Dominant Spinocerebellar Ataxia Research Articles

Impairment of Human KV4.3 Protein Biosynthesis and Channel Gating by Novel SCA19/22-associated Mutations

The autosomal dominant neurodegenerative disorder spinocerebellar ataxia types 19 and 22 (SCA19/22) is associated with mutations in the human voltage-gated K+ channel subunit KV4.3. The precise mechanism underlying the dominant inheritance pattern of SCA19/22 remains unclear. Using in vitro heterologous expression systems, we employed biophysical and biochemical analyses to characterize several novel SCA19/22-causing mutant human KV4.3 channels. Compared to the wild-type (WT) counterpart, the peak current amplitudes of these KV4.3 mutant channels are notably smaller, consistent with the presence of loss-of-function phenotype. Electrophysiological analyses further reveal that these SCA19/22-associated KV4.3 mutant channels manifest altered voltage-dependent activation and inactivation properties. Upon co-expression with the WT channel, the KV4.3 mutants exert considerable dominant-negative effects on both voltage-dependent gating and effective K+ current level of human KV4.3 channel. Protein chemistry analyses demonstrate that the KV4.3 mutants are associated with significantly lower total protein levels, reduced protein half-life values, and defective membrane trafficking. Moreover, co-expression with the mutants substantially decreases the total and cell surface levels of KV4.3 WT protein. Taken together, we propose that the dominant inheritance pattern of SCA19/22 may be explained by the aberrant effects of the mutants on protein biosynthesis and voltage-dependent gating of KV4.3 WT channel.

Cerebellar ataxias: an update.

Providing an update on the pathophysiology, cause, diagnosis and treatment of cerebellar ataxias. This is a group of sporadic or inherited disorders with heterogeneous clinical presentation and notorious impact on activities of daily life in many cases. Patients may exhibit a pure cerebellar phenotype or various combinations of cerebellar deficits and extracerebellar deficits affecting the central/peripheral nervous system. Relevant animal models have paved the way for rationale therapies of numerous disorders affecting the cerebellum. Clinically, the cerebellar syndrome is now divided into a cerebellar motor syndrome, vestibulocerebellar syndrome and cerebellar cognitive affective syndrome with a novel clinical scale. This subdivision on three cornerstones is supported by anatomical findings and neuroimaging. It is now established that the basal ganglia and cerebellum, two major subcortical nodes, are linked by disynaptic pathways ensuring bidirectional communication. Inherited ataxias include autosomal recessive cerebellar ataxias (ARCAs), autosomal dominant spinocerebellar ataxias and episodic ataxias and X-linked ataxias. In addition to the Movement Disorders Society genetic classification of ARCAs, the classification of ARCAs by the Society for Research on the Cerebellum and Ataxias represents major progress for this complex subgroup of cerebellar ataxias. The advent of next-generation sequencing has broadened the spectrum of cerebellar ataxias. Cerebellar ataxias require a multidisciplinary approach for diagnosis and management. The demonstration of anatomical relationships between the cerebellum and basal ganglia impacts on the understanding of the cerebello-basal ganglia-thalamo-cortical system. Novel therapies targeting deleterious pathways, such as therapies acting on RNA, are under development.

Content of selenium in the serum of patients with autosomal dominant spinocerebellar ataxia in the Khabarovsk region

In patients with autosomal dominant spinocerebellar ataxia (AD SCA), the level of selenium in the blood serum was lower by a factor of 1.6 than the result obtained in the control group. There is a weak correlation between the severity of ataxia and selenium content in the blood serum of patients with AD SCA, which possibly suggests the participation of selenium in the pathogenesis of the disease. Given the decrease in selenium content in blood serum in patients with AD SCA, it is probably advisable to include selenium preparations in the symptomatic therapy for these patients.

The Deubiquitinating Enzyme Ataxin-3 Regulates Ciliogenesis and Phagocytosis in the Retina

Expansion of a CAG repeat in ATXN3 causes the dominant polyQ disease Spinocerebellar ataxia type 3 (SCA3), yet the physiological role of ATXN3 remains unclear. We focused on the function of ATXN3 in the retina, a relevant neurological organ amenable to morphological and physiological studies. We show that depletion of Atxn3 in zebrafish and mice causes retinal morphological and functional alterations with photoreceptor outer segment elongation, cone opsin mislocalisation, and cone hyperexcitation. A pool of ATXN3 resides at the basal body and axoneme of the photoreceptor cilium, where it controls the levels and recruitment of the regulatory proteins KEAP1 and HDAC6. Abrogation of Atxn3 expression causes delayed phagosome maturation in the retinal pigment epithelium. We propose that ATXN3 regulates two relevant biological processes in the retina, ciliogenesis and phagocytosis, by modulating microtubule polymerization and microtubule-dependent retrograde transport, thus positing ATXN3 as a causative or modifier gene in retinal/macular dystrophies.

