Conferencia Asociacion de Ataxias de Andalucia-2010
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Este documento proporciona una introducción a las ataxias. Define las ataxias como trastornos que afectan la coordinación motora. Explica que pueden ser hereditarias o adquiridas y enumera varios tipos específicos como la ataxia de Friedreich, las ataxias espinocerebelosas (SCA) y las ataxias episódicas. También resume varios tratamientos en investigación como la riluzol, la coenzima Q10 y la eritropoyetina. Finalmente, destaca la importancia de los neurólogos
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Conferencia Asociacion de Ataxias de Andalucia-2010
- 1. Ataxias: La visión del neurólogo Pedro J. Serrano Castro Director de la Unidad de Neurología y Neurofisiología. CHT
- 2. Concepto: ¿Qué es una ataxia? Etimológicamente deriva del griego tassein, que significa arreglar o poner en orden
- 3. Apuntes históricos Sileno ataxico, 500 a. C. apr. Nicholaus Friedreich, 1825-1882
- 5. Anatomía
- 6. Aferencias cerebelosas Informacion posicional (haz espinocerebeloso) Motilidad voluntaria (haz cortico-ponto-cerebeloso) (haz cortico-olivo-cerebeloso) (haz córtico-retinculo-cerebeloso) Información vestibular (haces vestibulo- cerebelosos) Centro de integración de información
- 7. Eferencias cerebelosas Modula y corrige la respuesta motora Controla la motilidad de la cabeza y los ojos Hace consciente toda esta información Hace consciente toda esta información
- 9. ¿De qué puede enfermar el cerebelo?
- 10. Ataxias degenerativas > 730 trastornos hereditarios asociados con Ataxia
- 11. Ataxias hereditarias Autosomal dominant • Spinocerebellar ataxias 1-29 • Dentatorubral-pallidoluysian atrophy (DRPLA) • Episodic ataxias (EA1, EA2, EA3, EA4, EA5, EA6) • Other Autosomal recessive • Friedreich ataxia • Ataxia with primary vitamin E deficiency • Abetalipoproteinemia • Ataxia-telangiectasia and other disorders of DNA repair • Ataxia with oculomotor apraxia • Congenital ataxias • Early-onset cerebellar ataxia Metabolic (inborn errors of metabolism) X-linked • Adrenoleukodystrophy: Spinocerebellar ataxia variant • X-linked sideroblastic anemia with ataxia (XLSA/A) • Other Mitochondrial • Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes • Myoclonic epilepsy with ragged red fibers • Kearns-Sayre syndrome • Neuropathy, ataxia, retinitis pigmentosa
- 12. Ataxias AR: Ataxia de Friedreich Gene map locus: 9q13, 9p23-p11 Debut antes de la adolescencia: Disartria, nistagmus, incoordinacion, apalestesia, escoliosis, pies cavos Miocardiopatia hipertrófica/hipoquinética Diabetes mellitus Disfunción visual Gen de la Frataxina 98% Expansion GAA en intron 1 2% muntuales Función biológica de la Frataxina Regular la homeostasis del Fe intramitocondrial, formación de clusters Fe-S y, secundariamente la función respiratoria de la neurona. Déficit asociado de una enzima del ciclo de Krebs que se denomina Acomitasa
