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Supplementary data is available online at https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awad105/7091433#supplementary-data . Accepted manuscripts are PDF versions of the author’s final manuscript, as accepted for publication by the journal but prior to copyediting or typesetting. They can be cited using the author(s), article title, journal title, year of online publication, and DOI. They will be replaced by the final typeset articles, which may therefore contain changes. The DOI will remain the same throughout. Copyright © The Author(s) 2023. The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer’s disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression. The Progressive Supranuclear Palsy–Corticobasal Syndrome–Multiple System Atrophy (PROSPECT-M-UK) study is supported by grants for PROSPECT, cerebrospinal fluid biomarker measurements, and PROSPECT magnetic resonance imaging and Sara Koe Fellowship grants from the PSP Association UK, CBD Solutions, the MSA Trust, the Wellcome Trust (103838; 220258); the NIHR Cambridge Biomedical Research Centre and Cambridge Brain Bank (BRC 1215-20014; NIHR203312: The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care); Cambridge Centre for Parkinson-Plus; Medical Research Council (SUAG/092 116768); and the NIHR UCLH Biomedical Research Centre. Queen Square Brain Bank is supported by the Reta Lila Weston Institute for Neurological Studies and the MRC. The fluid biomarker measurements were supported in part by the UK Dementia Research Institute at UCL and a multiuser equipment grant from Wellcome Trust. The Cambridge Brain Bank is part of the Cambridge Human research Tissue Bank funded by the Biomedical Research Council. The Oxford Brain Bank is supported by the MRC, Brains for Dementia Research (Alzheimer’s Society and Alzheimer’s Research UK), and the NIHR Oxford Biomedical Research Centre. In addition, this study was supported by the Medical Research Council (MRC 548211) (Dr Jabbari); the Association of British Neurologists Clinical Research Training Fellowships (Dr Holland, Dr Goh and Dr Chelban); the MSA Trust (Dr Chelban, Dr Goh); Guarantors of Brain (Dr Chelban); CBD Solutions (Dr Revesz, and Dr Morris); the NIHR Oxford Health Clinical Research Facility (Dr Klein); the NIHR Queen Square Biomedical Research Centre based at UCLH (Dr Revesz and Dr Jaunmuktane) a Wallenberg Academy fellowship (Dr Zetterberg); the Monument Trust Discovery Award from Parkinson’s UK (Dr Hu). Dr Bocchetta is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). Dr Bocchetta’s work was also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. Professor Rohrer is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Professor Zetterberg is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), European Union Joint Program for Neurodegenerative Disorders (JPND2021-00694), and the UK Dementia Research Institute at UCL. Professor Roncaroli’s work is supported by The Manchester Brain Bank, which is part of BDR, jointly funded by Alzheimer’s Society and Alzheimer’s Research UK. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission, under a Creative Commons Attribution 4.0 International License.

Peripheral administration (oral, intranasal, intraperitoneal, intravenous) of assembled A53T ��-synuclein induced synucleinopathy in heterozygous mice transgenic for human mutant A53T ��-synuclein (line M83). The same was the case when cerebellar extracts from a case of multiple system atrophy with type II ��-synuclein filaments were administered intraperitoneally, intravenously or intramuscularly. We observed abundant immunoreactivity for pS129 ��-synuclein in nerve cells and severe motor impairment, resulting in hindlimb paralysis and shortened lifespan. Filaments immunoreactive for pS129 ��-synuclein were in evidence. A 70% loss of motor neurons was present five months after an intraperitoneal injection of assembled A53T ��-synuclein or cerebellar extract with type II ��-synuclein filaments from an individual with a neuropathologically confirmed diagnosis of multiple system atrophy. Microglial cells changed from a predominantly ramified to a dystrophic appearance. Taken together, these findings establish a close relationship between the formation of ��-synuclein inclusions in nerve cells and neurodegeneration, accompanied by a shift in microglial cell morphology. Propagation of ��-synuclein inclusions depended on the characteristics of both seeds and transgenically expressed protein.

