Autosomal Dominant Ataxia Research Articles

Goal‐Directed Rehabilitation Versus Standard Care for Individuals with Hereditary Cerebellar Ataxia: A Multicenter, Single‐Blind, Randomized Controlled Superiority Trial

ObjectiveRehabilitation is thought to reduce ataxia severity in individuals with hereditary cerebellar ataxia (HCA). This multicenter, randomized controlled superiority trial aimed to examine the efficacy of a 30‐week goal‐directed rehabilitation program compared with 30 weeks of standard care on function, ataxia, health‐related quality of life, and balance in individuals with an HCA.MethodsIndividuals with an autosomal dominant or recessive ataxia (aged ≥15 years) were enrolled at 5 sites in Australia. Participants were randomized (1:1) to receive rehabilitation (6 weeks of outpatient physiotherapy followed by a 24‐week home exercise program) (n = 39) or continued their usual activity (n = 37). The primary outcome measure was the motor domain of the Functional Independence Measure (mFIM) at 7 weeks. Secondary outcomes included the Scale for the Assessment and Rating of Ataxia (SARA) and the SF‐36v2, assessed at 7, 18, and 30 weeks. Outcome assessors were blinded to treatment allocation.ResultsSeventy‐one participants (rehabilitation, 37; standard‐care, 34) were included in the intention‐to‐treat analysis. At 7 weeks, mFIM (mean difference 2.26, 95% confidence interval [CI]: 0.26 to 4.26, p = 0.028) and SARA (−1.21, 95% CI: −2.32 to −0.11, p = 0.032) scores improved after rehabilitation compared with standard care. Compared with standard care, rehabilitation improved SARA scores at 30 weeks (mean difference −1.51, 95% CI: −2.76 to −0.27, p = 0.017), but not mFIM scores (1.74, 95% CI: −0.32 to 3.81, p = 0.098). Frequent adverse events in both groups were fatigue, pain, and falls.InterpretationGoal‐directed rehabilitation improved function at 7 weeks, with improvement in ataxia and health‐related quality of life maintained at 30 weeks in individuals with HCA, beyond that of standard care. ANN NEUROL 2024

Spinocerebellar Ataxia Type 27B (SCA27B): A Hereditary Ataxia in Portugal.

Spinocerebellar ataxia type 27B (SCA27B) is a recently discovered hereditary disease caused by (GAA)≥250 repeat expansion in the fibroblast growth factor 14 (FGF14) gene, and multiple studies have recognized it as one of the most common causes of autosomal dominant ataxia in the European population. We present the case of a 62-year-old Portuguese patient who developed a slowly progressive gait impairment associated with wide-base ataxic gait, dysarthria, left upper limb dysmetria, and dysdiadochokinesia. This pure cerebellar phenotype had an episodic worsening induced by intense physical activity and alcohol intake. The patient had an older brother with a late-onset cerebellar ataxia of unknown cause. Genetic testing detected a heterozygotic intronic FGF14 repeat expansion with complete penetrance (> 360 repeats), confirming the diagnosis of SCA27B. To our knowledge, we present the first reported case of SCA27B in the Portuguese population.

Clinical and Video-Oculographic Characteristics of Spinocerebellar Ataxia Type 27B (GAA-FGF14 Ataxia): A Single-Center Retrospective Study

An intronic GAA repeat expansion in the FGF14 gene was recently identified as a common cause of autosomal dominant GAA-FGF14 ataxia (SCA27B). We aimed to characterize in detail the clinical and video-oculographic features in our cohort of SCA27B patients. We genotyped the FGF14 GAA repeat expansion in 52 patients with unsolved late-onset cerebellar ataxia. Brain MRI and nerve conduction study, as well as video-oculographic (VOG) assessment, were performed. Eight patients (15.4%) with pathogenic GAA repeat expansion in the FGF14 gene were found. The median age at onset was 51 years (range—23–63 years). Sensory axonal neuropathy was found in 5/8 patients. Cerebellar atrophy was observed in 5/8 patients, and in one case, pontocerebellar atrophy was found. All tested patients had impaired smooth pursuit, 5/6 patients had impaired vestibulo-ocular reflex suppression, nystagmus, and an increased number of square wave jerks, 4/6 patients had horizontal gaze-evoked nystagmus, 3/6 had spontaneous downbeat nystagmus, and 1/6 had an upbeat one. Video head impulse test gain was lower than 0.8 on both sides in 2/4 patients, along with the presence of overt saccades. Further studies in different cohorts are needed to complete the phenotype of the FGF14-related disorders.