- 14. Ataxias AD: SCA Name Chrom Gene Product Mutation Spinocerebellar ataxia type 1 6p23 Ataxin-1 CAG repeat expansion Spinocerebellar ataxia type 2 12q24.1 Ataxin-2 CAG repeat expansion Spinocerebellar ataxia type 3 14q32.1 Ataxin-3 CAG repeat expansion Spinocerebellar ataxia type 4 16q22.1 Spinocerebellar ataxia type 5 11p13 SPTBN2 gene Spinocerebellar ataxia type 6 19p13.1 Calcium channel CACNLA1 CAG repeat expansion Spinocerebellar ataxia type 7 3p14 Ataxin-7 CAG repeat expansion Spinocerebellar ataxia type 8 13q21 Ataxin-8 CTA/CTG repeat expansion Spinocerebellar ataxia type 10 22q13 Ataxin-10 ATTCT repeat expansion Spinocerebellar ataxia type 11 15q14-q21.3 Spinocerebellar ataxia type 12 5q32 PPP2R2B Noncoding CAG expansion Spinocerebellar ataxia type 13 19q13.3-4 KCNC3 Spinocerebellar ataxia type 14 19q13.4 Protein kinase C gamma Spinocerebellar ataxia type 15 3p24.2-3pter
- 15. Ataxias AD: SCA Spinocerebellar ataxia type 16 3p26.2-pter Spinocerebellar ataxia type 17 6q27 TATA-binding protein CAG/CAA repeat expansion Spinocerebellar ataxia type 18 7q22-q32 Spinocerebellar ataxia type 19 1p21-q12 Spinocerebellar ataxia type 20 Chrom 11 Spinocerebellar ataxia type 21 7p21.3-p15.1 Spinocerebellar ataxia type 22 1p21-q23 Spinocerebellar ataxia type 23 20p13-12.3 Spinocerebellar ataxia type 25 2p21-p13 Spinocerebellar ataxia type 26 19p13.3 Spinocerebellar ataxia type 27 13q34 FGF14 gene Spinocerebellar ataxia type 28 18p11.22- q11.2 Spinocerebellar ataxia type 29 3p26 Dentatorubral pallidoluysian atrophy 12p13.31 Atrophin-1 CAG repeat expansion Episodic ataxia 1 12p13 K channel (KCNA1) Missense mutations Episodic ataxia 2 19p13.1 Calcium channel (CACNLA1) Truncating, missense, or CAG repeat expansion Episodic ataxia 3 1q42 unknown Episodic ataxia 4 unknown unknown Episodic ataxia 5 2q22-q23 CACNB4 Episodic ataxia 6 5p SLC1A3
- 16. Investigaciones en marcha en el estudio de las ataxias
- 17. Moleculas en investigación Riluzol Coenzima Q10 Alpha-tocopherolquinone Eritropoyetina Carbamilada Litio Sodium Phenylbutyrate Deferiprone GH/IGF1 Memantine Amantadine Pioglitazone KPS-573 Idebenone EGb761 Varenicline
- 18. Idebenona
- 20. Deferiprone
- 21. Coenzima Q10-Vitamina E ↓ CoQ10 35% ↓ Vitamina E 27% La suplementación de CoQ10 y Vitamina E no produjo beneficios de forma global Se pudo identificar un subgrupo de Respondedores No hubo diferencias en función de la dosis
- 22. Riluzol
- 23. 13 Neurólogos 4 Residentes de Neurología 1 Unidad de Trastornos del movimiento 1 Unidad de Enfermedades Neuromusculares 1 Unidad de Enfermedades Desmielinizantes 1 Unidad de Epilepsia 1 Unidad de Enfermedades Cerebrovasculares Juventud Capacidad Entusiasmo
Notes de l'éditeur
- Ataxia is a neurologic symptom of incoordination derived from the Greek verb tassein , meaning to arrange or put in order, and refers to movements that are poorly ordered or organized. El prefico –a es negativo, por lo que atassein viene a significar “fuera de orden”. The Greek physician Herophilus recognized the cerebellum as a distinct division of the brain, but early studies of cerebellar anatomy and function were not performed until the 17th and 18th centuries (Dow and Moruzzi 1958) . The first extensive clinical studies that defined cerebellar syndromes included World War I soldiers who received gunshot wounds to the head (Holmes 1939) . Comparative studies between human and animal cerebelli helped define the function of the various cerebellar regions.
