since 5000 BC. It is used in Neurology as nerve tonic, for treatment of insanity and epilepsy. It has been mentioned to improve process of learning, restoring memory, enhancing power of speech and imagination. Bacopa was documented to exert antiamnesic effect on diazepam induced anterograde amnesia in mice by the author. Brahmi has anti-oxidant effect, improving activities of defense enzymes. It has anti-stress activity in rat. Bacopa protects against electric shock seizures and chemoconvulsion. Tulsi (Occimum sanctum) called Holy Basil in West is known for its religious / spiritual sanctity. Included in Rigveda – 5000 BC. It is known to protect and reduce stress, enhance stamina, boost immune system and lessen aging factor. It has antibiotic, antioxidant and antiepileptic properties. Guggulipid (Commiphora mukul) is used in stroke to treat hyperlipidaemia. It reduces cholesterol production in liver. Sarapgandha (Rauwolfia sarpantina), Dashmool and Ashwagandha are also used in management of stroke. Ashwagandha is also used in Epilepsy. Mucuna pruriens and Vicia fava beans (English dwarf beans) have long been used in Parkinson’s disease, as natural source of L-dopa. IN72-FR-02 Traditional medicine for neurological diseases C.Z. Lu. Department of Neurology, Hua Shan Hospital, Shanghai, China China is well known for its long history of using traditional medicine (TCM) to treating the patients with various disease including neurological disorders. Traditional Medicine used in Neurological disorders includes Chinese Herbs, acupuncture and meditations. 1. Chinese herbs’ under present conditions, a new wave of modernization of TCM isoccuring along with a trend of exploring TCM as a source for discover of newtherapeutic compounds. Now a days, we have several compounds which extracted and isolated from herbs, such as Huperizine-A isolated from a Chinese herb called Qian Ceng Ta has been widely used in treating Alzheimer’s disease and cognitive disease, Egb extracted from the leaf of Gingo Biloba used in stroke, both have intravenous agent and tables: DinsengRg1,g3 and Re are used as a neuroprotectives for neurodegenerative disoders. 2. Accpuncture has been widely used in stroke, bells palsy, Sciatica and against pain. The mechanisms of pain treatment is continuely on going. 3. Meditations, we have several report that meditation can improve the epilepsy, delay the progressive of parkinsonism. IN72-FR-03 Brain and metabolic system: a holistic view on migraine from the aspect of polarity O. Koob. General Practitioner, Berlin, Germany The basis of western orientated medicine is quantity and analysis. The traditional medicine of the East and the West is more based on quality and synthesis: the inner relation of the different organs (“organ families”). One of the leading ideas for diagnosis and therapy is polarity and the connection of rhythm as a guarantee for health. In Chinese thinking it is yin and yang, in Anthroposophical medicine (a spirituell based view on the human being and nature) it is the relation of the threefold human organism in nerve and sense, rhythmical and metabolic/limb system. It has to be shown how in evolution there is an inner connection between the evolution of brain and the colon system. In migraine we have in a way a kind of over accentuation of the metabolic process. In Anthroposophical medicine there are remedies – like Kephalodoron and remedies for liver and bile- to counterbalance the tendency of migraine. Especially Kephalodoron which is a special preparation of quartz (silica), iron and sulphur helps in long terms to harmonize the brain and metabolic system.
IN73 – Neurodegeneration 2 IN73-FR-01 Ion channels in degenerative ataxias: causative mutations, genetic modifiers and targets for treatment S.M.P. Pulst. Neurology, University of Utah, Salt Lake City, United States Spinocerebellar ataxias are neurodegenerative diseases with autosomal dominant inheritance affecting the cerebellum and its connections. In this presentation, we will examine the functional interactions between polyglutamine (polyQ) proteins, voltage-gated ion channels, and intracellular Ca++ release. The CACNA1A channel subunit is important for cerebellar functioning. It is essential for generation of P/Q currents and the complex spike in Purkinje cells (PCs). CACNA1A is mutated in SCA6 by polyQ expansion in the cytoplasmic tail. Both Ca++ and Na+ currents in PCs are modulated by different classes of K+ channels. We recently mapped an ataxia mutation to CHR19 into the region containing KCNC3 (Kv3.3). Indeed, KCNC3 was mutated in a number of families now collectively referred to as SCA13. The importance of intracellular calcium levels also extends to spinocerebellar ataxia type 2 (SCA2), a polyQ disease. Although CAG length is highly correlated with age of onset (AO), the CAG repeat explains less than two-thirds of AO variance. We found that variation in the CACNA1A polyQ tract modified AO in that longer normal alleles predisposed to earlier onset. We have also explored the effects of mutant ataxin-2 on intracellular calcium release. The inositol 1,4,5-triphosphate receptor type 1 (IP3R1) has a greatly enhanced physical interaction with mutant ataxin-2. This abnormal interaction results in enhanced calcium release and exaggerated cell death upon glutamate receptor activation. Cellular toxicity was ameliorated by dantrolene, an inhibitor of the ryanodine receptor. In initial tests in an SCA2 mouse model, dantrolene treatment delayed onset of motor and morphologic abnormalities. IN73-FR-02 Friedreich’s ataxia update M. Pandolfo. Universit´e Libre de Bruxelles, Hˆ opital Erasme, Brussels, Belgium Friedreich’s ataxia (FRDA) is neuropathologically characterized by a sensory neuronopathy associated with pyramidal tract and cerebellar deep nuclei degeneration that gives rise to a very characteristic clinical picture of progressive ataxia, weakness, arefelexia, and extensor plantar responses. Visual and auditory loss, hypertrophic cardiomyopathy, skeletal abnormalities and diabetes are common complicating features. We made remarkable progress in understanding FRDA since the discovery in 1996 of the mutated gene, encoding the mitochondrial protein frataxin, and of its most common mutation, the unstable hyperexpansion of an intronic GAA triplet repeats sequence that suppresses the expression of the gene. The epigenetic mechanisms of frataxin gene silencing by the GAA repeat expansion, the structure of frataxin, its function and role in iron metabolism and antioxidant defenses and the downstream consequences of a lack of frataxin on cellular homeostasis are rapidly being elucidated. As a result, a number of therapeutic targets have been identified for this so far incurable genetic disorder. The development of cellular and animal models that recapitulate essential aspects of the disease has been key for this progress and it remains essential also to develop and pre-clinically test therapeutics. Recent clinical studies has provided a better picture of the clinical features of FRDA and generated tools to asses disease severity, its progression and the resulting functional impairment, that are essential to conduct clinical trials. There are, however, still major challenges. Several spects of pathogenesis are still undefined, the function of frataxin is incompletely understood and controversial, treatments are not yet able to stop disease progression, let alone restore lost functionality. Our current models are also