Objective To describe the histopathologic features of a case of facial-onset sensory and motor neuronopathy (FOSMN). Methods We describe a postmortem examination performed on a 54-year-old man with FOSMN associated with personality change. Results Postmortem examination revealed TAR DNA-binding protein (TDP) 43 proteinopathy with widespread distribution. TDP43 pathology was seen in the neurons and glial cells and was most pronounced in the subthalamic nucleus followed by the spinal cord, including dorsal root ganglia, brainstem, and other deep cerebral nuclei. In the medial temporal lobe, neocortex and subcortical hemispheric white matter TDP43 pathologic inclusions were very rare. In contrast to TDP43 pathologies associated with typical amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD)–TDP, in this case, there were more frequent TDP43-positive oligodendroglial, coiled body–like cytoplasmic inclusions than neuronal inclusions. Neuronal cytoplasmic TDP43 inclusions with globular and skein-like morphology were seen in both anterior horn cells and dorsal root ganglia. No β-amyloid, α-synuclein, or significant hyperphosphorylated tau pathology was seen. Conclusion This case provides further evidence that FOSMN is a neurodegenerative disease characterized by TDP43 pathology. Despite minimal cortical TDP43 pathology, the clinical features of the behavioral variant of FTD in this patient suggest that FOSMN may fall within or overlap with the FTD-ALS spectrum.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.

Additional file 4. Supplementary Table 1 Motor neuron numbers in lumbar spinal cord of M83+/- mice following intraperitoneal injection of PBS, assembled ��71-82 A53T ��-synuclein and assembled A53T ��-synuclein.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Additional file 5. Supplementary Table 2 Motor neuron numbers in lumbar spinal cord of M83+/- mice following intraperitoneal injection of extracts from control and MSA cerebellum. Comparison with uninjected M83+/- mice.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.Competing Interest StatementThomas G. Beach is a consultant for Prothena, Vivid Genomics and Avid Radiopharmaceuticals. He is a scientific advisory board member for Vivid Genomics. John A. Hardy, Huw R. Morris, Stuart Pickering-Brown, Andrew B. Singleton, and Bryan J. Traynor hold US, EU and Canadian patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Michael A. Nalls is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA; as a possible conflict of interest Dr. Nalls also consults for Neuron23 Inc., Lysosomal Therapeutics Inc., Illumina Inc., the Michael J. Fox Foundation and Vivid Genomics among others. Jose A. Palma is an editorial board member of Movement Disorders, Parkinsonism & Related Disorders, BMC Neurology, and Clinical Autonomic Research. Bradley F. Boeve, James Leverenz, and Sonja W. Scholz serve on the Scientific Advisory Council of the Lewy Body Dementia Association. Sonja W. Scholz is an editorial board member for the Journal of Parkinson's Disease. Bryan J. Traynor is an editorial board member for JAMA Neurology; Journal of Neurology, Neurosurgery, and Psychiatry; Brain; and Neurobiology of Aging. Zbigniew K. Wszolek serves as a principal investigator or co-principal investigator on Abbvie, Inc. (M15-562 and M15-563), Biogen, Inc. (228PD201) grant, and Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301). Zbigniew K. Wszolek serves as the principal investigator of the Mayo Clinic American Parkinson Disease Association (APDA) Information and Referral Center, and as co-principal investigator of the Mayo Clinic APDA Center for Advanced Research. All other authors report no competing interests.

Highlights • Novel IGHMBP2 variant found in a patient with early onset severe peripheral neuropathy. • IGHMBP2 mutations may cause enteral autonomic dysfunction. • Autonomic dysfunction in IGHMBP2-related disorders may be severe requiring parenteral nutrition., Biallelic mutations in the IGHMBP2 have been associated with two distinct phenotypes: spinal muscular atrophy with respiratory distress type 1 (SMARD1) and CMT2S. We describe a patient who developed progressive muscle weakness and wasting in her upper and lower limbs from infancy. She developed respiratory involvement at age 9, eventually requiring 24-h non-invasive ventilation, and severe autonomic dysfunction restricted to the gastrointestinal tract. Neurophysiological studies at age 27 years revealed absent sensory and motor responses and severe chronic denervation changes in proximal muscles of the upper limbs. Targeted multigene panel sequencing detected a novel homozygous missense variant in the IGHMBP2 gene (c.1325A > G; p.Tyr442Cys). This variant was validated by Sanger sequencing and co-segregation analysis confirmed that both parents were asymptomatic heterozygous carriers. This case report confirms that IGHMBP2 related disorders can result in a severe peripheral neuropathy with gastrointestinal autonomic dysfunction requiring parenteral nutrition.