- La ataxia es conocida por la humanidad como una enfermedad con personalidad propia desde practicamente sus albores. Así lo atestiguan muy diversos descubrimientos antropológicos. Por referirnos a alguno cercano, en la imagen aparece una figura de origen ibero hallada en la provincia de Badajoz en el que se representa al dios Sileno, caracterizado por su ataxia. Se puede ver como trata de reequilibrar su cuerpo extendiendo los brazos. Tambien es representativo de la incomprensión a la que ancestralmente se ha sometido a esta enfermedad, pues el dios sileno en la mitología griega tuvo, a causa de su enfermedad, que sufrir las burlas del resto de los diosis del Olimpo. Nikolaus Friedreich (July 1, 1825 – 1882) was a German pathologist and neurologist , and a third generation physician in the Friedreich family. His father was psychiatrist Johann Baptist Friedreich (1796-1862), and his grandfather was pathologist Nicolaus Anton Friedreich (1761-1836), who is remembered for his early description of idiopathic facial paralysis, which would later be known as Bell's palsy . [1] In the early part of his career he studied and practiced medicine at the University of Würzburg under the tutelage of noted men such as physiologist Albert von Kölliker and pathologist Rudolf Virchow . He later became a professor of pathological anatomy at the University of Würzburg , and in 1858 he was appointed professor of pathology and therapy at the University of Heidelberg , where he remained for the rest of his career. Some of his better known students and assistants included Adolf Kussmaul , Wilhelm Heinrich Erb and Friedrich Schultze . Friedreich was involved in the establishment of pathological correlations, notably in research of muscular dystrophy , spinal ataxia and brain tumors. He is remembered today for " Friedreich's ataxia ", which he identified in 1863 . It is a degenerative disease with sclerosis of the spinal cord which affects a person's speech, balance and coordination.
- Born in Ireland (Dundalk) in 1876, Holmes emerged as one of the great clinical neurologists in this discipline. He performed classic research on the localization of function in the cerebellum. In 1904, together with Grainger Stewart, they wrote a paper in precise localization of destructive lesions in the cerebellum. He published considerably on the symptoms of expanding lesions, on disturbances of vision (chiefly caused by cerebral lesions) with special attention drawn to the critical representation of the macula and visual orientation. His name appears in syndromes and signs of cerebellar disturbance.
- El cerebelo se asocia con un número clave: el 3. Son tres las áreas en las que se divide sagitalmente y 3 los lóbulos en los que se divide horizontalmente. Se conecta con el tronco cerebral por 3 pares de pedúnculos cerebelosos y su corteza está formada por tres capas histológicas. Por último, existen tres síndromes cerebelosos diferentes. En la imagen de la izquierda aparece un cerebelo visto por su parte superior y por su parte inferior. La parte del centro recibe el nombre de vermis cerebeloso, haciendo referencia a su parecido con un gusano. Es la parte que enferma en las enfermedades que llevan ataxia de la marcha. Las partes laterales se denominan hemisferios cerebelosos. De adelante hacia atrás la división se realiza en dos lóbulos: anterior y posterior, separados por el surco primario. En la imagen de la derecha se visualiza una seccion lateral del cerebelo, identificandose el lóbulo posterior y el lóbulo anterior, con una estructura totalmente diferente. Pero más importante que su distribución anatómica es su distribución funcional. En este sentido tienen importancia 3 nucleos: dentado, interpuesto y fastigial.
