Does SCA45 Cause Very Late-Onset Pure Cerebellar Ataxia?
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ABSTRACT:
SUBMITTER: Tonholo Silva TY
PROVIDER: S-EPMC8054959 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Publications
Does SCA45 Cause Very Late-Onset Pure Cerebellar Ataxia?
Tonholo Silva Thiago Y TY Rosa Augusto B R ABR Quaio Caio R CR Verbeek Dineke D Pedroso José Luiz JL Barsottini Orlando O
Neurology. Genetics 20210326 3
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| S-EPMC8370166 | biostudies-literature
Project description:Sporadic late onset cerebellar ataxia is a well-described clinical presentation with a broad differential diagnosis that adult neurologists should be familiar with. However, despite extensive clinical investigations, an acquired cause is identified in only a minority of cases. Thereafter, an underlying genetic basis is often considered, even in those without a family history. Here we apply whole exome sequencing to a cohort of 12 patients with late onset cerebellar ataxia. We show that 33% of 'idiopathic' cases harbor compound heterozygous mutations in known ataxia genes, including genes not included on multi-gene panels, or primarily associated with an ataxic presentation.
| S-EPMC4539354 | biostudies-literature
Project description:BackgroundThe late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis.MethodsWe sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines.ResultsIn the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]≥250). There was significant association between FGF14 (GAA)≥250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA)≥250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein.ConclusionsA dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).
| S-EPMC10042577 | biostudies-literature
Project description:Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS: MIM 270550) is a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. This disorder, considered to be rare, was first described in the late seventies among French Canadians in the isolated Charlevoix-Saguenay region of Quebec. Nowadays, it is known that the disorder is not only limited to this region but occurs worldwide. Our objective was to identify cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) in Dutch patients with recessive early-onset cerebellar ataxia by sequencing the complete SACS gene. In a Dutch cohort of 43 index patients with ataxia onset before age 25, we identified 16 index patients (total 23 patients) with mutations in the SACS gene. Nine of them had homozygous mutations, and seven of them had compound heterozygous mutations. Retrospectively, the phenotype of patients carrying mutations was remarkably uniform: cerebellar ataxia with onset before age 13 years, lower limb spasticity and sensorimotor axonal neuropathy, and cerebellar (vermis) atrophy on magnetic resonance imaging, consistent with the core ARSACS phenotype previously described. The high rate of mutations (37%) identified in this cohort of Dutch patients suggests that ARSACS is substantially more frequent than previously estimated. We predict that the availability of SACS mutation analysis as well as an increasing awareness of the characteristic ARSACS phenotype will lead to the diagnosis of many additional patients, possibly even at a younger age.
| S-EPMC2441586 | biostudies-literature
Project description:PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.
| S-EPMC4245359 | biostudies-literature
Project description:Autosomal-recessive cerebellar ataxias (ARCA) are clinically and genetically heterogeneous conditions primarily affecting the cerebellum. Mutations in the PNPLA6 gene have been identified as the cause of hereditary spastic paraplegia and complex forms of ataxia associated with retinal and endocrine manifestations in a field where the genotype-phenotype correlations are rapidly expanding. We identified two cousins from a consanguineous family belonging to a large Zoroastrian (Parsi) family residing in Mumbai, India, who presented with pure cerebellar ataxia without chorioretinal dystrophy or hypogonadotropic hypogonadism. We used a combined approach of clinical characterisation, homozygosity mapping, whole-exome and Sanger sequencing to identify the genetic defect in this family. The phenotype in the family was pure cerebellar ataxia. Homozygosity mapping revealed one large region of shared homozygosity at chromosome 19p13 between affected individuals. Within this region, whole-exome sequencing of the index case identified two novel homozygous missense variants in the PNPLA6 gene at c.3847G>A (p.V1283M) and c.3929A>T (p.D1310V) in exon 32. Both segregated perfectly with the disease in this large family, with only the two affected cousins being homozygous. We identified for the first time PNPLA6 mutations associated with pure cerebellar ataxia in a large autosomal-recessive Parsi kindred. Previous mutations in this gene have been associated with a more complex phenotype but the results here suggest an extension of the associated disease spectrum.