Modeling spinocerebellar ataxia type 7 in the mouse

AbstractAutosomal dominant spinocerebellar ataxia 7 (SCA7) is associated with cone‐rod dystrophy. The causative gene codes for ATAXIN‐7, a ubiquitous protein part of the transcriptional complex SAGA. The coding region contains a CAG triplet repeat translated into a poly‐glutamine (Q) stretch. While there are 4 to 36 repeats per allele in the healthy population, higher numbers are found in SCA7 patients. Longer expansions are typically associated with early onset and cause visual loss before cerebellar ataxia. The SCA7 retinal degeneration has previously been modeled using an overexpression of 90‐repeats ATAXIN‐7 only in rods using the rhodopsin promoter (Rho‐90Q) or a knock‐in with 266 repeats in the mouse Ataxin‐7 gene (KI‐266Q). Rho‐90Q may not be a good model for a cone‐rod dystrophy due to the promoter used. KI‐266Q showed reduction of both photopic and scotopic ERG, but the early and severe phenotype compromises animal fertility and causes death at 4‐5 months, thus offering limited possibilities to test therapeutic approaches, especially in the pre‐symptomatic phase. We have thus characterized the retinal phenotype of KI‐140Q mice, in which mouse Ataxin‐7 includes a shorter (140) polyQ stretch. While the photopic ERG and cone opsins expression is comparable in the mutant and control mice at 5 weeks, they progressively decrease and are extinct around 20–25 weeks in KI‐140Q. The retinal structure is preserved at 9 weeks, followed by a moderate thinning of the segments and outer nuclear layer. Overall, the KI‐140Q recapitulates the symptoms of the cone‐rod dystrophy found in patients, and offer a reasonable time‐window to assess treatment efficacy in both the pre‐symptomatic and symptomatic phases of the disease.

Genetic identification, clinical features and prevalence of Spinocerebellar ataxia type 1 in Sakha Republic (Yakutia)

Over the past several decades, more than 500 cases of Autosomal dominant spinocerebellar ataxia type 1 (SCA1) have been identified in the Republic of Sakha (Yakutia) of North-Eastern Siberia. The disease leads to long-term disability and death, making it a serious public health burden. The prevalence of SCA1 in the indigenous Sakha population has been steadily increasing since the 1970s. It has recently stabilized at a level of 45-53 per 100,000 due to efforts undertaken to limit its further spread. We describe results of a multi-year study of SCA1 in the Sakha population, including molecular genetics, distribution, clinical, electrophysiological and histopathological characteristics. Each studied patient had a mutation in the coding region of the ATXN1 gene on chromosome 6p22.3. The mutation presents as an uncontrolled increase in the number of trinucleotide CAG repeats from normal 25-32 to 39-72 with a loss of a CAT bridge in the middle of the CAG stretch. The number of continuous CAG triplets in the mutant ATXN1 gene correlates with the age of onset and the severity of the disease. The instability of this genomic segment is manifested in meiosis: the number of CAG repeats in a mutant gene increases in transmission from the father by an average of +3.04 repetitions and from the mother by +0.182 repetitions. The total number of repeats transmitted from one generation to another in the Sakha population is on average +1.614, which explains the increase in SCA1 prevalence. Patients from three spatially separate geographic regions of the Republic have the same haplotype, which confirms the origin of the mutation from a common ancestor about 37 generations ago. SCA1 patients in Mongolia, China and the U.S. show a different haplotype. To determine the potential of SCA1 for further spread, the fertility rates of the ATXN1 mutation carriers were evaluated and the Crow selection index calculated. The resulting score of 0.19 indicates that the mutation has little chance of being eliminated from the population without targeted preventive measures.

A family with spinocerebellar ataxia and retinitis pigmentosa attributed to an ELOVL4 mutation.

