Oculomotor Apraxia Type Research Articles

Tight expression regulation of senataxin, linked to motor neuron disease and ataxia, is required to avert cell-cycle block and nucleolus disassembly

The Senataxin (SETX) protein exhibits strong sequence conservation with the helicase domain of the yeast protein Sen1p, and recessive SETX mutations cause a severe ataxia, known as Ataxia with Oculomotor Apraxia type 2, while dominant SETX mutations cause Amyotrophic Lateral Sclerosis type 4. SETX is a very low abundance protein, and its expression is tightly regulated, such that large increases in mRNA levels fail to significantly increase protein levels. Despite this, transient transfection in cell culture can boost SETX protein levels on an individual cell basis. Here we found that over-expression of normal SETX, but not enzymatically-dead SETX, is associated with S-phase cell-cycle arrest in HEK293A cells. As SETX interacts with the nuclear exosome to ensure degradation of incomplete RNA transcripts, and SETX localizes to sites of collision between the DNA replication machinery and the RNAP II complex, altered dosage or aberrant function of SETX may impede this process to promote S-phase cell-cycle arrest. Because neurons are enriched for long transcripts with additional antisense regulatory transcription, collisions of RNAP II complexes may occur in such post-mitotic cells, underscoring a role for SETX in maintaining neuron homeostasis.

Positional Hemiseesaw Nystagmus in Ataxia with Oculomotor Apraxia Type 2 due to a Novel Senataxin Gene Mutation: A New Phenotype

Positional Hemiseesaw Nystagmus in Ataxia with Oculomotor Apraxia Type 2 due to a Novel Senataxin Gene Mutation: A New Phenotype

Clinical Features and Molecular Genetics of Autosomal Recessive Ataxia in the Turkish Population.

ABSTRACTBackground:Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of inherited neurodegenerative disorders. The aim of this study was to present the clinical and genetic features of patients with ataxia complaints and those genetically diagnosed with ARCAs.Materials and Methods:Thirty-one children with ARCA were retrospectively analyzed.Results:Fourteen (45.2%) were boys and 17 (54.8%) were girls with the mean age at onset of symptoms of 46.13 ± 26.30 months (12–120 months). Of the 31 patients, 21 (67.7%) were from consanguineous marriages. Eight patients had Friedreich’s ataxia, five had ataxia telangiectasia, three had L-2-hydroxyglutaric aciduria, three had Joubert syndrome, two had neuronal ceroid lipofuscinosis, two had megalencephalic leukoencephalopathy with subcortical cysts, two had ataxia with ocular motor oculomotor apraxia type 1, one had cytochrome c oxidase deficiency, one had autosomal recessive spastic ataxia of Charlevoix-Saguenay, one had Niemann-Pick type C, one had congenital disorders of glycosylation, one had adrenoleukodystrophy, and one had cobalamin transport disorder.Conclusion:The prevalence of hereditary ataxia can vary among countries. The consanguineous marriage is an important finding in these diseases. These genetic tests will increase the number of ARCA patients diagnosed.

Progressive Ataxia with Elevated Alpha-Fetoprotein: Diagnostic Issues and Review of the Literature

<strong>Background:</strong> Ataxias represent a challenging group of disorders due to significant clinical overlap. Here, we present a patient with early-onset progressive ataxia, polyneuropathy and discuss how elevation of alpha fetoprotein (AFP) narrows the differential diagnosis. <strong>Case report:</strong> Ataxia, polyneuropathy, and mild elevation of AFP are features compatible with ataxia with oculomotor apraxia type 2 (AOA2) but also with ataxia with oculomotor apraxia type 4 (AOA4). A genetic analysis demonstrated biallelic mutations in senataxin (<em>SETX</em>), confirming the diagnosis of AOA2. <strong>Discussion:</strong> Mild elevation of AFP is found in patients with AOA2 and AOA4, and higher levels are commonly seen in ataxia-telangiectasia. AFP is a useful diagnostic tool but not a biomarker for disease progression in AOA2.

