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Background: In Belgian Malinois, a KCNJ10 variant causes progressive spinocerebellar degeneration. Hypothesis/objectives: Describe the clinical, diagnostic, pathological and genetic features of spinocerebellar degeneration in the Bouvier des Ardennes breed. Animals: Five affected Bouvier des Ardennes puppies with spinocerebellar ataxia (SCA), 8 healthy related dogs, and 63 healthy unrelated Bouvier des Ardennes. Methods: Sequential case study. Results: Clinical signs started at 6 weeks of age in 1 puppy with severe signs of cerebellar disease, and at 7 to 10 weeks of age in the 4 remaining puppies with milder signs of spinocerebellar disease. The first puppy displayed severe intention tremors and rapidly progressive generalized hypermetric ataxia, whereas the 4 others developed a milder progressive SCA. Euthanasia after progression to nonambulatory status was performed by 8 weeks of age in the first puppy, and before 11 months of age in the 4 remaining puppies. Histopathology revealed cerebellar spongy degeneration and a focal symmetrical demyelinating myelopathy. All cases were homozygous for KCNJ10 XM_545752.6:c.986T>C(p.(Leu329Pro)), which is pathogenic for SCA with (or without) myokymia, seizures or both (SAMS) and spongy degeneration and cerebellar ataxia (SDCA) 1 in Belgian Malinois dogs. All sampled parents were heterozygous and none of the healthy dogs were homozygous for this recessive variant. This variant has an allele frequency of 15% in the 63 healthy dogs studied. Conclusions and clinical importance: Inherited spinocerebellar degeneration also affects the Bouvier des Ardennes breed and is caused by a KCNJ10 variant. It can present with a spectrum of severity grades, ranging from severe cerebellar to milder spinocerebellar signs.

Movement disorders 37(9), 1850-1860 (2022). doi:10.1002/mds.29135, Published by Wiley, New York, NY

The genetically heterozygous spinocerebellar ataxias are all characterized by cerebellar atrophy and pervasive Purkinje Cell degeneration. Up to date, more than 35 functionally diverse spinocerebellar ataxia genes have been identified. The main question that remains yet unsolved is why do some many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia? To address this question it is important to identify intrinsic pathways important for Purkinje Cell function and survival. In this review, we discuss the current consensus on shared mechanisms underlying the pervasive Purkinje Cell loss in spinocerebellar ataxia. Additionally, using recently published cell type specific expression data, we identified several Purkinje Cell-specific genes and discuss how the corresponding pathways might underlie the vulnerability of Purkinje Cells in response to the diverse genetic insults causing spinocerebellar ataxia.

The genetically heterozygous spinocerebellar ataxias are all characterized by cerebellar atrophy and pervasive Purkinje Cell degeneration. Up to date, more than 35 functionally diverse spinocerebellar ataxia genes have been identified. The main question that remains yet unsolved is why do some many genetic insults lead to Purkinje Cell degeneration and spinocerebellar ataxia? To address this question it is important to identify intrinsic pathways important for Purkinje Cell function and survival. In this review, we discuss the current consensus on shared mechanisms underlying the pervasive Purkinje Cell loss in spinocerebellar ataxia. Additionally, using recently published cell type specific expression data, we identified several Purkinje Cell-specific genes and discuss how the corresponding pathways might underlie the vulnerability of Purkinje Cells in response to the diverse genetic insults causing spinocerebellar ataxia.