Somatic instability of the FGF14-SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum.

Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. Neuropathological studies have shown that neuronal loss is largely restricted to the cerebellum. Although the repeat locus is highly unstable during intergenerational transmission, it remains unknown whether it exhibits cerebral mosaicism and progressive instability throughout life. We conducted an analysis of the FGF14 GAA•TTC repeat somatic instability across 156 serial blood samples from 69 individuals, fibroblasts, induced pluripotent stem cells, and post-mortem brain tissues from six controls and six patients with SCA27B, alongside methylation profiling using targeted long-read sequencing. Peripheral tissues exhibited minimal somatic instability, which did not significantly change over periods of more than 20 years. In post-mortem brains, the GAA•TTC repeat was remarkably stable across all regions, except in the cerebellar hemispheres and vermis. The levels of somatic expansion in the cerebellar hemispheres and vermis were, on average, 3.15 and 2.72 times greater relative to other examined brain regions, respectively. Additionally, levels of somatic expansion in the brain increased with repeat length and tissue expression of FGF14. We found no significant difference in methylation of wild-type and expanded FGF14 alleles in post-mortem cerebellar hemispheres between patients and controls. In conclusion, our study revealed that the FGF14 GAA•TTC repeat exhibits a cerebellar-specific expansion bias, which may explain the pure cerebellar involvement in SCA27B.

Neuropsychiatric Manifestations of Degenerative Cerebellar Ataxia.

Degenerative cerebellar ataxias (DCA) present a group of complex neurological disorders primarily affecting the cerebellum and its pathways. Classic manifestations include motor symptoms of cerebellar ataxia. However, emerging evidence suggests that the cerebellum also plays a crucial role in various cognitive and emotional processes. The objective was to assess the psychiatric profile of a heterogeneous group of patients with degenerative cerebellar ataxia. Our sample comprised 107 participants diagnosed with cerebellar degenerative ataxia. All patients were clinically evaluated using SARA, INAS, and different neuropsychiatric scales (ACE-R, HAMA, HAMD, AS, and GAF). The majority of patients had autosomal dominant ataxia (38.3%) followed by sporadic ataxia (32.7%) with an average age at the moment of diagnosis of 35.3 ± 16.23 years, while the mean duration of disease at the study beginning was 12.1 ± 9.9 years. Psychiatric disorders were present in 40 patients (37.4%), with dysthymia (14.2%), major depressive disorder (9.4%), and MDD with melancholic features (7.6%). The presence of MDD with melancholic features was statistically significantly correlated with a lower ACE-R total score (r = -0.223; p = 0.022), while dysthymia was statistically significantly associated with a shorter duration of the disease (r = -0.226; p = 0.020) and older age (r = 0.197; p = 0.043). Statistically significant differences were observed between MSA-C patients and those with sporadic ataxia (HDRS p < 0.001, HARS p < 0.001, Apathy Scale p = 0.003, and GAF p = 0.004). Based on our findings, we can conclude that the degree of motor deficit has a significant impact on the development of psychiatric disorders, including depression, anxiety, and apathy. However, it is not the only factor, and the impact also depends on the type of DCA.

Treatment of neurologic pathology and inflammation in Machado-Joseph disease through in vivo self-assembled siRNA.