- Aferencias Cerebelosas Como se mencionó al principio el cerebelo se divide en tres lóbulos y cada uno de ellos recibe aferencias específicas diferentes. Así por ejemplo el neocerebelo recibe las aferencias provenientes de la corteza cerebral, la cual regula la actividad del cerebelo a través de tres circuitos; 1) el córtico-póntico-cerebeloso, 2) el córtico-ólivo-cerebeloso y 3) el córtico-retículo-cerebeloso. El circuito córtico-póntico-cerebeloso se origina en amplias regiones de la corteza frontal, parietal, temporal y occipital. Los axones de las neuronas piramidales de esas áreas descienden a través de la corona radiada, cápsula interna, pedúnculos cerebrales para sinaptar luego en los núcleos pontinos ipsilaterales. Desde estos núcleos los axones cruzan al lado opuesto formando las fibras transversales del puente para luego ingresar por los pedúnculos cerebelosos medios a la corteza del hemisferio contralateral, como fibras musgosas. El circuito córtico-ólivo-cerebeloso se origina también en áreas de la corteza frontal, parietal, temporal y occipital, de allí igual que el circuito anterior los axones descienden a través de la corona radiada, cápsula interna, para terminar sinaptando directamente en el núcleo olivar del bulbo o llegar a éste a trevés de una conección previa en cuerpo estriado. El núcleo olivar proyecta a su vez a la corteza neocerebelosa por los pedúnculos cerebelosos inferiores mediante las fibras trepadoras. El circuito córtico-retículo-cerebeloso se origina en áreas amplias de la corteza cerebral, especialmente las áreas sómatosensorial y motora. Desde allí los axones descienden hasta la formación reticular del tronco la cual conecta a su vez con el neocerebelo vía pedúnculo cerebeloso inferior y medio, mediante fibras musgosas. Todos los circuitos que la corteza cerebral establece con el cerebelo son importantes en el control de los movimientos voluntarios, ejerciendo estos circuitos los mecanismos de ajuste, coordinación y sincronización necesarios. El paleocerebelo recibe la información propioceptiva del cuerpo a través de tres vías 1) el tracto espinocerebeloso anterior, 2) el tracto espinocerebeloso posterior, 3) el tracto cuneocerebeloso. El tracto espinocerebeloso anterior se origina del núcleo torácico de la médula espinal. La mayoría de los axones de las neuronas de éste núcleo cruzan al lado opuesto, otros axones ascienden por el mismo lado. Este tracto penetra al cerebelo por el pedúnculo cerebeloso superior, terminando en la corteza del paleocerebelo como fibras musgosas. La información que conduce es propiocepción de husos neuromusculares receptores de tendones y articulaciones de mienbro superior e inferior, además de información de la piel y fascia superficial. El tracto espinocerebeloso posterior tambien se origina en el núcleo torácico de la médula espinal, pero en éste caso todos los axones que forman este tracto no se decusan, ascendiendo por el mismo lado de la médula para luego entrar al cerebelo vía pedúnculo cerebeloso inferior y terminar en la corteza del paleocerebelo como fibras musgosas. La información conducida es propiocepción del tronco y extremidad inferior. El tracto cuneocerebeloso se origina en el núcleo cuneatus accesorio del bulbo raquídeo. Los axones penetran al cerebelo por el pedúnculo cerebeloso inferior terminando en la corteza del paleocerebelo como fibras musgosas. Este circuito lleva información propioceptiva de músculos del cuello. El arquicerebelo recibe información vestibular de posición de la cabeza en el espacio. Estas aferencias provienen de núcleos vestibulares o directamente de neuronas del ganglio vestibular del oído interno. Los axones penetran por los pedúnculos cerebelosos inferiores y terminan en la corteza del arquicerebelo como fibras musgosas.
- Eferencias del Cerebelo La corteza cerebelosa envía todas sus eferencias por medio de las neuronas de Purkinje hacia los núcleos intracerebelosos. Estos núcleos a su vez proyectan hacia el tronco cerebral y al diencéfalo a través de circuitos que transcurren por el pedúnculo cerebeloso superior. diversos -Vía dentotalámica. Los núcleos dentados envían axones que transcurriendo por el pedúnculo cerebeloso superior, lugar en que decusan al lado opuesto, terminan sinaptando en el tálamo (núcleo ventral lateral principalmente). Luego los axones del tálamo ascienden por cápsula interna y corona radiada para terminar en el área motora primaria de la corteza cerebral. Este circuito permite que el neocerebelo de un lado influya en la actividad de la corteza motora del lado opuesto. Como la corteza motora a su vez controla los movimientos voluntarios de las motoneuronas inferiores del lado contralatreral, se entiende que el hemicerebelo de un lado coordine la actividad muscular del mismo lado del cuerpo. -Vías