Inborn errors of metabolism in adults are still largely unexplored. Despite the fact that adult-onset phenotypes have been known for many years, little attention is given to these disorders in neurological practice. The adult-onset presentation differs from childhood-onset phenotypes, often leading to considerable diagnostic delay. The identification of these patients at the earliest stage of disease is important, given that early treatment may prevent or lessen further brain damage. Neurological and psychiatric symptoms occur more frequently in adult forms. Abnormalities of eye movements are also common and can be the presenting sign. Eye movement disorders can be classified as central or peripheral. Central forms are frequently observed in lysosomal storage disorders, whereas peripheral forms are a key feature of mitochondrial disease. Furthermore, oculogyric crisis is an important feature in disorders affecting dopamine syntheses or transport. Ocular motor disorders are often not reported by the patient, and abnormalities can be easily overlooked in a general examination. In adults with unexplained psychiatric and neurological symptoms, a special focus on examination of eye movements can serve as a relatively simple clinical tool to detect a metabolic disorder. Eye movements can be easily quantified and analyzed with video-oculography, making them a valuable biomarker for following the natural course of disease or the response to therapies. Here, we review, for the first time, eye movement disorders that can occur in inborn errors of metabolism, with a focus on late-onset forms. We provide a step-by-step overview that will help clinicians to examine and interpret eye movement disorders. (c) 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

ObjectiveTo characterize the genetic background of molecularly undefined childhood-onset ataxias in Finland.MethodsThis study examined a cohort of patients from 50 families with onset of an ataxia syndrome before the age of 5 years collected from a single tertiary center, drawing on the advantages offered by next generation sequencing. A genome-wide genotyping array (Illumina Infinium Global Screening Array MD-24 v.2.0) was used to search for copy number variation undetectable by exome sequencing.ResultsExome sequencing led to a molecular diagnosis for 20 probands (40%). In the 23 patients examined with a genome-wide genotyping array, 2 additional diagnoses were made. A considerable proportion of probands with a molecular diagnosis had de novo pathogenic variants (45%). In addition, the study identified a de novo variant in a gene not previously linked to ataxia: MED23. Patients in the cohort had medically actionable findings.ConclusionsThere is a high heterogeneity of causative mutations in this cohort despite the defined age at onset, phenotypical overlap between patients, the founder effect, and genetic isolation in the Finnish population. The findings reflect the heterogeneous genetic background of ataxia seen worldwide and the substantial contribution of de novo variants underlying childhood ataxia.

ispartof: MOVEMENT DISORDERS CLINICAL PRACTICE vol:7 issue:2 pages:230-231 ispartof: location:United States status: published

Objective: to foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). Methods: cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results: fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that >= 48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. Interpretation: this study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia., European Union (European Union); Horizon 2020; European Union's Horizon 2020 Research and Innovation Program by the BMBF, E-Rare-3 network PREPARE; European Union's Horizon 2020 Research and Innovation Program, Solve-RD; German Bundesministerium fur Bildung und Forschung (BMBF), in der Systemmedizin "mitOmics; University of Tubingen, Medical Faculty, for the Clinician Scientist; Italian Ministry of Health; German Research Foundation/Deutsche Forschungsgemeinschaft; NIH; NSF; Wellcome Trust Investigator; ; Medical Research Council (UK); European Research Council (ERC); Wellcome Trust Pathfinder Scheme; Newton Fund; Senior Clinical Researcher mandate of the Research Fund - Flanders (FWO); ZonMW, Hersenstichting, Gossweiler Foundation; Radboud University Medical Centre; VolkswagenStiftung (Freigeist Fellowship; Deutsche Forschungsgemeinschaft; German Parkinson Society and Actelion Pharmaceuticals; Italian Ministry of Health Ricerca Finalizzata Suna and İnan Kıraç Foundation and Koç University School of Medicine