Objective: To determine the prevalence and clinical and genetic characteristics of patients with X-linked Charcot-Marie-Tooth disease (CMT) due to mutations in noncoding regions of the gap junction β-1 gene (GJB1). Methods: Mutations were identified by bidirectional Sanger sequence analysis of the 595 bases of the upstream promoter region, and 25 bases of the 3′ untranslated region (UTR) sequence in patients in whom mutations in the coding region had been excluded. Clinical and neurophysiologic data were retrospectively collected. Results: Five mutations were detected in 25 individuals from 10 kindreds representing 11.4% of all cases of CMTX1 diagnosed in our neurogenetics laboratory between 1996 and 2016. Four pathogenic mutations, c.-17G>A, c.-17+1G>T, c.-103C>T, and c.-146-90_146-89insT were detected in the 5′UTR. A novel mutation, c.*15C>T, was detected in the 3′ UTR of GJB1 in 2 unrelated families with CMTX1 and is the first pathogenic mutation in the 3′UTR of any myelin-associated CMT gene. Mutations segregated with the phenotype, were at sites predicted to be pathogenic, and were not present in the normal population. Conclusions: Mutations in noncoding DNA are a major cause of CMTX1 and highlight the importance of mutations in noncoding DNA in human disease. Next-generation sequencing platforms for use in inherited neuropathy should therefore include coverage of these regions.

Average CNV loads of cerebellar and reference glioma methylation classes. (PDF 135 kb)

Additional file 2: Figure S1. Summary of bioinformatic pipeline for single cell WGS. Figure S2. Number of cells counted and analysed in each case / category in the cingulate cortex (a,b) and SN (c,d). Figure S3. SNCA CNVs and α-synuclein nuclear inclusions in MSA pontine neurons. Figure S4. Mate-pair sequencing results of MSA SNand cerebellum. Figure S5. Visual isolation of nuclei on an inverted microscope. Figure S6. Profiles of cells with CNVs. Figure S7. Detailed visualisation of boundaries of gains with evidence of shared breakpoints suggesting clonality, and gains possibly arising at segmental duplications (SDs). Figure S8. Pathway analysis of neuronal CNVs in each SN separately.

Methylation-based clustering analysis of 86 cerebellar glioblastomas (cGBMs) with 707 reference cases. (PDF 16356 kb)

Additional file 3: Table S2. Mosaicism % in MSA-SND and mixed MSA in the cingulate cortex and substantia nigra. Table S3. Detailedcorrelation analyses of cingulate cortex and substantia nigra mosaicism. Table S4. Correlation of GCI in the cingulate cortex and sub-cortical region with mosaicism in MSA. Table S5. SNCA mosaicism in occipital cortex, putamen and pons. Table S6 All CNVs which passed filtering. Table S7. Relative over-representation of gene categories in CNVs. Table S8. Enrichment factor in neuronal CNVs in SN.

Summary copy number variation (CNV) profiles. (PDF 1900 kb)

Primary antibodies used for immunohistochemistry. (PDF 52 kb)

BACKGROUND Mitochondrial disease can present as a movement disorder. Data on this entity's epidemiology, genetics, and underlying pathophysiology, however, is scarce. OBJECTIVE The objective of this study was to describe the clinical, genetic, and volumetric imaging data from patients with mitochondrial disease who presented with movement disorders. METHODS In this retrospective analysis of all genetically confirmed mitochondrial disease cases from three centers (n = 50), the prevalence and clinical presentation of video-documented movement disorders was assessed. Voxel-based morphometry from high-resolution MRI was employed to compare cerebral and cerebellar gray matter volume between mitochondrial disease patients with and without movement disorders and healthy controls. RESULTS Of the 50 (30%) patients with genetically confirmed mitochondrial disease, 15 presented with hypokinesia (parkinsonism 3/15), hyperkinesia (dystonia 5/15, myoclonus 3/15, chorea 2/15), and ataxia (3/15). In 3 patients, mitochondrial disease presented as adult-onset isolated dystonia. In comparison to healthy controls and mitochondrial disease patients without movement disorders, patients with hypo- and hyperkinetic movement disorders had significantly more cerebellar atrophy and an atrophy pattern predominantly involving cerebellar lobules VI and VII. CONCLUSION This series provides clinical, genetic, volumetric imaging, and histologic data that indicate major involvement of the cerebellum in mitochondrial disease when it presents with hyper- and hypokinetic movement disorders. As a working hypothesis addressing the particular vulnerability of the cerebellum to energy deficiency, this adds substantially to the pathophysiological understanding of movement disorders in mitochondrial disease. Furthermore, it provides evidence that mitochondrial disease can present as adult-onset isolated dystonia. © 2017 International Parkinson and Movement Disorder Society.

Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5′ region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.

Riboflavin metabolites are critical components of the mitochondrial electron transport chain. Manole et al. describe the genetics, phenotypes and neuropathology of a large patient series with riboflavin-responsive neuropathy. Using in-vitro and in-vivo models, they reveal mitochondrial dysfunction in the disorder, and validate riboflavin esters as a potential therapeutic strategy., Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column–medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.