Genetic and phenotypic features of patients with childhood ataxias diagnosed by next-generation sequencing gene panel

BackgroundThe purpose of this prospective study was to identify the characteristics of pediatric recessive ataxias and the mutations leading to them. MethodsEighty-four pediatric patients aged 0–18 years presenting to our clinic, evaluated by means of imaging, metabolic or pathological investigation, or single-gene test, in whom Friedreich’s ataxia was excluded, and predicted to carry the progressive autosomal recessive ataxia gene were included in the study. Patients’ demographic, clinical, laboratory, and radiological characteristics were recorded. DNA and panel sequencing directed toward ataxia-related genes was performed using the next-generation sequencing method. ResultsA molecular diagnosis was established in 21 (25%) of the 84 patients. Genetically, infantile neuroaxonal dystrophy (7/21), ataxia with oculomotor apraxia type 1 (5/21), neuronal ceroid lipofuscinosis type 5 (2/21), ataxia with oculomotor apraxia type 2 (1/21), Lafora disease (1/21), tremor ataxia syndrome accompanying central hypomyelination (1/21), Charlevoix-Saguenay ataxia (1/21), Marinesco-Sjögren syndrome (1/21), VLDRL-associated cerebellar hypoplasia (1/21), and TSEN54-related pontocerebellar hypoplasia (1/21) mutations were detected. ConclusionsApproximately 25% of our patients were diagnosed. Novel mutations in the known genes were identified and are important in terms of phenotype-genotype correlation.

Disruption of spermatogenesis and infertility in Ataxia with Oculomotor Apraxia Type 2 (AOA2) (P4.7-003)

Disruption of spermatogenesis and infertility in Ataxia with Oculomotor Apraxia Type 2 (AOA2) (P4.7-003)

Ataxia with Oculomotor Apraxia Type 4 with PNKP Common "Portuguese" and Novel Mutations in Two Belarusian Families.

Ataxia with oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive, PNKP -related disorder delineated in 2015 in Portugal. We diagnosed AOA4 by next generation sequencing (NGS) followed by Sanger's sequencing in three boys from two unrelated Belarusian families. In both families, one of the heterozygous PNKP mutations was c.1123G>T, common in Portuguese patients; biallelic mutations, c.1270_1283dup14 and c.1029+2T>C, respectively, were novel. These are the first reported AOA4 Slavic cases and the first with a "Portuguese" PNKP mutation outside Portugal. Distinction in two brothers was microcephaly but their disease was not severe in contrast to PNKP -related "microcephaly, seizures, and developmental delay" and reported cases with features of both phenotypes.

Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis in Aprataxin-deficient cells.

Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset progressive spinocerebellar ataxia caused by mutation in aprataxin (APTX). APTX removes 5'-AMP groups from DNA, a product of abortive ligation during DNA repair and replication. APTX deficiency has been suggested to compromise mitochondrial function; however, a detailed characterization of mitochondrial homeostasis in APTX-deficient cells is not available. Here, we show that cells lacking APTX undergo mitochondrial stress and display significant changes in the expression of the mitochondrial inner membrane fusion protein optic atrophy type 1, and components of the oxidative phosphorylation complexes. At the cellular level, APTX deficiency impairs mitochondrial morphology and network formation, and autophagic removal of damaged mitochondria by mitophagy. Thus, our results show that aberrant mitochondrial function is a key component of AOA1 pathology. This work corroborates the emerging evidence that impaired mitochondrial function is a characteristic of an increasing number of genetically diverse neurodegenerative disorders.

Ataxia with Oculomotor Apraxia Type 1-New Mutation, Characteristic Phenotype.

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Diagnostic algorithm for autosomal recessive ataxia

To develop a complex algorithm for autosomal recessive ataxia (ARA) diagnosis applicable for Russian patients with degenerative ataxias. 48 patients with of presumably degenerative ataxias were examined. Clinical evaluation was performed with the use of the SARA and ICARS scales (for ataxia) and MoCA (cognitive functions), and a set of laboratory tests was carried out, including electromyography, brain MRI, and DNA analysis of mutations responsible for Friedreich's disease and spinocerebellar ataxias (SCAs) types 1, 2, 3, 6 and 17. 28 patients underwent mutation screening using a multigenic MPS panel. 8 patients (16.7%) with non-hereditary causes of ataxia were identified: cerebellar alcoholic degeneration (n = 6) and multiple system atrophy of cerebellar type (n = 2); 3 patients (6.3%) with genetic ataxias were identified using routine DNA tests, such as with SCA type 1, 2 and 17, and 9 (18.8%) patients with Friedreich's disease. The MPS panel enabled molecular diagnosis of ARA in 8 patients (28.6%): ataxia-telangiectasia (n = 2), SANDO syndrome (n = 2), ataxia with oculomotor apraxia type 2 (n = 1), SCAR10 (n = 1), SCAR16 (n = 1), and atypical form of neuroaxonal dystrophy (n = 1). The diagnosis was not established in 20 patients. We have proposed an appropriate algorithm for degenerative ataxia diagnosis which is recommended to be used when examining patients with sporadic and autosomal recessive cases of the disorders with dyscoordination of movements.