Physiotherapy, including vibration-assisted therapy, has been proven to be effective for patients with ataxic cerebral palsy. Herewith, we studied the effect of a functional, goal-oriented interval rehabilitation program, including vibration-assisted home-training on the motor function of children with congenital ataxias.45 children (mean age 7.7 years, SD 4.70) with ataxia, having received a 6-month home-based side-alternating vibration-assisted therapy combined with intensive, goal-oriented, functional rehabilitation intervals, were included in the study, classified according to the progressive or non-progressive ataxia character.Retrospective analysis of the prospectively collected data of the registry of the Cologne rehabilitation program "Auf die Beine". Motor abilities have been assessed prior to the intervention (M0), after 6 months of home-training (M6) as well as in a follow-up 6 months later (M12). We performed a gait analysis, a 1-minute walking test (1-MWT), and the Gross Motor Function Measure (GMFM-66).The GMFM-66 improvement (M6-M0 vs. M12-M6) was statistically significant with median improvement of 2.4 points (non-progressive) and 2.9 points (progressive) respectively, and clinically relevant. The 1-MWT improvement was statistically significant and clinically relevant for non-progressive ataxia.The intensive training, including vibration-assisted therapy significantly improved the motor function of children with ataxia. Six months later the skills were preserved in children with progressive ataxia and could be further developed in non-progressive forms.Vibrationstherapie hat sich bei Patienten mit ataktischer Zerebralparese als wirksam erwiesen. Dabei untersuchten wir, wie sich ein funktionelles, zielgerichtetes Intervallrehabilitationsprogramm mit vibrationsgestütztem Heimtraining auf die motorische Funktion von Kindern mit angeborener Ataxie auswirkt.45 Kinder (mittleres Alter 7,7 Jahre, SD 4,70) mit Ataxie, die eine 6-monatige seitenalternierende vibrationsunterstützte Therapie in Kombination mit intensiven, zielgerichteten, funktionellen Rehabilitationsintervallen erhielten, wurden in die Studie eingeschlossen und nach dem nicht progressiven oder progressivem klinischen Verlauf in 2 Gruppen eingeteilt.Retrospektive Analyse aus dem Register des Kölner Rehabilitationsprogramms „Auf die Beine“. Die motorischen Fähigkeiten wurden vor dem Training (M0), nach 6-monatigem Heimtraining (M6) sowie nach weiteren 6 Monaten (M12) beurteilt. Wir führten eine Ganganalyse, einen Ein-Minuten-Gehtest (1-MWT) sowie ein Gross Motor Function Measure (GMFM-66) durch.Die GMFM-66-Verbesserung (M6–M0 vs. M12–M6) war statistisch signifikant mit medianer Verbesserung von 2,4 Punkten (nicht progressiv) bzw. 2,9 Punkten (progressiv) und klinisch relevant. Ähnlich war die 1-MWT-Verbesserung statistisch signifikant und klinisch relevant für nicht-progressive Ataxie.Das intensive Training, einschließlich der häuslichen, vibrationsgestützten Physiotherapie, hat die motorische Funktion von Kindern mit Ataxie signifikant verbessert. Sechs Monate später waren die motorischen Fähigkeiten der Kindern mit progressiver Ataxie gleichgeblieben und konnten in der nicht-progressiven Gruppe weiter gesteigert werden.

Objective: To systematically review the symptoms reported by patients with bilateral vestibulopathy (BV) in clinical studies and case reports. This would serve as the first step in establishing a validated patient-reported outcome measures (PROM) for BV. Methods: A search on symptoms reported by patients with BV was performed in PubMed, and all publications covering these symptoms were included. Exclusion criteria comprised reviews and insufficient details about the frequency of occurrence of symptoms. Results: 1,442 articles were retrieved. 88 studies were included (41 clinical studies, 47 case reports). In consensus, 68 descriptions of symptoms were classified into 6 common and generic symptoms. Frequency of symptoms in clinical studies and case reports were reviewed, respectively; imbalance (91 and 86%), chronic dizziness (58 and 62%), oscillopsia (50 and 70%), and recurrent vertigo (33 and 67%). BV could be accompanied by hearing loss (33 and 43%) and tinnitus (15 and 36%). 15 clinical studies and 10 case reports reported symptoms beyond vestibular and hearing deficits such as limited social activities, depression, concentration, and memory impairment and reduced quality of life in general. Conclusion: The literature on BV symptomatology mainly focuses on classic symptoms such as imbalance and oscillopsia, while only few report additional symptoms such as cognitive memory impairment and performing dual tasks. In fact, none of the reviewed clinical studies and case reports provided a comprehensive overview of BV symptoms. To develop a validated PROM, qualitative research using semi-structured and unstructured interviews is needed to explore the full spectrum of BV symptoms.

