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1.
JAMA Neurol ; 75(4): 495-502, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29356829

RESUMO

Importance: Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels. Objectives: To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations. Design, Setting, and Participants: This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016. Main Outcomes and Measures: The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations. Results: The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (ρ = -0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001). Conclusions and Relevance: The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.


Assuntos
Apraxias/congênito , Ataxia/genética , Síndrome de Cogan/genética , Proteínas de Ligação a DNA/genética , Estudos de Associação Genética , Mutação/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Apraxias/complicações , Apraxias/diagnóstico por imagem , Apraxias/genética , Ataxia/complicações , Ataxia/diagnóstico por imagem , Síndrome de Cogan/complicações , Síndrome de Cogan/diagnóstico por imagem , Avaliação da Deficiência , Feminino , Humanos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Canais de Cátion TRPC/genética , Adulto Jovem , alfa-Fetoproteínas/metabolismo
2.
Arch Neurol ; 65(7): 958-62, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18625865

RESUMO

BACKGROUND: Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease caused by SETX mutations in 9q34 resulting in cerebellar ataxia in association with peripheral neuropathy, cerebellar atrophy on imaging, an elevated alpha-fetoprotein (AFP) serum level, and occasional oculomotor apraxia. OBJECTIVE: To describe the clinical and molecular findings of 7 patients with a clinical presentation of AOA2 and their relatives. DESIGN: Case report. SETTING: Projet Hospitalier de Recherche Clinique. PATIENTS: Seven patients with AOA2 and their family members. INTERVENTION: Linkage analysis and direct sequencing of all exons of SETX were performed in all patients. Magnetic resonance imaging and electroneuromyography were performed and the patients' AFP serum levels were tested. RESULTS: We identified 7 patients with AOA2 from 4 unrelated families. Three novel SETX mutations were found. The clinical picture of the patients reported is fairly homogeneous and in accordance with the classic AOA2 presentation: onset from 13 to 18 years of progressive cerebellar ataxia and areflexia. Oculomotor apraxia was detected in 1 patient. Predominant axonal neuropathy and a diffuse cerebellar atrophy were found in the 4 patients tested. All patients had elevated AFP serum levels and 5 of 8 nonsymptomatic heterozygous relatives had moderately increased AFP serum levels as well. CONCLUSIONS: Ataxia with oculomotor apraxia type 2 is a homogeneous form of cerebellar ataxia with occasional oculomotor apraxia. Most nonsymptomatic heterozygous carriers present with increased AFP serum levels.


Assuntos
Apraxias/genética , Ataxia/genética , Doenças do Nervo Oculomotor/genética , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Apraxias/complicações , Apraxias/diagnóstico , Ataxia/complicações , Ataxia/diagnóstico , Criança , Feminino , Ligação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Doenças do Nervo Oculomotor/complicações , Doenças do Nervo Oculomotor/diagnóstico , Linhagem
3.
Neurobiol Dis ; 23(1): 97-108, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16644229

RESUMO

A severe recessive cerebellar ataxia, Ataxia-Oculomotor Apraxia 2 (AOA2) and a juvenile onset form of dominant amyotrophic lateral sclerosis (ALS4) result from mutations of the Senataxin (SETX) gene. To begin characterization this disease protein, we developed a specific antibody to the DNA/RNA helicase domain of SETX. In murine brain, SETX concentrates in several regions, including cerebellum, hippocampus and olfactory bulb with a general neuronal expression profile, colocalizing with NeuN. In cultured cells, we found that SETX was cytoplasmically diffuse, but in the nucleus, SETX was punctate, colocalizing with fibrillarin, a marker of the nucleolus. In differentiated non-cycling cells, nuclear SETX was not restricted to the nucleolus but was diffuse within the nucleoplasm, suggesting cell-cycle-dependent localization. SETX missense mutations cluster within the N-terminus and helicase domains. Flag tagging at the N-terminus caused protein mislocation to the nucleoplasm and failure to export to the cytoplasm, suggesting that the N-terminus may be essential for correct SETX localization. We report here the first characterization of SETX protein, which may provide future insights into a new mechanism leading to neuron death.


Assuntos
Ataxia/metabolismo , Doença dos Neurônios Motores/metabolismo , RNA Helicases/fisiologia , Adulto , Animais , Western Blotting , Células COS , Chlorocebus aethiops , Eletroforese em Gel de Poliacrilamida , Feminino , Imunofluorescência , Células HeLa , Humanos , Mutação
4.
DNA Repair (Amst) ; 3(11): 1493-502, 2004 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-15380105

RESUMO

Ataxia-oculomotor apraxia 1 (AOA1) is an autosomal recessive neurodegenerative disease that is reminiscent of ataxia-telangiectasia (A-T). AOA1 is caused by mutations in the gene encoding aprataxin, a protein whose physiological function is currently unknown. We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T. In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionising radiation, hydrogen peroxide, and methyl methanesulphonate (MMS). Strikingly, however, aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4. Aprataxin possesses a divergent forkhead associated (FHA) domain that closely resembles the FHA domain present in polynucleotide kinase, and appears to mediate the interactions with CK2-phosphorylated XRCC1 and XRCC4 through this domain. Aprataxin is therefore physically associated with both the DNA single-strand and double-strand break repair machinery, raising the possibility that AOA1 is a novel DNA damage response-defective disease.