To analyse and describe the clinical and genetic spectrum of Charcot-Marie-Tooth disease (CMT) caused by mutations in the neurofilament light polypeptide gene (NEFL).

Background: Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a hereditary, adult onset leukodystrophy which is characterised by the presence of axonal loss, axonal spheroids and variably present pigmented macrophages on pathological examination. It most frequently presents in adulthood with dementia and personality change. HDLS has recently been found to be caused by mutations in the colony stimulating factor-1 receptor (CSF1R) gene. Methods: In this study, we sequenced the CSF1R gene in a cohort of 48 patients from the UK, Greece and Ireland with adult onset leukodystrophy of unknown cause. Results: Five pathogenic mutations were found, including three novel mutations. The presentations ranged from suspected central nervous system (CNS) vasculitis to extrapyramidal to cognitive phenotypes. The case histories and imaging are presented here, in addition to neuropathological findings from two cases with novel mutations. Conclusion: We estimate that CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies and that genetic testing for CSF1R mutations is essential in adult patients presenting with undefined CNS vasculitis or a leukodystrophy with prominent neuropsychiatric signs or dementia.

The estimation of pathogenicity and penetrance of novel prion protein gene (PRNP) variants presents significant challenges, particularly in the absence of family history, which precludes the application of Mendelian segregation. Moreover, the ambiguities of prion disease pathophysiology renders conventional in silico predictions inconclusive. Here, we describe 2 patients with rapid cognitive decline progressing to akinetic mutism and death within 10 weeks of symptom onset, both of whom possessed the novel T201S variant in PRNP. Clinically, both satisfied diagnostic criteria for probable sporadic Creutzfeldt-Jakob disease and in one, the diagnosis was confirmed by neuropathology. While computational analyses predicted that T201S was possibly deleterious, molecular strain typing, prion protein structural considerations, and calculations leveraging large-scale population data (gnomAD) indicate that T201S is at best either of low penetrance or nonpathogenic. Thus, we illustrate the utility of harnessing multiple lines of prion disease-specific evidence in the evaluation of the T201S variant, which may be similarly applied to assess other novel variants in PRNP.

Gerstmann9s syndrome is a rare disorder resulting from damage to the angular gyrus of the dominant parietal lobe leading to agraphia, acalculia, finger agnosia and left-right disorientation. In adults the syndrome is usually seen after stroke. Particularly in young patients other causes need to be considered. We present video, MRI and pathological evidence of the case of a 30 year old woman who developed Gerstmann9s syndrome as a result of a tumefactive multiple sclerosis (MS) lesion affecting the left cerebral hemisphere. Intravenous corticosteroids failed to stop rapid enlargement of the index lesion and occurrence of additional hemispheric lesions leading to clinical deterioration. Brain biopsy confirmed the diagnosis of MS. Strong contrast enhancement of the lesions prompted us to start treatment with natalizumab 300 mg i.v. every four weeks leading to sustained disease remission over a 14 month follow-up period though complex-focal epileptic seizures require ongoing anti-epileptic treatment. This case highlights the heterogeneous presentation of tumefactive MS, the need in some cases of an early brain biopsy, and the worthwhile consideration of natalizumab treatment where additional evidence supports a diagnosis of relapsing MS.

Ataxia, causing imbalance, dizziness and falls, is a leading cause of neurological disability. We have recently identified a biallelic intronic AAGGG repeat expansion in replication factor complex subunit 1 (RFC1) as the cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and a major cause of late onset ataxia. Here we describe the full spectrum of the disease phenotype in our first 100 genetically confirmed carriers of biallelic repeat expansions in RFC1 and identify the sensory neuropathy as a common feature in all cases to date. All patients were Caucasian and half were sporadic. Patients typically reported progressive unsteadiness starting in the sixth decade. A dry spasmodic cough was also frequently associated and often preceded by decades the onset of walking difficulty. Sensory symptoms, oscillopsia, dysautonomia and dysarthria were also variably associated. The disease seems to follow a pattern of spatial progression from the early involvement of sensory neurons, to the later appearance of vestibular and cerebellar dysfunction. Half of the patients needed walking aids after 10 years of disease duration and a quarter were wheelchair dependent after 15 years. Overall, two-thirds of cases had full CANVAS. Sensory neuropathy was the only manifestation in 15 patients. Sixteen patients additionally showed cerebellar involvement, and six showed vestibular involvement. The disease is very likely to be underdiagnosed. Repeat expansion in RFC1 should be considered in all cases of sensory ataxic neuropathy, particularly, but not only, if cerebellar dysfunction, vestibular involvement and cough coexist.