The inherited optic neuropathies comprise a group of genetically heterogeneous disorders causing optic nerve dysfunction. In some cases, optic neuropathies are associated with cerebellar atrophy which mainly affects the vermis. Here, we describe a Moroccan girl of consanguineous parents with optic atrophy and cerebellar atrophy. Exome sequencing revealed a novel homozygous mutation (c.283+3G>T) in the donor splice site for exon 1 of SLC25A46. RNA analysis revealed that an alternative splice site within exon 1 was used leading to a premature termination codon within exon 2. SLC25A46 mRNA expression showed there is no wild-type transcript present in the patient and the mutant transcript does not undergo nonsense mediated mRNA decay. Futhermore, we observed c.283+3G>T SLC25A46 mutation induces mitochondrial fragmentation. An additional 10 patients with optic atrophy and cerebellar atrophy, which were negative for mtDNA and OPA1 variants, were tested for pathogenic mutations in the SLC25A46 gene. However, no additional variants were identified. Our findings confirm the recent report of pathogenic SLC25A46 mutations as a novel cause for optic atrophy spectrum disorder.

This paper describes the diagnostic criteria for bilateral vestibulopathy (BVP) by the Classification Committee of the Barany Society. The diagnosis of BVP is based on the patient history, bedside examination and laboratory evaluation. Bilateral vestibulopathy is a chronic vestibular syndrome which is characterized by unsteadiness when walking or standing, which worsen in darkness and/or on uneven ground, or during head motion. Additionally, patients may describe head or body movement-induced blurred vision or oscillopsia. There are typically no symptoms while sitting or lying down under static conditions. The diagnosis of BVP requires bilaterally significantly impaired or absent function of the vestibulo-ocular reflex (VOR). This can be diagnosed for the high frequency range of the angular VOR by the head impulse test (HIT), the video-HIT (vHIT) and the scleral coil technique and for the low frequency range by caloric testing. The moderate range can be examined by the sinusoidal or step profile rotational chair test. For the diagnosis of BVP, the horizontal angular VOR gain on both sides should be 68 degrees (time constant of = 0.2 logMAR is considered pathological); b) Romberg (indicating a sensory deficit of the vestibular or somatosensory system and therefore not specific); and c) abnormal cervical and ocular vestibular-evoked myogenic potentials for otolith function. At present the scientific basis for further subdivisions into subtypes of BVP is not sufficient to put forward reliable or clinically meaningful definitions. Depending on the affected anatomical structure and frequency range, different subtypes may be better identified in the future: impaired canal function in the low-or high-frequency VOR range only and/or impaired otolith function only; the latter is evidently very rare. Bilateral vestibulopathy is a clinical syndrome and, if known, the etiology (e.g., due to ototoxicity, bilateral Meniere's disease, bilateral vestibular schwannoma) should be added to the diagnosis. Synonyms include bilateral vestibular failure, deficiency, areflexia, hypofunction and loss.

Sirtuin 1 (Sirt1) is a NAD(+)-dependent deacetylase capable of countering age-related neurodegeneration, but the basis of Sirt1 neuroprotection remains elusive. Spinocerebellar ataxia type 7 (SCA7) is an inherited CAG-polyglutamine repeat disorder. Transcriptome analysis of SCA7 mice revealed downregulation of calcium flux genes accompanied by abnormal calcium-dependent cerebellar membrane excitability. Transcription-factor binding-site analysis of downregulated genes yielded Sirt1 target sites, and we observed reduced Sirt1 activity in the SCA7 mouse cerebellum with NAD(+) depletion. SCA7 patients displayed increased poly(ADP-ribose) in cerebellar neurons, supporting poly(ADP-ribose) polymerase-1 upregulation. We crossed Sirt1-overexpressing mice with SCA7 mice and noted rescue of neurodegeneration and calcium flux defects. NAD(+) repletion via nicotinamide riboside ameliorated disease phenotypes in SCA7 mice and patient stem cell-derived neurons. Sirt1 thus achieves neuroprotection by promoting calcium regulation, and NAD(+) dysregulation underlies Sirt1 dysfunction in SCA7, indicating that cerebellar ataxias exhibit altered calcium homeostasis because of metabolic dysregulation, suggesting shared therapy targets.