Machado-Joseph disease, also known as Spinocerebellar ataxia type 3 (MJD/SCA3), is a fatal autosomal dominant hereditary ataxia characterized by cerebellar ataxia resulting from the abnormal expansion of CAG repeats in exon 10 of the ATXN3 gene. Presently, there is no effective treatment for SCA3. Small interfering RNAs (siRNAs) are emerging as potential therapeutic strategies to specifically target the disease-causing mutant ATXN3 (mATXN3) protein. However, the delivery efficiency of siRNAs remains a major obstacle for clinical application, particularly in brain disorders. This study aimed to develop a synthetic biology strategy to reprogram the host liver as a tissue chassis to induce and deliver in vivo self-assembled siRNAs (IVSA-siRNAs) to target the ATXN3 gene. A synthetic construct directed by a cytomegalovirus promoter was designed to encode a neuron-targeting rabies virus glycoprotein tag and mATXN3-siRNA. After intravenous injection, the synthetic construct was taken up by mouse livers, which were then reprogrammed to enable the self-assembly, production, and secretion of small extracellular vesicles (sEVs) encapsulating mATXN3-siRNA. The sEV-encapsulated mATXN3-siRNA was further transported through the endogenous circulating system of sEVs, crossing the blood-brain barrier and reaching the cerebellar cortex and spinal cerebellar tract, where they silenced the ATXN3 gene. Treatment with the synthetic construct for 8 or 12 weeks led to significant improvements in motor balance ability and reduction of cerebellar atrophy in YACMJD84.2 transgenic mice. The number of Purkinje cells in the cerebellar cortex was significantly increased, and the loss of myelin basic protein was reduced. Moreover, the quantity of neurotoxic nuclear inclusion bodies and the expression of glial fibrillary acidic protein, which promotes neuroinflammation in activated astrocytes, were decreased significantly. The synthetic construct facilitated the generation and delivery of IVSA-siRNA to the cerebellar cortex and spinal cerebellar tract, thereby inhibiting the expression of mATXN3 protein. This treatment successfully addressed motor impairments, alleviated neuropathological phenotypes, and mitigated neuroinflammation in YACMJD84.2 transgenic mice. Our strategy effectively overcomes the primary challenges associated with siRNA therapy for cerebellar ataxia, offering a promising avenue for future clinical treatments.

Somatic instability of the FGF14 -SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum.

Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14 . Neuropathological studies have shown that neuronal loss is largely restricted to the cerebellum. Although the repeat locus is highly unstable during intergenerational transmission, it remains unknown whether it exhibits cerebral mosaicism and progressive instability throughout life. We conducted an analysis of the FGF14 GAA•TTC repeat somatic instability across 156 serial blood samples from 69 individuals, fibroblasts, induced pluripotent stem cells, and post-mortem brain tissues from six controls and six patients with SCA27B, alongside methylation profiling using targeted long-read sequencing. Peripheral tissues exhibited minimal somatic instability, which did not significantly change over periods of more than 20 years. In post-mortem brains, the GAA•TTC repeat was remarkably stable across all regions, except in the cerebellar hemispheres and vermis. The levels of somatic expansion in the cerebellar hemispheres and vermis were, on average, 3.15 and 2.72 times greater relative to other examined brain regions, respectively. Additionally, levels of somatic expansion in the brain increased with repeat length and tissue expression of FGF14 . We found no significant difference in methylation of wild-type and expanded FGF14 alleles in post-mortem cerebellar hemispheres between patients and controls. In conclusion, our study revealed that the FGF14 GAA•TTC repeat exhibits a cerebellar-specific expansion bias, which may explain the pure and late-onset cerebellar involvement in SCA27B.

Extended haplotype with rs41524547-G defines the ancestral origin of SCA10.

Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant ataxia caused by a large expansion of the (ATTCT)n repeat in ATXN10. SCA10 was described in Native American and Asian individuals which prompted a search for an expanded haplotype to confirm a common ancestral origin for the expansion event. All patients with SCA10 expansions in our cohort share a single haplotype defined at the 5'-end by the minor allele of rs41524547, located ~35kb upstream of the SCA10 expansion. Intriguingly, rs41524547 is located within the miRNA gene, MIR4762, within its DROSHA cleavage site and just outside the seed sequence for mir4792-5p. The world-wide frequency of rs41524547-G is less than 5% and found almost exclusively in the Americas and East Asia-a geographic distribution that mirrors reported SCA10 cases. We identified rs41524547-G(+) DNA from the 1000 Genomes/International Genome Sample Resource and our own general population samples and identified SCA10 repeat expansions in up to 25% of these samples. The reduced penetrance of these SCA10 expansions may be explained by a young (pre-onset) age at sample collection, a small repeat size, purity of repeat units, or the disruption of miR4762-5p function. We conclude that rs41524547-G is the most robust at-risk SNP allele for SCA10, is useful for screening of SCA10 expansions in population genetics studies and provides the most compelling evidence to date for a single, prehistoric origin of SCA10 expansions sometime prior to or during the migration of individuals across the Bering Land Bridge into the Americas.

A de novo mutation in CACNA1A is associated with autosomal dominant bovine familial convulsions and ataxia in Angus cattle.

Bovine familial convulsions and ataxia (BFCA) is considered an autosomal dominant syndrome with incomplete penetrance. Nine Angus calves from the same herd were diagnosed with BFCA within days of birth. Necropsy revealed cerebellar and spinal cord lesions associated with the condition. Parentage testing confirmed that all affected calves had a common sire. The sire was then bred to 36 cows across two herds using artificial insemination, producing an additional 14 affected calves. The objective of this investigation was to identify hypothesized dominant genetic variation underlying the condition. Whole-genome sequencing was performed on the sire, six affected and seven unaffected paternal half-sibling calves and combined with data from 135 unrelated controls. The sire and five of the six affected calves were heterozygous for a nonsense variant (Chr7 g.12367906C>T, c.5073C>T, p.Arg1681*) in CACNA1A. The other affected calves (N = 8) were heterozygous for the variant but it was absent in the other unaffected calves (N = 7) and parents of the sire. This variant was also absent in sequence data from over 6500 other cattle obtained via public repositories and collaborator projects. The variant in CACNA1A is expressed in the cerebellum of the ataxic calves as detected in the transcriptome and was not differentially expressed compared with controls. The CACNA1A protein is part of a highly expressed cerebellar calcium voltage gated channel. The nonsense variant is proposed to cause haploinsufficiency, preventing proper transmission of neuronal signals through the channel and resulting in BFCA.

Expanding the genetic and phenotypic spectrum of congenital myasthenic syndrome: new homozygous VAMP1 splicing variants in 2 novel individuals.

We report the cases of two Spanish pediatric patients with hypotonia, muscle weakness and feeding difficulties at birth. Whole-exome sequencing (WES) uncovered two new homozygous VAMP1 (Vesicle Associated Membrane Protein 1) splicing variants, NM_014231.5:c.129+5 G > A in the boy patient (P1) and c.341-24_341-16delinsAGAAAA in the girl patient (P2). This gene encodes the vesicle-associated membrane protein 1 (VAMP1) that is a component of a protein complex involved in the fusion of synaptic vesicles with the presynaptic membrane. VAMP1 has a highly variable C-terminus generated by alternative splicing that gives rise to three main isoforms (A, B and D), being VAMP1A the only isoform expressed in the nervous system. In order to assess the pathogenicity of these variants, expression experiments of RNA for VAMP1 were carried out. The c.129+5 G > A and c.341-24_341-16delinsAGAAAA variants induced aberrant splicing events resulting in the deletion of exon 2 (r.5_131del; p.Ser2TrpfsTer7) in the three isoforms in the first case, and the retention of the last 14 nucleotides of the 3' of intron 4 (r.340_341ins341-14_341-1; p.Ile114AsnfsTer77) in the VAMP1A isoform in the second case. Pathogenic VAMP1 variants have been associated with autosomal dominant spastic ataxia 1 (SPAX1) and with autosomal recessive presynaptic congenital myasthenic syndrome (CMS). Our patients share the clinical manifestations of CMS patients with two important differences: they do not show the typical electrophysiological pattern that suggests pathology of pre-synaptic neuromuscular junction, and their muscular biopsies present hypertrophic fibers type 1. In conclusion, our data expand both genetic and phenotypic spectrum associated with VAMP1 variants.