ObjectiveTo identify the genetic cause of autosomal dominant spinocerebellar ataxia and retinitis pigmentosa in a large extended pedigree.MethodsClinical studies were done at 4 referral centers. Ten individuals in the same extended family participated in at least a portion of the study. Records were obtained from an 11th, deceased, individual. Neurologic and dermatological examinations were performed. Ophthalmologic evaluation including funduscopic examination and in some cases ocular coherence tomography were used to identify the presence of retinal disease. Whole exome sequencing (WES), in conjunction with Sanger sequencing and segregation analysis, was used to identify potential genetic mutation.ResultsAffected individuals reported slowly progressive cerebellar ataxia with age at onset between 38 and 57. Imaging demonstrated cerebellar atrophy (3/3). WES identified a novel heterozygous mutation in the elongation of very long chain fatty acids 4 (ELOVL4) gene (c.512T>C, p.Ile171Thr) that segregated with ataxia in 7 members tested. Four of 8 members who underwent ophthalmologic evaluation were found to have retinitis pigmentosa. No skin findings were identified or reported. Ocular movement abnormalities and pyramidal tract signs were also present with incomplete penetrance.ConclusionsWe report a family with both spinocerebellar ataxia and retinal dystrophy associated with an ELOVL4 mutation. In addition, to supporting prior reports that ELOVL4 mutations can cause spinocerebellar ataxia, our findings further broaden the spectrum of clinical presentations associated with spinocerebellar ataxia 34.

Novel SCA19/22-associated KCND3 mutations disrupt human KV 4.3 protein biosynthesis and channel gating.

Mutations in the human voltage-gated K+ channel subunit KV 4.3-encoding KCND3 gene have been associated with the autosomal dominant neurodegenerative disorder spinocerebellar ataxia types 19 and 22 (SCA19/22). The precise pathophysiology underlying the dominant inheritance pattern of SCA19/22 remains elusive. Using cerebellar ataxia-specific targeted next-generation sequencing technology, we identified two novel KCND3 mutations, c.950 G>A (p.C317Y) and c.1123 C>T (p.P375S) from a cohort with inherited cerebellar ataxias in Taiwan. The patients manifested notable phenotypic heterogeneity that includes cognitive impairment. We employed in vitro heterologous expression systems to inspect the biophysical and biochemical properties of human KV 4.3 harboring the two novel mutations, as well as two previously reported but uncharacterized disease-related mutations, c.1013 T>A (p.V338E) and c.1130 C>T (p.T377M). Electrophysiological analyses revealed that all of these SCA19/22-associated KV 4.3 mutant channels manifested loss-of-function phenotypes. Protein chemistry and immunofluorescence analyses further demonstrated that these mutants displayed enhanced protein degradation and defective membrane trafficking. By coexpressing KV 4.3 wild-type with the disease-related mutants, we provided direct evidence showing that the mutants instigated anomalous protein biosynthesis and channel gating of KV 4.3. We propose that the dominant inheritance pattern of SCA19/22 may be explained by the dominant-negative effects of the mutants on protein biosynthesis and voltage-dependent gating of KV 4.3 wild-type channel.

Clinical Characteristics and Possible Drug Targets in Autosomal Dominant Spinocerebellar Ataxias.

The autosomal dominant spinocerebellar ataxias (SCAs) belong to a large and expanding group of neurodegenerative disorders. SCAs comprise more than 40 subtypes characterized by progressive ataxia as a common feature. The most prevalent diseases among SCAs are caused by CAG repeat expansions in the coding-region of the causative gene resulting in polyglutamine (polyQ) tract formation in the encoded protein. Unfortunately, there is no approved therapy to treat cerebellar motor dysfunction in SCA patients. In recent years, several studies have been conducted to recognize the clinical and pathophysiological aspects of the polyQ SCAs more accurately. This scientific progress has provided new opportunities to develop promising gene therapies, including RNA interference and antisense oligonucleotides. The aim of the current work is to give a brief summary of the clinical features of SCAs and to review the cardinal points of pathomechanisms of the most common polyQ SCAs. In addition, we review the last few year's promising gene suppression therapies of the most frequent polyQ SCAs in animal models, on the basis of which human trials may be initiated in the near future.

Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia.

Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next-generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.

Hereditary primary lateral sclerosis and progressive nonfluent aphasia.