In degenerative adult onset ataxia (AOA), dystonic comorbidity is attributed to one disease continuum. However, in early adult onset ataxia (EOA), the prevalence and pathogenesis of dystonic comorbidity (EOAD+), are still unclear. In 80 EOA-patients, we determined the EOAD+-prevalence in association with MRI-abnormalities. Subsequently, we explored underlying biological pathways by genetic network and functional enrichment analysis. We checked pathway-outcomes in specific EOAD+-genotypes by comparing results with non-specifically (in-silico-determined) shared genes in up-to-date EOA, AOA and dystonia gene panels (that could concurrently cause ataxia and dystonia). In the majority (65%) of EOA-patients, mild EOAD+-features concurred with extra-cerebellar MRI abnormalities (at pons and/or basal-ganglia and/or thalamus (p = 0.001)). Genetic network and functional enrichment analysis in EOAD+-genotypes indicated an association with organelle- and cellular-component organization (important for energy production and signal transduction). In non-specifically, in-silico-determined shared EOA, AOA and dystonia genes, pathways were enriched for Krebs-cycle and fatty acid/lipid-metabolic processes. In frequently occurring EOAD+-phenotypes, clinical, anatomical and biological pathway analyses reveal shared pathophysiology between ataxia and dystonia, associated with cellular energy metabolism and network signal transduction. Insight in the underlying pathophysiology of heterogeneous EOAD+-phenotype-genotype relationships supports the rationale for testing with complete, up-to-date movement disorder gene lists, instead of single EOA gene-panels.

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a rare disorder with an unknown etiology. We present a British family with presumed autosomal dominant CANVAS with incomplete penetrance and variable expressivity. Exome sequencing identified a rare missense variant in the ELF2 gene at chr4:g.140058846 C > T, c.10G > A, p.A4T which segregated in all affected patients. By using transduced BE (2)-M17 cells, we found that the mutated ELF2 (mt-ELF2) gene increased ATXN2 and reduced ELOVL5 gene expression, the causal genes of type 2 and type 38 spinocerebellar ataxias. Both, western blot and confocal microscopy confirmed an increase of ataxin-2 in BE(2)-M17 cells transduced with lentivirus expressing mt-ELF2 (CEE-mt-ELF2), which was not observed in cells transduced with lentivirus expressing wt-ELF2 (CEE-wt-ELF2). Moreover, we observed a significant decrease in the number and size of lipid droplets in the CEE-mt-ELF2-transduced BE (2)-M17 cells, but not in the CEE-wt-ELF2-transduced BE (2)-M17. Furthermore, changes in the expression of ELOVL5 could be related with the reduction of lipid droplets in BE (2)-M17 cells. This work supports that ELF2 gene regulates the expression of ATXN2 and ELOVL5 genes, and defines new molecular links in the pathophysiology of cerebellar ataxias.