Episodic ataxia type 2 with a novel missense variant (Leu602Arg) in CACNA1A

Autosomal dominant episodic ataxia type 2 (EA2) is caused by variants in CACNA1A. We examined a 20-year-old male with EA symptoms from a Japanese family with hereditary EA. Cerebellar atrophy was not evident, but single photon emission computed tomography showed cerebellar hypoperfusion. We identified a novel nonsynonymous variant in CACNA1A, NM_001127222.2:c.1805T>G (p.Leu602Arg), which is predicted to be functionally deleterious; therefore, this variant is likely responsible for EA2 in this pedigree.

Adaptive Long-Read Sequencing Reveals GGC Repeat Expansion in ZFHX3 Associated with Spinocerebellar Ataxia Type 4.

Spinocerebellar ataxia type 4 (SCA4) is an autosomal dominant ataxia with invariable sensory neuropathy originally described in a family with Swedish ancestry residing in Utah more than 25 years ago. Despite tight linkage to the 16q22 region, the molecular diagnosis has since remained elusive. Inspired by pathogenic structural variation implicated in other 16q-ataxias with linkage to the same locus, we revisited the index SCA4 cases from the Utah family using novel technologies to investigate structural variation within the candidate region. We adopted a targeted long-read sequencing approach with adaptive sampling on the Oxford Nanopore Technologies (ONT) platform that enables the detection of segregating structural variants within a genomic region without a priori assumptions about any variant features. Using this approach, we found a heterozygous (GGC)n repeat expansion in the last coding exon of the zinc finger homeobox 3 (ZFHX3) gene that segregates with disease, ranging between 48 and 57 GGC repeats in affected probands. This finding was replicated in a separate family with SCA4. Furthermore, the estimation of this GGC repeat size in short-read whole genome sequencing (WGS) data of 21,836 individuals recruited to the 100,000 Genomes Project in the UK and our in-house dataset of 11,258 exomes did not reveal any pathogenic repeats, indicating that the variant is ultrarare. These findings support the utility of adaptive long-read sequencing as a powerful tool to decipher causative structural variation in unsolved cases of inherited neurological disease. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The Impact of Demographic and Clinical Factors on the Quality of Life in Patients with Neurodegenerative Cerebellar Ataxias.

In neurodegenerative cerebellar ataxias, not only ataxia but also extra-cerebellar signs have a significant impact on patients' health related to quality of life (HRQoL). The aim of this study was to evaluate the various aspects of HRQoL and predictors of QoL in patients with neurodegenerative cerebellar ataxias. We included a total of 107 patients with cerebellar degenerative ataxia. Patients filled out the validated Serbian version of the SF-36 used for the assessment of HRQoL. All patients were clinically evaluated using SARA, INAS, and neuropsychological tests to assess their global cognitive status and different psychiatric scales. The most frequent types of neurodegenerative cerebellar ataxias were autosomal dominant ataxias (38.3%) and sporadic ataxias (32.7%). Mean age at diagnosis was 35.3 ± 16.23 years, and disease duration was on average 12.1 ± 9.91 years. Mean total SF-36 score was 50.63 ± 20.50. Hierarchical regression analysis showed that in the case of the PHC score, the most significant predictors are the patient's actual age, severity of ataxia, and ACE total score. For MHC, the Hamilton depression score was the most important predictor. Our study has shown that HRQoL measured by SF-36 in patients with neurodegenerative cerebellar disorders is strongly influenced by impaired mobility and depression.

Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3/Machado-Joseph disease is the most common autosomal dominant ataxia. In view of the development of targeted therapies, knowledge of early biomarker changes is needed. We analyzed cross-sectional data of 292 spinocerebellar ataxia type 3/Machado-Joseph disease mutation carriers. Blood concentrations of mutant ATXN3 were high before and after ataxia onset, whereas neurofilament light deviated from normal 13.3 years before onset. Pons and cerebellar white matter volumes decreased and deviated from normal 2.2 years and 0.6 years before ataxia onset. We propose a staging model of spinocerebellar ataxia type 3/Machado-Joseph disease that includes a biomarker stage characterized by objective indicators of neurodegeneration before ataxia onset. ANN NEUROL 2024;95:400-406.

Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease

Autosomal-dominant ataxia with sensory and autonomic neuropathy is a highly specific combined phenotype that we described in two Swedish kindreds in 2014; its genetic cause had remained unknown. Here, we report the discovery of exonic GGC trinucleotide repeat expansions, encoding poly-glycine, in zinc finger homeobox 3 (ZFHX3) in these families. The expansions were identified in whole-genome datasets within genomic segments that all affected family members shared. Non-expanded alleles carried one or more interruptions within the repeat. We also found ZFHX3 repeat expansions in three additional families, all from the region of Skåne in southern Sweden. Individuals with expanded repeats developed balance and gait disturbances at 15 to 60 years of age and had sensory neuropathy and slow saccades. Anticipation was observed in all families and correlated with different repeat lengths determined through long-read sequencing in two family members. The most severely affected individuals had marked autonomic dysfunction, with severe orthostatism as the most disabling clinical feature. Neuropathology revealed p62-positive intracytoplasmic and intranuclear inclusions in neurons of the central and enteric nervous system, as well as alpha-synuclein positivity. ZFHX3 is located within the 16q22 locus, to which spinocerebellar ataxia type 4 (SCA4) repeatedly had been mapped; the clinical phenotype in our families corresponded well with the unique phenotype described in SCA4, and the original SCA4 kindred originated from Sweden. ZFHX3 has known functions in neuronal development and differentiation n both the central and peripheral nervous system. Our findings demonstrate that SCA4 is caused by repeat expansions in ZFHX3.

Therapeutic effects of engineered exosome-based miR-25 and miR-181a treatment in spinocerebellar ataxia type 3 mice by silencing ATXN3

BackgroundSpinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant hereditary ataxia worldwide, which is however in a lack of effective treatment. In view of that engineered exosomes are a promising non-invasive gene therapy transporter that can overcome the traditional problem of poor drug delivery, the aim of this study was to evaluate, for the first time, the value of exosome-based microRNA therapy in SCA3 and the therapeutic effects of intravenously administrated ATXN3 targeting microRNAs in transgenic SCA3 mouse models.MethodsThe rabies virus glycoprotein (RVG) peptide–modified exosomes loaded with miR-25 or miR-181a were peripherally injected to enable targeted delivery of miRNAs to the brain of SCA3 mice. The behaviors, ATXN3 level, purkinje cell and other neuronal loss, and neuroinflammation were evaluated 4 weeks after initial treatment.ResultsThe targeted and efficient delivery of miR-25 and miR-181a by modified exosomes substantially inhibited the mutant ATXN3 expression, reduced neuron apoptosis and induced motor improvements in SCA3 mouse models without increasing the neuroinflammatory response.ConclusionsOur study confirmed the therapeutic potential of engineered exosome-based miR-25 and miR-181a treatment in substantially reducing ATXN3 aggregation and cytotoxicity by relying on its targeted and efficient drug delivery performance in SCA3 mice. This treatment method shows a promising prospect for future clinical applications in SCA3.