To report a kindred with an association between hereditary primary lateral sclerosis (PLS) and progressive nonfluent aphasia. Six members from a kindred with 15 affected individuals spanning three generations, suffered from spasticity without muscle atrophy or fasciculation, starting in the lower limbs and spreading to the upper limbs and bulbar musculature, followed by effortful speech, nonfluent language and dementia, in 5 deceased members. Disease onset was during the sixth decade of life, or later. Cerebellar ataxia was the inaugural manifestation in two patients, and parkinsonism, in another. Neuropathological examination in two patients demonstrated degeneration of lateral corticospinal tracts in the spinal cord, without loss of spinal, brainstem, or cerebral motor neurons. Greater loss of corticospinal fibers at sacral and lumbar, rather than at cervical or medullary levels was demonstrated, supporting a central axonal dying-back pathogenic mechanism. Marked reduction of myelin and nerve fibers in the frontal lobes was also present. Argyrophilic grain disease and primary age-related tauopathy were found in one case each, and considered incidental findings. Genetic testing, including exome sequencing aimed at PLS, ataxia, hereditary spastic paraplegia, and frontotemporal lobe dementia, triplet-repeated primed polymerase chain reaction aimed at dominant spinocerebellar ataxias, and massive sequencing of the human genome, yielded negative results. A central distal axonopathy affecting the corticospinal tract, exerted a pathogenic role in the dominantly inherited PLS-progressive nonfluent aphasia association, described herein. Further molecular studies are needed to identify the causative mutation in this disease.

Motor Performances of Spontaneous and Genetically Modified Mutants with Cerebellar Atrophy.

Chance discovery of spontaneous mutants with atrophy of the cerebellar cortex has unearthed genes involved in optimizing motor coordination. Rotorod, stationary beam, and suspended wire tests are useful in delineating behavioral phenotypes of spontaneous mutants with cerebellar atrophy such as Grid2Lc, Grid2ho, Rorasg, Agtpbp1pcd, Relnrl, and Dab1scm. Likewise, transgenic or null mutants serving as experimental models of spinocerebellar ataxia (SCA) are phenotyped with the same tests. Among experimental models of autosomal dominant SCA, rotorod deficits were reported in SCA1 to 3, SCA5 to 8, SCA14, SCA17, and SCA27 and stationary beam deficits in SCA1 to 3, SCA5, SCA6, SCA13, SCA17, and SCA27. Beam tests are sensitive to experimental therapies of various kinds including molecules affecting glutamate signaling, mesenchymal stem cells, anti-oligomer antibodies, lentiviral vectors carrying genes, interfering RNAs, or neurotrophic factors, and interbreeding with other mutants.

Targeting Ubiquitin Proteasome Pathway with Traditional Chinese Medicine for Treatment of Spinocerebellar Ataxia Type 3.

Nine autosomal dominant spinocerebellar ataxias (SCAs) are caused by an abnormal expansion of CAG trinucleotide repeats that encodes a polyglutamine (polyQ) tract within different genes. Accumulation of aggregated mutant proteins is a common feature of polyQ diseases, leading to progressive neuronal dysfunction and degeneration. SCA type 3 (SCA3), the most common form of SCA worldwide, is characterized by a CAG triplet expansion in chromosome 14q32.1 ATXN3 gene. As accumulation of the mutated polyQ protein is a possible initial event in the pathogenic cascade, clearance of aggregated protein by ubiquitin proteasome system (UPS) has been proposed to inhibit downstream detrimental events and suppress neuronal cell death. In this study, Chinese herbal medicine (CHM) extracts were studied for their proteasome-activating, polyQ aggregation-inhibitory and neuroprotective effects in GFPu and ATXN3/Q -GFP 293/SH-SY5Y cells. Among the 14 tested extracts, 8 displayed increased proteasome activity, which was confirmed by 20S proteasome activity assay and analysis of ubiquitinated and fused GFP proteins in GFPu cells. All the eight extracts displayed good aggregation-inhibitory potential when tested in ATXN3/Q -GFP 293 cells. Among them, neuroprotective effects of five selected extracts were shown by analyses of polyQ aggregation, neurite outgrowth, caspase 3 and proteasome activities, and ATXN3-GFP, ubiquitin, BCL2 and BAX protein levels in neuronal differentiated ATXN3/Q -GFP SH-SY5Y cells. Finally, enhanced proteasome function, anti-oxidative activity and neuroprotection of catalpol, puerarin and daidzein (active constituents of Rehmannia glutinosa and Pueraria lobata) were demonstrated in GFPu and/or ATXN3/Q -GFP 293/SH-SY5Y cells. This study may have therapeutic implication in polyQ-mediated disorders.