OBJECTIVE: To systematically review the symptoms reported by patients with bilateral vestibulopathy (BV) in clinical studies and case reports. This would serve as the first step in establishing a validated patient reported outcome measures for BV. METHODS: A search on symptoms reported by patients with BV was performed in PubMed, and all publications covering these symptoms were included. Exclusion criteria comprised reviews and insufficient details about the frequency of occurrence of symptoms. RESULTS: Fourteen-hundred-forty-two (1442) articles were retrieved. Eighty-eight studies were included (41 clinical studies, 47 case-reports). In consensus, 68 descriptions of symptoms were classified into six common and generic symptoms. Frequency of symptoms in clinical studies and case reports were reviewed respectively; imbalance (91% and 86%), chronic dizziness (58% and 62%), oscillopsia (50% and 70%) and recurrent vertigo (33% and 67%). BV could be accompanied by hearing loss (33% and 43%) and tinnitus (15% and 36%). Fifteen clinical studies and ten case reports reported symptoms beyond vestibular and hearing deficits such as limited social activities, depression, concentration and memory impairment, and reduced quality of life in general. CONCLUSIONS: The literature on BV symptomatology mainly focuses on classic symptoms such as imbalance and oscillopsia, while only few report additional symptoms such as cognitive memory impairment and performing dual tasks. In fact, none of the reviewed clinical studies and case reports provided a comprehensive overview of BV symptoms. In order to develop a validated patient reported outcome measures, qualitative research using semi-structured and unstructured interviews is needed to explore the full spectrum of BV symptoms.

To investigate the interobserver agreement on phenotypic early-onset ataxia (EOA) assessment and to explore whether the Scale for Assessment and Rating of Ataxia (SARA) could provide a supportive marker.Seven movement disorder specialists provided independent phenotypic assessments of potentially ataxic motor behaviour in 40 patients (mean age 15y [range 5-34]; data derived from University Medical Center Groningen medical records 1998-2012). We determined interobserver agreement by Fleiss' kappa. Furthermore, we compared percentage SARA subscores ([subscore/total score]×100%) between 'indisputable' (primary ataxia recognition by at least six observers) and 'mixed' (ataxia recognition, unfulfilling 'indisputable' criteria) EOA phenotypes.Agreement on phenotypic EOA assessment was statistically significant (p0.001), but of moderate strength (Fleiss' kappa=0.45; 95% CI 0.38-0.51). During mild disease progression, percentage SARA gait subscores discriminated between 'indisputable' and 'mixed' EOA phenotypes. In patients with percentage SARA gait subscores30%, primary ataxia was more frequently present than in those with subscores30% (p=0.001).Among movement-disorder professionals from different disciplines, interobserver agreement on phenotypic EOA recognition is of limited strength. SARA gait subscores can provide a supportive discriminative marker between EOA phenotypes. Hopefully, future phenotypic insight will contribute to the inclusion of uniform, high-quality data in international EOA databases.

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

This paper describes the diagnostic criteria for bilateral vestibulopathy (BVP) by the Classification Committee of the Barany Society. The diagnosis of BVP is based on the patient history, bedside examination and laboratory evaluation. Bilateral vestibulopathy is a chronic vestibular syndrome which is characterized by unsteadiness when walking or standing, which worsen in darkness and/or on uneven ground, or during head motion. Additionally, patients may describe head or body movement-induced blurred vision or oscillopsia. There are typically no symptoms while sitting or lying down under static conditions. The diagnosis of BVP requires bilaterally significantly impaired or absent function of the vestibulo-ocular reflex (VOR). This can be diagnosed for the high frequency range of the angular VOR by the head impulse test (HIT), the video-HIT (vHIT) and the scleral coil technique and for the low frequency range by caloric testing. The moderate range can be examined by the sinusoidal or step profile rotational chair test. For the diagnosis of BVP, the horizontal angular VOR gain on both sides should be 68 degrees (time constant of = 0.2 logMAR is considered pathological); b) Romberg (indicating a sensory deficit of the vestibular or somatosensory system and therefore not specific); and c) abnormal cervical and ocular vestibular-evoked myogenic potentials for otolith function. At present the scientific basis for further subdivisions into subtypes of BVP is not sufficient to put forward reliable or clinically meaningful definitions. Depending on the affected anatomical structure and frequency range, different subtypes may be better identified in the future: impaired canal function in the low-or high-frequency VOR range only and/or impaired otolith function only; the latter is evidently very rare. Bilateral vestibulopathy is a clinical syndrome and, if known, the etiology (e.g., due to ototoxicity, bilateral Meniere's disease, bilateral vestibular schwannoma) should be added to the diagnosis. Synonyms include bilateral vestibular failure, deficiency, areflexia, hypofunction and loss.