Assuntos
Apraxias/genética , Apraxias/metabolismo , Ataxia/genética , Ataxia/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/metabolismo , Linhagem Celular , Dano ao DNA , Reparo do DNA , Proteínas de Ligação a DNA/química , Humanos , Técnicas In Vitro , Proteínas Nucleares/química , Doenças do Nervo Oculomotor/genética , Doenças do Nervo Oculomotor/metabolismo , Tolerância a Radiação , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Técnicas do Sistema de Duplo-Híbrido , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
5.
Nat Genet ; 36(3): 225-7, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14770181

RESUMO

Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination.


Assuntos
Ataxia Cerebelar/genética , Proteínas Fúngicas/genética , Transtornos da Motilidade Ocular/genética , RNA Helicases/genética , Mapeamento Cromossômico , Cromossomos Humanos Par 9 , DNA Helicases , Humanos , Enzimas Multifuncionais , Mutação , Proteínas de Saccharomyces cerevisiae/genética , alfa-Fetoproteínas/metabolismo
6.
Brain ; 127(Pt 4): 759-67, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-14736755

RESUMO

Ataxia with oculomotor apraxia type 2 (AOA2) is a newly described autosomal recessive cerebellar ataxia (ARCA) defined by genetic location to 9q34 of three families sharing gait ataxia, oculomotor apraxia and/or elevated alpha-foetoprotein (AFP) levels. We have evaluated 77 families with progressive non-Friedreich ARCA and have identified six families with a phenotype suggestive of AOA2. Linkage was confirmed in all six families, with a maximal lod score of 5.91 at D9S1830. We report the first detailed phenotypic study, including neuropsychological, oculographic and brain imaging investigations, in the largest series of AOA2 patients yet recruited. The mean age at onset was 15.1 +/- 3.8 years. Sensory motor neuropathy (92%) and choreic or dystonic movements (44%) were frequent. Oculomotor apraxia was observed in 56% of patients and characterized by increased horizontal saccade latencies and hypometria. AFP levels were elevated in 100% of the families, making it a useful biological marker. This study shows for the first time that AOA2 can be found in Europe, North Africa and the West Indies, and its relative frequency represents approximately 8% of non-Friedreich ARCA, which is more frequent than ataxia telangiectasia and ataxia with oculomotor apraxia type 1 (AOA1), in our series of adult patients. In adults, AOA2 may be, therefore, the most frequent cause of ARCA identified so far, after Friedreich's ataxia.


Assuntos
Apraxias/genética , Marcha Atáxica/genética , Transtornos da Motilidade Ocular/genética , Adolescente , Adulto , Idade de Início , Apraxias/fisiopatologia , Biomarcadores/sangue , Criança , Pré-Escolar , Progressão da Doença , Marcha Atáxica/fisiopatologia , Ligação Genética , Haplótipos , Humanos , Escore Lod , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos da Motilidade Ocular/fisiopatologia , Linhagem , Fenótipo , alfa-Fetoproteínas/análise
7.
Brain ; 126(Pt 12): 2761-72, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14506070

RESUMO

Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes aprataxin, has been identified recently. We studied a large series of 158 families with non-Friedreich progressive ARCA. We identified 14 patients (nine families) with five different missense or truncating mutations in the aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8 +/- 4.8 years (range 2-18 years). Cerebellar ataxia with cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with 'slow saccades'. We emphasize the phenotypic variability over the course of the disease. Cerebellar ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich's ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington's disease.


Assuntos
Apraxias/genética , Ataxia Cerebelar/genética , Transtornos da Motilidade Ocular/genética , Adulto , Apraxias/patologia , Apraxias/psicologia , Ataxia Cerebelar/patologia , Ataxia Cerebelar/psicologia , Transtornos Cognitivos/etiologia , Proteínas de Ligação a DNA/genética , Progressão da Doença , Eletroculografia , Humanos , Imageamento por Ressonância Magnética , Masculino , Mutação , Testes Neuropsicológicos , Proteínas Nucleares/genética , Transtornos da Motilidade Ocular/patologia , Transtornos da Motilidade Ocular/psicologia , Fenótipo , Nervo Sural/ultraestrutura
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