Recent advances in understanding dominant spinocerebellar ataxias from clinical and genetic points of view.

Spinocerebellar ataxias (SCAs) are rare types of cerebellar ataxia with a dominant mode of inheritance. To date, 47 SCA subtypes have been identified, and the number of genes implicated in SCAs is continually increasing. Polyglutamine (polyQ) expansion diseases ( ATXN1/SCA1, ATXN2/SCA2, ATXN3/SCA3, CACNA1A/SCA6, ATXN7/SCA7, TBP/SCA17, and ATN1/DRPLA) are the most common group of SCAs. No preventive or curative treatments are currently available, but various therapeutic approaches, including RNA-targeting treatments, such as antisense oligonucleotides (ASOs), are being developed. Clinical trials of ASOs in SCA patients are already planned. There is, therefore, a need to identify valid outcome measures for such studies. In this review, we describe recent advances towards identifying appropriate biomarkers, which are essential for monitoring disease progression and treatment efficacy. Neuroimaging biomarkers are the most powerful markers identified to date, making it possible to reduce sample sizes for clinical trials. Changes on brain MRI are already evident at the premanifest stage in SCA1 and SCA2 carriers and are correlated with CAG repeat size. Other potential biomarkers have also been developed, based on neurological examination, oculomotor study, cognitive assessment, and blood and cerebrospinal fluid analysis. Longitudinal studies based on multimodal approaches are required to establish the relationships between parameters and to validate the biomarkers identified.

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.

Repeated Mesenchymal Stromal Cell Treatment Sustainably Alleviates Machado-Joseph Disease.

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3, the most common dominant spinocerebellar ataxia (SCA) worldwide, is caused by over-repetition of a CAG repeat in the ATXN3/MJD1 gene, which translates into a polyglutamine tract within the ataxin-3 protein. There is no treatment for this fatal disorder. Despite evidence of the safety and efficacy of mesenchymal stromal cells (MSCs) in delaying SCA disease progression in exploratory clinical trials, unanticipated regression of patients to the status prior to treatment makes the investigation of causes and solutions urgent and imperative. In the present study, we compared the efficacy of a single intracranial injection with repeated systemic MSC administration in alleviating the MJD phenotype of two strongly severe genetic rodent models. We found that a single MSC transplantation only produces transient effects, whereas periodic administration promotes sustained motor behavior and neuropathology alleviation, suggesting that MSC therapies should be re-designed to get sustained beneficial results in clinical practice. Furthermore, MSC promoted neuroprotection, increased the levels of GABA and glutamate, and decreased the levels of Myo-inositol, which correlated with motor improvements, indicating that these metabolites may serve as valid neurospectroscopic biomarkers of disease and treatment. This study makes important contributions to the design of new clinical approaches for MJD and other SCAs/polyglutamine disorders.

Clinical, genetic and neuropathological characterization of spinocerebellar ataxia type 37.

The autosomal dominant spinocerebellar ataxias (SCAs) consist of a highly heterogeneous group of rare movement disorders characterized by progressive cerebellar ataxia variably associated with ophthalmoplegia, pyramidal and extrapyramidal signs, dementia, pigmentary retinopathy, seizures, lower motor neuron signs, or peripheral neuropathy. Over 41 different SCA subtypes have been described evidencing the high clinical and genetic heterogeneity. We previously reported a novel spinocerebellar ataxia type subtype, SCA37, linked to an 11-Mb genomic region on 1p32, in a large Spanish ataxia pedigree characterized by ataxia and a pure cerebellar syndrome distinctively presenting with early-altered vertical eye movements. Here we demonstrate the segregation of an unstable intronic ATTTC pentanucleotide repeat mutation within the 1p32 5' non-coding regulatory region of the gene encoding the reelin adaptor protein DAB1, implicated in neuronal migration, as the causative genetic defect of the disease in four Spanish SCA37 families. We describe the clinical-genetic correlation and the first SCA37 neuropathological findings caused by dysregulation of cerebellar DAB1 expression. Post-mortem neuropathology of two patients with SCA37 revealed severe loss of Purkinje cells with abundant astrogliosis, empty baskets, occasional axonal spheroids, and hypertrophic fibres by phosphorylated neurofilament immunostaining in the cerebellar cortex. The remaining cerebellar Purkinje neurons showed loss of calbindin immunoreactivity, aberrant dendrite arborization, nuclear pathology including lobulation, irregularity, and hyperchromatism, and multiple ubiquitinated perisomatic granules immunostained for DAB1. A subpopulation of Purkinje cells was found ectopically mispositioned within the cerebellar cortex. No significant neuropathological alterations were identified in other brain regions in agreement with a pure cerebellar syndrome. Importantly, we found that the ATTTC repeat mutation dysregulated DAB1 expression and induced an RNA switch resulting in the upregulation of reelin-DAB1 and PI3K/AKT signalling in the SCA37 cerebellum. This study reveals the unstable ATTTC repeat mutation within the DAB1 gene as the underlying genetic cause and provides evidence of reelin-DAB1 signalling dysregulation in the spinocerebellar ataxia type 37.