A case series of hereditary cerebellar ataxias in a highly consanguineous population from Northeast Brazil

BackgroundThere are few studies reporting characteristics of patients with cerebellar ataxias in the Brazilian population. The aim of this study was to provide a detailed neurological description of patients with hereditary ataxia followed by a neurology outpatient service in Brazil. MethodsNeurological and clinical evaluation of patients with hereditary ataxia was performed at a neurology service outpatient clinic of a hospital in Northeast Brazil between October 2013 and January 2015. ResultsA total of 47 patients had ataxia as the main symptom. A high prevalence of consanguinity was found in the population studied (40.4%). Mean age was 38.4 ± 15.3 years, mean age at disease onset was 25.6 ± 17.3 years, mean disease duration was 12.8 ± 9.7 years, and mean score on the Scale for the Assessment and Rating of Ataxia (SARA) was 18.4 ± 7.7. Patients with recessive pattern of inheritance were younger, had earlier age at disease onset and greater severity of ataxia, measured by the SARA. Diagnosis was confirmed by molecular analysis, laboratory exams or biopsy in 42.56% (n = 20) of these patients. The most prevalent diseases were: Friedreich's ataxia in 35% (n = 7), Niemann-Pick type C (NPC) in 15% (n = 3), and ataxia with oculomotor apraxia type 2 in 15% (n = 3). ConclusionsIn contrast with other studies, our prevalence of recessive ataxias was much higher than that of dominant ataxias. These findings might be explained by the high number of patients living in rural areas with a higher rate of consanguineous marriages, absence of a dominant ataxia founder effect or difficult access to healthcare system.

Genetic analysis of undiagnosed ataxia-telangiectasia-like disorders

ObjectivesDefects in DNA damage responses or repair mechanisms cause numerous rare inherited diseases, referred to as “DNA-repair defects” or “DNA damage deficiency”, characterized by neurodegeneration, immunodeficiency, and/or cancer predisposition. Early accurate diagnosis is important for informing appropriate clinical management; however, diagnosis is frequently challenging and can be delayed, due to phenotypic heterogeneity. Comprehensive genomic analysis could overcome this disadvantage. The objectives of this study were to determine the prevalence of ataxia-telangiectasia (A-T) and A-T-like DNA-repair defects in Japan and to determine the utility of comprehensive genetic testing of presumptively diagnosed patients in facilitating early diagnosis. MethodsA nationwide survey of diseases presumably caused by DNA-repair defects, including A-T, was performed. Additionally, comprehensive next-generation sequencing (NGS) analysis, targeting known disease-causing genes, was conducted. ResultsSixty-three patients with A-T or other diseases with characteristics of DNA-repair defects were identified. Thirty-four patients were genetically or clinically definitively diagnosed with A-T (n = 22) or other DNA-repair defects (n = 12). Genetic analysis of 17 presumptively diagnosed patients revealed one case of ataxia with oculomotor apraxia type 1 (AOA1); one ataxia with oculomotor apraxia type 2 (AOA2); two types of autosomal dominant spinocerebellar ataxia (SCA5, SCA29); two CACNA1A-related ataxias; one microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR); and one autosomal dominant KIF1A-related disorder with intellectual deficit, cerebellar atrophy, spastic paraparesis, and optic nerve atrophy. The diagnostic yield was 58.8%. ConclusionComprehensive genetic analysis of targeted known disease-causing genes by NGS is a powerful diagnostic tool for subjects with indistinguishable neurological phenotypes resembling DNA-repair defects.