The inherited optic neuropathies comprise a group of genetically heterogeneous disorders causing optic nerve dysfunction. In some cases, optic neuropathies are associated with cerebellar atrophy which mainly affects the vermis. Here, we describe a Moroccan girl of consanguineous parents with optic atrophy and cerebellar atrophy. Exome sequencing revealed a novel homozygous mutation (c.283+3G>T) in the donor splice site for exon 1 of SLC25A46. RNA analysis revealed that an alternative splice site within exon 1 was used leading to a premature termination codon within exon 2. SLC25A46 mRNA expression showed there is no wild-type transcript present in the patient and the mutant transcript does not undergo nonsense mediated mRNA decay. Futhermore, we observed c.283+3G>T SLC25A46 mutation induces mitochondrial fragmentation. An additional 10 patients with optic atrophy and cerebellar atrophy, which were negative for mtDNA and OPA1 variants, were tested for pathogenic mutations in the SLC25A46 gene. However, no additional variants were identified. Our findings confirm the recent report of pathogenic SLC25A46 mutations as a novel cause for optic atrophy spectrum disorder.

The protein kinase C γ (PKCγ) undergoes multistep activation and participates in various cellular processes in Purkinje cells. Perturbations in its phosphorylation state, conformation or localization can disrupt kinase signalling, such as in spinocerebellar ataxia type 14 (SCA14) that is caused by missense mutations in PRKCG encoding for PKCγ. We previously showed that SCA14 mutations enhance PKCγ membrane translocation upon stimulation owing to an altered protein conformation. As the faster translocation did not result in an increased function, we examined how SCA14 mutations induce this altered conformation of PKCγ and what the consequences of this conformational change are on PKCγ life cycle. Here, we show that SCA14-related PKCγ-V138E exhibits an exposed C-terminus as shown by fluorescence resonance energy transfer-fluorescence lifetime imaging microscopy in living cells, indicative of its partial unfolding. This conformational change was associated with faster phorbol 12-myristate 13-acetate-induced translocation and accumulation of fully phosphorylated PKCγ in the insoluble fraction, which could be rescued by coexpressing PDK1 kinase that normally triggers PKCγ autophosphorylation. We propose that the SCA14 mutation V138E causes unfolding of the C1B domain and exposure of the C-terminus of the PKCγ-V138E molecule, resulting in a decrease of functional kinase in the soluble fraction.Here, we show that the mutation V138E of the protein kinase C γ (PKCγ) C1B domain (PKCγ-V138E), which is implicated in spinocerebellar ataxia type 14, exhibits a partially unfolded C-terminus. This leads to unusually fast phorbol 12-myristate 13-acetate-induced membrane translocation and accumulation of phosphorylated PKCγ-V138E in the insoluble fraction, causing loss of the functional kinase. In contrast to general chaperones, coexpression of PKCγ's ‘natural chaperone’, PDK1 kinase, could rescue the PKCγ-V138E phenotype.

Sir, With the introduction of next generation sequencing into research and the clinic, geneticists now face the problem of variant interpretation in single cases, which is a challenging task due to the lack of data from additional affected family members. For the majority of the variants in our genome we do not know whether they are damaging and pathogenic or just harmless rare polymorphisms. We therefore must rely heavily on in silico prediction programs and the information found in large genetic databases such as ExAC \[Exome Aggregation Consortium (ExAC), Cambridge, MA\] (http://exac.broadinstitute.org) to predict the pathogenicity of variants. The letter from Pedroso et al. (2016) addresses this problem. Pedroso et al. (2016) state that many of the reported SCA23 mutations in PDYN are present in ExAC and suggest that this brings into question the validity of PDYN as the disease-causing gene for SCA23. They point out that the SCA23 mutations were detected in 37 of 60 700 individuals in ExAC, a database that was founded in 2014, 4 years after our original SCA23 report was published, when none of these PDYN variations had been detected in controls or any genetic database, supporting our conclusion that PDYN is the SCA23 disease gene. ExAC combines multi-ethnic sequencing data from several sources, as it includes sequencing studies on heart disease, type 2 diabetes, schizophrenia, bipolar disorder, and Tourette’s syndrome, …