dentato-rubral, globoso-rubral y emboliforme-rubral. Tanto los núcleos dentados, globosos como emboliforme envian axones, por pedúnculos cerebelosos superiores, al núcleo rojo del lado opuesto. Este núcleo proyecta hacia médula espinal por el tracto rubro-espinal que también se decusa. Del mismo modo que el circuito anterior los núcleos dentados, globosos y emboliformes que reciben aferencias de las neuronas de Purkinje del neocerebelo y del paleocerebelo, influyen en la actividad motora del mismo lado del cuerpo. -Vía fastigio vestibular. Los axones de las neuronas de los núcleos fastigio que transcurren por los pedúnculos cerebelosos inferiores sinaptan principalmente en los núcleos vestibulares laterales. El núcleo vestibular lateral da origen al tracto vestíbulo espinal influyendo así en las motoneuronas del asta anterior. Algunos axones de los núcleos fastigios proyectan a la formación reticular del tronco cerebral de modo que vía tracto retículo-espinal también pueden influir en la motoneurona inferior. Como resumen de todo el funcionamiento de los circuitos antes mencionados podemos decir que el cerebelo actua automáticamente (sin participación de la conciencia) en la coordinación de los movimientos precisos y finos del cuerpo, comparando la actidad de la corteza motora con la información propioceptiva que recibe de músculos tendones y articulaciones. Así puede realizar los ajustes necesarios de la actividad de las motoneuronas inferiores, como por ejemplo el nivel de descarga de ellas. Tambien el cerebelo envía información a la corteza cerebral motora para inhibir la musculatura antagonista y estimular los musculos agonistas, permitiendo hacer mas fluidos y precisos los movimientos voluntarios. Otra función en la que participa el cerebelo es la mantención del equilibrio por las conecciones que mantiene con el sistema vestibular y por las modificaciones que puede realizar del tonus muscular. Por último el cerebelo juega un rol importante en la mantención de la postura del cuerpo.
- La ataxia no es una enfermedad, sino un signo y tambien un síntoma clínico. Como sabeis, la neurologia es la especialidad semiológica por antonomasia. Es labor del neurólogo clasificar las características de cada una, identificarla y posteriormente indagar acerca de su etiologia
- Friedreich ataxia is one of the most common forms of autosomal recessive ataxia. Clinical Features: FRDA, the spinocerebellar tracts, dorsal columns, pyramidal tracts and, to a lesser extent, the cerebellum and medulla are involved. The disorder is usually manifest before adolescence and is generally characterized by incoordination of limb movements, dysarthria, nystagmus, diminished or absent tendon reflexes, Babinski sign, impairment of position and vibratory senses, scoliosis, pes cavus, and hammer toe. The triad of hypoactive knee and ankle jerks, signs of progressive cerebellar dysfunction, and preadolescent onset is commonly regarded as sufficient for diagnosis. McLeod (1971) found abnormalities in motor and sensory nerve conduction. Molecular Genetics Back to Top Delatycki et al. (1999) stated that 2% of cases of Friedreich ataxia are due to point mutations in the FXN gene ( 606829 ), the other 98% being due to expansion of a GAA trinucleotide repeat in intron 1 of the FXN gene ( 606829.0001 ). They indicated that 17 mutations had so far been described. Similarly, Lodi et al. (1999) cited data indicating that the GAA triplet expansion in the first intron of the FXN gene is the cause of Friedreich ataxia in 97% of patients. Genotype/Phenotype Correlations Back to Top Filla et al. (1996) studied the relationship between the trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. The length of the FA alleles ranged from 201 to 1,186 repeat units. There was no overlap between the size of normal alleles and the size of alleles found in FA. The lengths of both the larger and the smaller alleles varied inversely with the age of onset of the disorder. Filla et al. (1996) reported that the mean allele length was significantly higher in FA patients with diabetes and in those with cardiomyopathy. They noted that there was meiotic instability with a median variation of 150 repeats. Isnard et al. (1997) examined the correlation between the severity of left ventricular hypertrophy in Friedreich ataxia and the number of GAA repeats. Left ventricular wall thickness was measured in 44 patients using M-mode echocardiography and correlated with GAA expansion size on the smaller allele (267 to 1200 repeats). A significant correlation was found (r = 0.51, p less than 0.001), highlighting an important role for frataxin in the regulation of cardiac hypertrophy. In a study of 187 patients with autosomal recessive ataxia, Durr et al. (1996) found that 140, with ages at onset ranging from 