The polynucleotide kinase 3\u2032-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25

Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of hereditary peripheral neuropathies. We previously reported a CMT locus on chromosome 19q13.3 segregating with the disease in a large Costa Rican family with axonal neuropathy and autosomal recessive pattern of inheritance (CMT2B2). We proposed a homozygous missense variant in the Mediator complex 25 (MED25) gene as causative of the disease. Nevertheless, the fact that no other CMT individuals with MED25 variants were reported to date led us to reevaluate the original family. Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3′-phosphatase (PNKP) gene. It encodes a DNA repair protein recently associated with recessive ataxia with oculomotor apraxia type 4 (AOA4) and microcephaly, seizures, and developmental delay (MCSZ). Subsequently, five unrelated Costa Rican CMT2 subjects initially identified as being heterozygous for the same MED25 variant were found to be also compound heterozygote for PNKP. All were heterozygous for the same variant found homozygous in the large family and a second one previously associated with ataxia (p.Thr408del). Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay. We propose that PKNP variants are the major causative variant for the CMT2 phenotype in these individuals and that the milder clinical manifestation is due to an allelic effect.

Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1

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. To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations. 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. The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations. 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). 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.

Senataxin, A Novel Helicase at the Interface of RNA Transcriptome Regulation and Neurobiology: From Normal Function to Pathological Roles in Motor Neuron Disease and Cerebellar Degeneration.

Senataxin (SETX) is a DNA-RNA helicase whose C-terminal region shows homology to the helicase domain of the yeast protein Sen1p. Genetic discoveries have established the importance of SETX for neural function, as recessive mutations in the SETX gene cause Ataxia with Oculomotor Apraxia type 2 (AOA2) (OMIM: 606002), which is the third most common form of recessive ataxia, after Friedreich's ataxia and Ataxia-Telangiectasia. In addition, rare, dominant SETX mutations cause a juvenile-onset form of Amyotrophic Lateral Sclerosis (ALS), known as ALS4. SETX performs a number of RNA regulatory functions, including maintaining RNA transcriptome homeostasis. Over the last decade, altered RNA regulation and aberrant RNA-binding protein function have emerged as a central theme in motor neuron disease pathogenesis, with evidence suggesting that sporadic ALS disease pathology may overlap with the molecular pathology uncovered in familial ALS. Like other RNA processing proteins linked to ALS, the basis for SETX gain-of-function motor neuron toxicity remains ill-defined. Studies of yeast Sen1p and mammalian SETX protein have revealed a range of important RNA regulatory functions, including resolution of R-loops to permit transcription termination, and RNA splicing. Growing evidence suggests that SETX may represent an important genetic modifier locus for sporadic ALS. In cycling cells, SETX is found at nuclear foci during the S/G2 cell-cycle transition phase, and may function at sites of collision between components of the replisome and transcription machinery. While we do not yet know which SETX activities are most critical to neurodegeneration, our evolving understanding of SETX function will undoubtedly be crucial for not only understanding the role of SETX in ALS and ataxia disease pathogenesis, but also for delineating the mechanistic biology of fundamentally important molecular processes in the cell.

A Novel Homozygous Variant of SETX Causes Ataxia with Oculomotor Apraxia Type 2.

Background and PurposeAutosomal recessive cerebellar ataxias constitute a highly heterogeneous group of neurodegenerative disorders. This study was carried out to determine the clinical and genetic causes of ataxia in two families from Pakistan.MethodsDetailed clinical investigations were carried out on probands in two consanguineous families. Magnetic resonance imaging was performed. Exome sequencing data were examined for likely pathogenic variants. Candidate variants were checked for cosegregation with the phenotype using Sanger sequencing. Public databases including ExAC, GnomAD, dbSNP, and the 1,000 Genome Project as well as ethnically matched controls were checked to determine the frequencies of the alleles. Conservation of missense variants was ensured by aligning orthologous protein sequences from diverse vertebrate species.ResultsReverse phenotyping identified spinocerebellar ataxia, autosomal recessive 1 [OMIM 606002, also referred to as ataxia oculomotor apraxia type 2 (AOA2)] and ataxia telangiectasia (OMIM 208900) in the two families. A novel homozygous missense mutation c.202 C>T (p.Arg68Cys) was identified within senataxin, SETX in the DNA of both patients in one of the families with AOA2. The patients in the second family were homozygous for a known variant in ataxia-telangiectasia mutated (ATM) gene: c.7327 C>T (p.Arg2443Ter). Both variants were absent from 100 ethnically matched control chromosomes and were either absent or present at very low frequencies in the public databases.ConclusionsThis report extends the allelic heterogeneity of SETX mutations causing AOA2 and also presents an asymptomatic patient with a pathogenic ATM variant.