Cerebellar lncRNA Expression Profile Analysis of SCA3/MJD Mice

Spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease (MJD) is the most common autosomal dominant spinocerebellar ataxia in China with highly clinical heterogeneity, such as progressive cerebellar ataxia, dysarthria, pyramidal signs, external ophthalmoplegia, dysphagia, and distal muscle atrophy. It is caused by the abnormal expansion of CAG repeats in a coding region of ATXN3. However, by focusing on the ATXN3 itself cannot fully explain the heterogeneous clinical features of SCA3/MJD. With the discovery of the increasing number of long noncoding RNAs (lncRNAs) that are believed to be involved in spinocerebellar ataxia type 8 (SCA8) and Huntington disease (HD), we wonder whether the lncRNAs are differentially expressed in the SCA3/MJD patients compared to the nonpatients. As the first step, we used lncRNA-Seq to investigate differential expression of the lncRNAs in the SCA3/MJD mice. Two known lncRNAs, n297609 and n297477, and a novel lncRNA TCONS_00072962 have been identified in SCA3/MJD mice with abnormal expression. The first discovery of the novel lncRNA TCONS_00072962 enriched the lncRNA expression profile in the SCA3/MJD mouse model.

Sleep apnea in Machado-Joseph disease: a clinical and polysomnographic evaluation

Objective/BackgroundMachado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is the most common type of autosomal dominant spinocerebellar ataxia (SCA). Sleep disorders have been described as frequent non-motor symptoms in MJD, and with marked impairment on quality of life. However, few studies have evaluated the frequency and characteristics of sleep apnea in MJD. Patients/MethodsThis study analyzed the prevalence of sleep apnea in 47 patients with MJD by using polysomnography. Clinical variables such as age, age at onset of symptoms, duration of symptoms (at time of evaluation), body index mass, ataxia scales severity and CAG repeat length were compared with polysomnographic findings. ResultsThirty four percent of MJD patients had OSAS, and 42.5% had excessive daytime somnolence. There were no differences considering ataxia severity, CAG repetition length or other clinical variable. ConclusionsPatients with MJD have high frequency of obstructive sleep apnea, and this sleep disorder is not correlated with ataxia severity, CAG repetition length or other clinical variable.

Clinical Features of Machado-Joseph Disease.

Machado-Joseph disease (MJD) also known as Spinocerebellar ataxia type 3, is a hereditary neurodegenerative disease associated with severe clinical manifestations and premature death. Although rare, it is the most common autosomal dominant spinocerebellar ataxia worldwide and has a distinct geographic distribution, reaching peak prevalence in certain regions of Brazil, Portugal and China. Due to its clinical heterogeneity, it was initially described as several different entities and as had many designations over the last decades. An accurate diagnosis become possible in 1994, after the identification of the MJD1 gene. Among its wide clinical spectrum, progressive cerebellar ataxia is normally present. Other symptoms include pyramidal syndrome, peripheral neuropathy, oculomotor abnormalities, extrapyramidal signs and sleep disorders. On the basis of the presence/absence of important extra-pyramidal signs, and the presence/absence of peripheral signs, five clinical types have been defined. Neuroimaging studies like MRI, DTI and MRS, can be useful as they can characterize structural and functional differences in specific subgroups of patients with MJD. There is no effective treatment for MJD. Symptomatic therapies are used to relieve some of the clinical symptoms and physiotherapy is also helpful in improving quality of live. Several clinical trials have been carried out using different molecules like sulfamethoxazole-trimethoprim, varenicline and lithium carbonate, but the results of these trials were negative or showed little benefit. Future studies sufficiently powered and adequately designed are warranted.