2 to 51 years, were homozygous for a GAA expansion that had 120 to 1,700 repeats of the trinucleotides. About one-quarter of the patients, despite being homozygous, had atypical Friedreich ataxia; they were older at presentation and had intact tendon reflexes. Larger GAA expansions correlated with earlier age at onset and shorter times to loss of ambulation. The size of the GAA expansions (and particularly that of the smaller of each pair of alleles) was associated with the frequency of cardiomyopathy and loss of reflexes in the upper limbs. The GAA repeats were unstable during transmission. Thus, the clinical spectrum of Friedreich ataxia is broader than previously recognized, and the direct molecular test for the GAA expansion is useful for the diagnosis, prognosis, and genetic counseling. Pianese et al. (1997) presented data suggesting that (1) the FRDA GAA repeat is highly unstable during meiosis, (2) contractions outnumber expansions, (3) both parental source and sequence length are important factors in variability of FRDA expanded alleles, and (4) the tendency to contract or expand does not seem to be associated with particular haplotypes. Thus, they concluded that FRDA gene variability appears to be different from that found with other triplet diseases. Bidichandani et al. (1997) found an atypical FRDA phenotype associated with a remarkably slow rate of disease progression in a Caucasian family. It was caused by compound heterozygosity for a G130V missense mutation ( 606829.0005 ) and the GAA expansion of the FXN gene. The missense mutation G130V was the second mutation to be identified in the FXN gene and the first to be associated with a variant FRDA phenotype. This and the other reported missense mutation (I154F; 606829.0004) mapped within the highly conserved sequence domain in the C-terminus of the frataxin gene. Since the G130V mutation was unlikely to affect the ability of the first 16 exons of the neighboring STM7 gene to encode a functional phosphatidylinositol phosphate kinase, Bidichandani et al. (1997) questioned the role of STM7 in Friedreich ataxia. McCabe et al. (2002) reported phenotypic variability in 2 affected sibs with compound heterozygosity for the G130V mutation and a GAA expansion. The first sib, a 34-year-old man, first presented at age 10 with leg stiffness and mild gait ataxia and later developed significant limb spasticity. His sister had onset of disease at age 15, with progressive ataxia and lack of limb spasticity. Since Friedreich ataxia is an autosomal recessive disease, it does not show typical features observed in other dynamic mutation disorders, such as anticipation. Monros et al. (1997) analyzed the GAA repeat in 104 FA patients and 163 carrier relatives previously defined by linkage analysis. The GAA expansion was detected in all patients, most (94%) of them being homozygous for the mutation. They demonstrated that clinical variability in FA is related to the size of the expanded repeat: milder forms of the disease (late-onset FA and FA with retained reflexes) were associated with shorter expansions, especially with the smaller of the 2 expanded alleles. Absence of cardiomyopathy was also associated with shorter alleles. Dynamics of the GAA repeat were investigated in 212 parent-offspring pairs. Meiotic instability showed a sex bias: paternally transmitted alleles tended to decrease in a linear way that depended on the paternal expansion size, whereas maternal alleles either increased or decreased in size. All but 1 of the patients with late-onset FA were homozygous for the GAA expansion; the exceptional individual was heterozygous for the expansion and for another unknown mutation. All but 1 of the FA patients with retained reflexes exhibited an axonal sensory neuropathy. However, preservation of their tendon reflexes suggested that the physiologic pathways of the reflex arch remained functional. A close relationship was found between late-onset disease and absence of heart muscle disease. Delatycki et al. (1999) studied FRDA1 mutations in FA patients from Eastern Australia. Of the 83 people studied, 78 were homozygous for an expanded GAA repeat, while the other 5 had an expansion in one allele and a point mutation in the other. The authors presented a detailed study of 51 patients homozygous for an expanded GAA repeat. They identified an association between the size of the smaller of the 2 expanded alleles and age at onset, age into wheelchair, scoliosis, impaired vibration sense, and the presence of foot deformity. However, no significant association was identified between the size of the smaller allele and cardiomyopathy, diabetes mellitus, loss of proprioception, or bladder symptoms. The larger allele size was associated with bladder symptoms and the presence of foot deformity.