Ataxia with oculomotor apraxia type 2: an evolving axonal neuropathy

A 23-year-old woman had presented initially to a podiatrist complaining of poorly fitting shoes during her adolescence. After extensive neurological review, she was diagnosed with ataxia with oculomotor apraxia type...

Comparing ataxias with oculomotor apraxia: a multimodal study of AOA1, AOA2 and AT focusing on video-oculography and alpha-fetoprotein

Whether the recessive ataxias, Ataxia with oculomotor apraxia type 1 (AOA1) and 2 (AOA2) and Ataxia telangiectasia (AT), can be distinguished by video-oculography and alpha-fetoprotein level remains unknown. We compared 40 patients with AOA1, AOA2 and AT, consecutively referred between 2008 and 2015 with 17 healthy subjects. Video-oculography revealed constant impairments in patients such as cerebellar signs, altered fixation, impaired pursuit, hypometric saccades and abnormal antisaccades. Horizontal saccade latencies could be highly increased reflecting oculomotor apraxia in one third of patients. Specific distinctive alpha-fetoprotein thresholds were determined for AOA1 (7–15 µg/L), AOA2 (15–65 µg/L) and AT (>65 µg/L). Early age onset, severe walking disability, movement disorders, sensori-motor neuropathy and cerebellar atrophy were all shared. In conclusion, alpha-fetoprotein level seems to permit a distinction while video-oculography does not and therefore is not mandatory, even if an appropriate oculomotor examination remains crucial. Our findings are that AOA1, AOA2 and AT form a particular group characterized by ataxia with complex oculomotor disturbances and elevated AFP for which the final diagnosis is relying on genetic analysis. These findings could guide genetic analysis, assist reverse-phenotyping and provide background for the interpretation of the numerous variants of unknown significance provided by next-generation sequencing.

Altered translational repression of an RNA-binding protein, Elav by AOA2-causative Senataxin mutation.

Mutations in Senataxin (SETX) gene causes two types of neurological disorders, Amyotrophic Lateral Sclerosis (ALS4) and Ataxia with Oculomotor Apraxia type 2 (AOA2). Recent studies in cultured cells suggest that SETX plays a crucial role at the interface of transcription and the DNA damage response. Whether SETX can alter translational of specific RNA is not known. In this study, we report that expressing AOA2-causative truncated form of human SETX in Drosophila neurons alters the development of neuromuscular junction (NMJ) synapses. Interestingly, we found that expressing this truncated form of SETX in Drosophila muscles resulted in an alteration of translational repression of an RNA-binding protein, Embryonic Lethal Abnormal Vision (Elav). Elav is transcribed in all tissues but remains translationally repressed except in neurons. Thus, our data suggest that an altered repression profile of RNA by SETX mutants could be one of the mechanisms underlying ALS4 or AOA2 pathogenesis.

Sen1, the homolog of human Senataxin, is critical for cell survival through regulation of redox homeostasis, mitochondrial function, and theTORpathway inSaccharomyces cerevisiae

Mutations in the Senataxin gene, SETX are known to cause the neurodegenerative disorders, ataxia with oculomotor apraxia type 2 (AOA2), and amyotrophic lateral sclerosis 4 (ALS4). However, the mechanism underlying disease pathogenesis is still unclear. The Senataxin N-terminal protein-interaction and C-terminal RNA/DNA helicase domains are conserved in the Saccharomyces cerevisiae homolog, Sen1p. Using genome-wide expression analysis, we first show alterations in key cellular pathways such as: redox, unfolded protein response, and TOR in the yeast sen1 ΔN mutant (N-terminal truncation). This mutant exhibited growth defects on nonfermentable carbon sources, was sensitive to oxidative stress, and showed severe loss of mitochondrial DNA. The growth defect could be partially rescued upon supplementation with reducing agents and antioxidants. Furthermore, the mutant showed higher levels of reactive oxygen species, lower UPR activity, and alterations in mitochondrial membrane potential, increase in vacuole acidity, free calcium ions in the cytosol, and resistance to rapamycin treatment. Notably, the sen1 ∆N mutant showed increased cell death and shortened chronological life span. Given the strong similarity of the yeast and human Sen1 proteins, our study thus provides a mechanism for the progressive neurological disorders associated with mutations in human senataxin.