Clinical, Electroencephalographic and Neuroimage Findings of Patients with Cerebellar Ataxia and Epilepsy (P9-11.003)

<h3>Objective:</h3> To describe phenotypical, imaging and neurophysiological features of patients affected by cerebellar ataxia and epilepsy. <h3>Background:</h3> The association of epilepsy with hereditary cerebellar ataxia is an emerging issue that has raised interest among researchers in the fields of movement disorders, epilepsy and neurogenetics, particularly the characterization of clinical and neurophysiological findings of affected patients. Although there are thorough descriptions of clinical and electroencephalographic findings of some diseases (such as SCA10 and progressive myoclonic epilepsies), there are no studies that accomplish a systematic correlation of clinical features, EEG and neuroimaging findings as a group of diseases. <h3>Design/Methods:</h3> 30 patients from southern Brazil diagnosed with both cerebellar ataxia and epilepsy were retrospectively assessed regarding specific diagnosis, clinical characteristics (severity, disease duration, seizure type and frequency), EEG and neuroimaging findings. Patients were also divided in 3 groups: autosomal dominant ataxias (SCAs), recessive ataxias and progressive myoclonic epilepsies and the findings were compared between those groups. <h3>Results:</h3> The most common diagnosis in each group was SCA10, undefined recessive ataxia and Unverricht Lundborg disease, respectively. A higher severity of ataxia symptoms (SARA rating scale) and worse seizure frequency control was found in patients with progressive myoclonic epilepsies. In 62%, seizure onset was determined to be generalized, with a higher frequency of tonic-clonic seizures. EEG analysis showed higher prevalence of epileptiform activity in the recessive ataxia group (57%, p&lt;0.005). 80% of patients presented cerebellar atrophy on brain MRI, being the isolated abnormal finding in 56%. <h3>Conclusions:</h3> The heterogeneity of the diseases that present cerebellar ataxia and epilepsy can be challenging. Higher frequency of SCA 10 was expected in the AD group, although in the southern Brazilian cohort this is the exception. PME ataxia was more severe and seizure control was poorer, compared to other groups. The results highlight the need for better characterization of epileptic ataxic patients and syndromes. <b>Disclosure:</b> Dr. Cassou has nothing to disclose. Luciano De Paola has nothing to disclose. Salmo Raskin has nothing to disclose. Paula Marques has nothing to disclose. Ms. Zulfiqar Ali has nothing to disclose. Ms. Qaiser has nothing to disclose. Dr. Andrade has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Andrade has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biocodex. Dr. Andrade has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zodiac. Dr. Andrade has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stoke therapeutics. Dr. Andrade has received publishing royalties from a publication relating to health care. Dr. Andrade has a non-compensated relationship as a Chair of task force on Transition with International League Against Epilepsy that is relevant to AAN interests or activities. Dr. Teive has nothing to disclose.

Spinocerebellar ataxia 21 and phenotypic variability within a single family (P9-11.004)

<h3>Objective:</h3> We describe four patients within a family who presented to our movement disorders centers for evaluation of unsteady gait, tremor, and cognitive impairment found to have the same pathogenic variant in TMEM240. We describe their clinical courses and response to treatments to include posterior subthalamic area deep brain stimulation (PSA DBS) and provide accompanying video. <h3>Background:</h3> Spinocerebellar ataxia 21 (SCA21) is a rare cause of autosomal dominant ataxia with few patients (~50) published. It is an early-onset, slowly progressive cerebellar ataxia and may also have tremor, parkinsonism, oculomotor abnormalities, cognitive impairment, and psychiatric conditions. Given its rarity, the neurodevelopmental phenotype has not been well defined and phenotypic variability within the same variant has not yet described. <h3>Design/Methods:</h3> The index case, 12 year-old girl, presented with mild intellectual disability, severe action tremor since infancy, oculomotor abnormalities, anxiety, and depression. The full brother was noted to have mild action tremor since early childhood, speech delay and growth delay. The paternal half-brother presented with progressively worsening action tremor since early childhood which became impairing in adolescence as well as similar oculomotor abnormalities, learning disabilities, ADHD, and OCD. The father of the patients had onset of mild non-progressive action tremor of the hands since age 8, progressive ataxia, mild parkinsonism, mild intellectual disability and new onset progressive memory impairment. All patients were found to have the same pathogenic variant in TMEM240 (c.196G&gt;A p.G66R)). <h3>Results:</h3> The index patient tried numerous oral medications as well as botulinum neurotoxin (BoNT) injections without improvement. She underwent PSA DBS with marked improvement in tremor. Tremor in the paternal half-brother responded well to BoNT injections. The father underwent treatment for parkinsonism with carbidopa-levodopa and was started on rivastigmine without improvement. <h3>Conclusions:</h3> SCA21 is a slowly progressive autosomal dominant spinocerebellar ataxia with variable neurodevelopmental phenotypes including multiple movement disorders within the same variant. <b>Disclosure:</b> Dr. Hull has received publishing royalties from a publication relating to health care. Dr. Parnes has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva Pharmaceuticals. Dr. Parnes has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva Pharmaceuticals. The institution of Dr. Parnes has received research support from NIH. The institution of Dr. Parnes has received research support from Alexion. Dr. Jankovic has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Revance. Dr. Jankovic has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Revance, Allergan. The institution of Dr. Jankovic has received research support from Baylor College of Medicine. Dr. Jankovic has received research support from Abbvie. The institution of Dr. Jankovic has received research support from Abbvie.