- The antioxidant idebenone, a homologue of ubiquinone that inhibits iron-induced cardiac injury, has been shown to decrease or stabilize cardiac hypertrophy (Hausse et al 2002; Mariotti et al 2003). However, other studies have failed to show a benefit of idebenone therapy (Lodi et al 2001; Schols et al 2001). Idebenone is well tolerated in paediatric and adult patients. Most trials demonstrated a positive effect on cardiac hypertrophy. The neurological function is in general not modified in adult patients, but a dose-dependent effect was demonstrated in young Friedreich's ataxia patients. Further double-blinded high-dose trials should evaluate idebenone in Friedreich's ataxia early in the disease course. BACKGROUND: Friedreich's ataxia (FA) is a progressive, multisystem, degenerative disorder caused by a reduction in frataxin. Loss of frataxin results in mitochondrial dysfunction and oxidative damage in patients and model systems. Previous studies have indicated that the antioxidant idebenone (5 mg/kg daily) reduces cardiac hypertrophy, but definite improvement in neurological function has not been shown. METHODS: 48 genetically confirmed FA patients, aged 9-17 years, were enrolled in a 6-month, randomised, double-blind, placebo-controlled study. The patients received placebo or one of three doses of idebenone (approximately 5 mg/kg, 15 mg/kg, and 45 mg/kg), stratified by body weight. The primary endpoint was change from baseline in urinary 8-hydroxy-2'-deoxyguanosine (8OH2'dG), a marker of oxidative DNA damage. Secondary endpoints included changes in the international cooperative ataxia rating scale (ICARS), the FA rating scale (FARS), and a survey of activities of daily living (ADL). This study is registered with ClinicalTrials.gov, number NCT00229632. FINDINGS: Idebenone was generally well tolerated with similar numbers of adverse events in each group. One child receiving high-dose idebenone developed neutropenia after 6 months, which resolved after discontinuation of treatment. 8OH2'dG concentrations were not increased, and did not significantly change with idebenone treatment. Whereas an overall analysis did not show a significant difference in ICARS, FARS, or ADL total scores, there were indications of a dose-dependent response in the ICARS score. A second, pre-specified analysis, excluding patients who required wheelchair assistance, showed a significant improvement in ICARS (Bonferroni p=0.03) and suggested a dose-related response in ICARS, FARS, and ADL scores. INTERPRETATION: Treatment with higher doses of idebenone was generally well tolerated and associated with improvement in neurological function and ADL in patients with FA. The degree of improvement correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a beneficial effect on neurological function.
- Eur J Clin Invest 2010 Abstract Background Friedreich's ataxia (FRDA) is a neurodegenerative disorder caused by decreased expression of the mitochondrial protein frataxin. Recently we showed in a clinical pilot study in Friedreich's ataxia patients that recombinant human erythropoietin (rhuEPO) significantly increases frataxin-expression. In this in vitro study, we investigated the role of the erythropoietin receptor (EPO-R) in the frataxin increasing effect of rhuEPO and if non-erythropoietic carbamylated erythropoietin (CEPO), which cannot bind to the classical EPO-R increases frataxin expression. Materials and methods In our experiments human erythroleukaemic K562 cells (+ EPO-R), human monocytic leukemia THP-1 cells (- EPO-R) and isolated primary lymphocytes from healthy control and FRDA patients were incubated with different concentrations of rhuEPO or CEPO. Frataxin-expression was detected by an electrochemical luminescence immunoassay (based on the principle of an ELISA). Results We show that rhuEPO increases frataxin-expression in K562 cells (expressing EPO-R) as well as in THP-1 cells (without EPO-R expression). These results were confirmed by the finding that CEPO, which cannot bind to the classical EPO-R increased frataxin expression in the same concentration range as rhuEPO. In addition, we show that both EPO derivatives significantly increase frataxin-expression in vitro in control and Friedreich's ataxia patients primary lymphocytes. Conclusion Our results provide a scientific basis for further studies examining the effectiveness of nonerythropoietic derivatives of erythropoietin for the treatment of Friedreich's ataxia patients.