| S-EPMC5243903 | biostudies-literature
Project description:BackgroundMutations in TGM6 gene, encoding for transglutaminase 6 (TG6), have been implicated in the pathogenesis of spinocerebellar ataxia type 35 (SCA35), a rare autosomal dominant disease marked by cerebellar degeneration and characterized by postural instability, incoordination of gait, features of cerebellar dysfunction and pyramidal signs.Case presentationHere we report the case of an Italian patient with late-onset, slowly progressive cerebellar features, including gait ataxia, scanning speech and ocular dysmetria and pyramidal tract signs. Whole exome sequencing revealed the rare heterozygous c.1024C > T (p.R342W) variant of TGM6, located at a highly evolutionary conserved position and predicted as pathogenic by in silico tools. Expression of TG6-R342W mutant in HEK293T cells led to a significant reduction of transamidase activity compared to wild-type TG6.ConclusionThis finding extends SCA35 genetic landscape, highlighting the importance of TGM6 screening in undiagnosed late-onset and slowly progressive cerebellar ataxias.
| S-EPMC7648302 | biostudies-literature
Project description:During the past two decades, an increasing number of patients with very-late-onset myasthenia gravis (v-LOMG) with an onset age of 65 years or older have been identified. However, few studies explore the predictors of secondary generalization in patients with v-LOMG with pure ocular onset. In this retrospective cohort study, 69 patients with v-LOMG were divided into ocular MG (OMG) and generalized MG (GMG), and the clinical characteristics and outcomes were compared. Cox regression analysis was performed to explore the predictors of generalization. The average onset age of the study population was 73.1 ± 4.2 years and the median disease duration was 48.0 months (interquartile range, 32.5-64.5 months). Serum acetylcholine receptor (AChR) antibody was detected in up to 86% of patients and concomitant diseases in approximately half of the patients. Male predominance was seen in OMG group while female predominance in GMG group (p = 0.043). Patients with OMG showed a lower positive rate of repetitive nerve stimulation (RNS) than those with GMG (p = 0.014), and favorable outcomes were obtained in more patients with OMG than those with GMG (p < 0.001). Of the 51 patients with pure ocular onset, 25 (49.0%) underwent secondary generalization. A higher probability of generalization was found in patients with positive RNS results and without immunotherapy (p = 0.018 and <0.001). Upon Cox regression analysis, immunotherapy was negatively associated with secondary generalization [HR (hazard ratio) 0.077, 95%CI [0.024-0.247], p < 0.001]. Altogether, compared to the patients with very-late-onset GMG, the counterparts with OMG exhibit a significantly higher female predominance and a lower positive rate of RNS tests, especially on facial and accessory nerves. Lack of immunotherapy is the only predictor of secondary generalization in those with pure ocular onset.
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Project description:Phenytoin (PHT) is a first line antiepileptic drug (AED) used to treat many epilepsy syndromes. As with other AEDs, there are various adverse effects associated with PHT. For this brief review, we searched for evidence of cerebellar ataxia as a chronic adverse effect of therapeutic-range PHT treatment. Many previous studies appeared related to this issue, but many of those studies were designed to resolve questions related to the persistent residual effects of toxic-range PHT therapy, or they were inconclusive due to an absence of critical information such as PHT serum concentration, cerebellar symptoms/signs, and other factors contributing to cerebellar degeneration. Nevertheless, there were a few reports suggesting that cerebellar ataxia may be a chronic adverse effect of therapeutic-range PHT therapy and that a possible pathomechanism for that effect is folate deficiency. Moreover, there is the possibility that there may be patient-specific susceptibility factors affecting ataxia. Further studies are needed to elucidate the incidence, risk factors, and pathomechanism of cerebellar ataxia as a chronic adverse effect of therapeutic-range PHT treatment.
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Project description:Bi-allelic variants in peroxiredoxin 3 (PRDX3) have only recently been associated with autosomal recessive spinocerebellar ataxia characterized by early onset slowly progressive cerebellar ataxia, variably associated with hyperkinetic and hypokinetic features, accompanied by cerebellar atrophy and occasional olivary and brainstem involvement. Herein, we describe a further simplex case carrying a reported PRDX3 variant as well as two additional cases with novel variants. We report the first Brazilian patient with SCAR32, replicating the pathogenic status of a known variant. All presented cases from the Brazilian and Indian populations expand the phenotypic spectrum of the disease by displaying prominent neuroradiological findings. SCAR32, although rare, should be included in the differential diagnosis of sporadic or recessive childhood and adolescent-onset pure and complex cerebellar ataxia.
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