Contains fulltext : 47801.pdf (Publisher’s version ) (Closed access) Missense mutations in the PRKCG gene have recently been identified in spinocerebellar ataxia 14 (SCA14) patients; these include the Gly118Asp mutation that we found in a large Dutch autosomal dominant cerebellar ataxia (ADCA) family. We subsequently screened the current Dutch ataxia cohort (approximately 900 individuals) for SCA14 mutations in the Cys2 region of the PRKCG gene. We identified the Gly118Asp mutation in another eight individuals from five small families. Haplotype analysis identified a shared chromosomal region surrounding the SCA14 gene, and genealogical research was able to link all these ADCA patients to a single common ancestor. We therefore confirmed that the Gly118Asp mutation is a SCA14 founder mutation in the Dutch ADCA population.

We identified nine children with a leukoencephalopathy of similar type according to clinical and MRI findings. The patients included three affected sibling pairs. The age range was 3 to 19 years. The onset of the disease was in childhood; the course was both chronic-progressive and episodic. There were episodes of deterioration following infections and minor head traumas, and these could result in unexplained coma. In eight patients with advanced disease, MRI revealed a diffuse cerebral hemispheric leukoencephalopathy, in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In one patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter, which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate, compatible with the presence of mainly CSF and little brain tissue. Spectra of the cortex were much better preserved. However, in addition to the normal resonances, there were signals representing lactate and glucose. MRS of the white matter in the patient whose disease was at an early stage was much less abnormal. Autopsy in one patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. Typical involvement of pontine tegmental white matter was suggested by MRI and confirmed by autopsy. The disease probably has an autosomal recessive mode of inheritance, but the basic metabolic defect is not known.

The relevant clinical, genetic, and cell biologic aspects of the dominantly inherited spinocerebellar ataxias (SCAs) are reviewed in this article. SCAs are diseases of the entire nervous system; in addition to cerebellar ataxia, the central (but not obligate) disease feature, many noncerebellar complications can be present as well. There are over 35 genetic subtypes: although those caused by expanded CAG repeats are still the more common ones, the majority of the recent SCAs have been caused by more conventional mutations. Genotype-phenotype correlations do exist and are most clear for the repeat expansion, where repeat length partially explains age at onset, disease severity and progression, and the core clinical phenotype. Some common themes within the disease mechanisms seem to emerge, including misfolding and aggregation, impairment of the protein quality control system, abnormal protein interactions, disruption of gene transcription, RNA toxicity, and changes in glutamate and calcium signaling. Yet despite this exciting progress in the molecular genetic background and suggested corresponding pathways, there is still no drug available that is specifically designed for or targeted at the mechanisms at play.

We identified nine children with a leukoencephalopathy of similar type according to clinical and MRI findings. The patients included three affected sibling pairs. The age range was 3 to 19 years. The onset of the disease was in childhood; the course was both chronic-progressive and episodic. There were episodes of deterioration following infections and minor head traumas, and these could result in unexplained coma. In eight patients with advanced disease, MRI revealed a diffuse cerebral hemispheric leukoencephalopathy, in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In one patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter, which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate, compatible with the presence of mainly CSF and little brain tissue. Spectra of the cortex were much better preserved. However, in addition to the normal resonances, there were signals representing lactate and glucose. MRS of the white matter in the patient whose disease was at an early stage was much less abnormal. Autopsy in one patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. Typical involvement of pontine tegmental white matter was suggested by MRI and confirmed by autopsy. The disease probably has an autosomal recessive mode of inheritance, but the basic metabolic defect is not known.

Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions., SCOPUS: ar.j, info:eu-repo/semantics/published