- Background: Friedreich ataxia is a neurological disease originating from an iron-sulfur cluster enzyme deficiency due to impaired iron handling in the mitochondrion, aconitase being particularly affected. As a mean to counteract disease progression, it has been suggested to chelate free mitochondrial iron. Recent years have witnessed a renewed interest in this strategy because of availability of deferiprone, a chelator preferentially targeting mitochondrial iron. Method: Control and Friedreich's ataxia patient cultured skin fibroblasts, frataxin-depleted neuroblastoma-derived cells (SK-N-AS) were studied for their response to iron chelation, with a particular attention paid to iron-sensitive aconitase activity. Results: We found that a direct consequence of chelating mitochondrial free iron in various cellsystems is a concentration and time dependent loss of aconitase activity. Impairing aconitase activity was shown to precede decreased cell proliferation. Conclusion: We conclude that, if chelating excessive mitochondrial iron may be beneficial at some stage of the disease, great attention should be paid to not fully deplete mitochondrial iron store in order to avoid undesirable consequences.
- BACKGROUND AND PURPOSE: A pilot study of high dose coenzyme Q(10) (CoQ(10))/vitamin E therapy in Friedreich's ataxia (FRDA) patients resulted in significant clinical improvements in most patients. This study investigated the potential for this treatment to modify clinical progression in FRDA in a randomized double blind trial. METHODS: Fifty FRDA patients were randomly divided into high or low dose CoQ(10)/ vitamin E groups. The change in International Co-operative Ataxia Ratings Scale (ICARS) was assessed over 2 years as the primary end-point. A post hoc analysis was made using cross-sectional data. RESULTS: At baseline serum CoQ(10) and vitamin E levels were significantly decreased in the FRDA patients (P < 0.001). During the trial CoQ(10) and vitamin E levels significantly increased in both groups (P < 0.01). The primary and secondary end-points were not significantly different between the therapy groups. When compared to cross-sectional data 49% of all patients demonstrated improved ICARS scores. This responder group had significantly lower baseline serum CoQ(10) levels. CONCLUSIONS: A high proportion of FRDA patients have a decreased serum CoQ(10) level which was the best predictor of a positive clinical response to CoQ(10)/vitamin E therapy. Low and high dose CoQ(10)/vitamin E therapies were equally effective in improving ICARS scores.
- BACKGROUND: The pleiotropic effects of riluzole may antagonize common mechanisms underlying chronic cerebellar ataxia, a debilitating and untreatable consequence of various diseases. METHODS: In a randomized, double-blind, placebo-controlled pilot trial, 40 patients presenting with cerebellar ataxias of different etiologies were randomly assigned to riluzole (100 mg/day) or placebo for 8 weeks. The following outcome measures were compared: proportion of patients with a decrease of at least 5 points in the International Cooperative Ataxia Rating Scale (ICARS) total score after 4 and 8 weeks compared with the baseline score; mean changes from the baseline to posttreatment ICARS (total score and subscores at 8 weeks); and occurrence of adverse events. RESULTS: Riluzole and placebo groups did not differ in baseline characteristics. The number of patients with a 5-point ICARS drop was significantly higher in the riluzole group than in the placebo group after 4 weeks (9/19 vs 1/19; odds ratio [OR] = 16.2; 95% confidence interval [CI ] 1.8-147.1) and 8 weeks (13/19 vs 1/19; OR = 39.0; 95% CI 4.2-364.2). The mean change in the riluzole group ICARS after treatment revealed a decrease (p < 0.001) in the total score (-7.05 [4.96] vs 0.16 [2.65]) and major subscores (-2.11 [2.75] vs 0.68 [1.94] for static function, -4.11 [2.96] vs 0.37 [2.0] for kinetic function, and -0.74 [0.81] vs 0.05 [0.40] for dysarthria). Sporadic, mild adverse events occurred. CONCLUSIONS: These findings indicate the potential effectiveness of riluzole as symptomatic therapy in diverse forms of cerebellar ataxia. Classification of evidence: This study provides Class I evidence that riluzole reduces, by at least 5 points, the ICARS score in patients with a wide range of disorders that cause cerebellar ataxia (risk difference 63.2%, 95% CI 33.5%-79.9%).