Blood transcriptome sequencing identifies biomarkers able to track disease stages in spinocerebellar ataxia type 3.

Transcriptional dysregulation has been described in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), an autosomal dominant ataxia caused by a polyglutamine expansion in the ataxin-3 protein. As ataxin-3 is ubiquitously expressed, transcriptional alterations in blood may reflect early changes that start before clinical onset and might serve as peripheral biomarkers in clinical and research settings. Our goal was to describe enriched pathways and report dysregulated genes, which can track disease onset, severity or progression in carriers of the ATXN3 mutation (pre-ataxic subjects and patients). Global dysregulation patterns were identified by RNA sequencing of blood samples from 40 carriers of ATXN3 mutation and 20 controls and further compared with transcriptomic data from post-mortem cerebellum samples of MJD patients and controls. Ten genes-ABCA1, CEP72, PTGDS, SAFB2, SFSWAP, CCDC88C, SH2B1, LTBP4, MEG3 and TSPOAP1-whose expression in blood was altered in the pre-ataxic stage and simultaneously, correlated with ataxia severity in the overt disease stage, were analysed by quantitative real-time PCR in blood samples from an independent set of 170 SCA3/MJD subjects and 57 controls. Pathway enrichment analysis indicated the Gαi signalling and the oestrogen receptor signalling to be similarly affected in blood and cerebellum. SAFB2, SFSWAP and LTBP4 were consistently dysregulated in pre-ataxic subjects compared to controls, displaying a combined discriminatory ability of 79%. In patients, ataxia severity was associated with higher levels of MEG3 and TSPOAP1. We propose expression levels of SAFB2, SFSWAP and LTBP4 as well as MEG3 and TSPOAP1 as stratification markers of SCA3/MJD progression, deserving further validation in longitudinal studies and in independent cohorts.

A Review of Ocular Movement Abnormalities in Hereditary Cerebellar Ataxias.

Cerebellar ataxias are a wide heterogeneous group of disorders that may present with fine motor deficits as well as gait and balance disturbances that have a significant influence on everyday activities. To review the ocular movements in cerebellar ataxias in order to improve the clinical knowledge of cerebellar ataxias and related subtypes. English papers published from January 1990 to May 2022 were selected by searching PubMed services. The main search keywords were ocular motor, oculomotor, eye movement, eye motility, and ocular motility, along with each ataxia subtype. The eligible papers were analyzed for clinical presentation, involved mutations, the underlying pathology, and ocular movement alterations. Forty-three subtypes of spinocerebellar ataxias and a number of autosomal dominant and autosomal recessive ataxias were discussed in terms of pathology, clinical manifestations, involved mutations, and with a focus on the ocular abnormalities. A flowchart has been made using ocular movement manifestations to differentiate different ataxia subtypes. And underlying pathology of each subtype is reviewed in form of illustrated models to reach a better understanding of each disorder.