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Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune neuroinflammatory disorder of the central nervous system that very rarely may be a paraneoplastic phenomenon. We describe the case of a woman with a longitudinally extensive transverse myelitis (LETM). We identified a previously undiagnosed, follicular lymphoma and she was treated with the immunochemotherapy regime (obinutuzumab, cyclophosphamide, vincristine and prednisolone; O-CVP) for paraneoplastic NMOSD. Following two cycles, there was almost complete radiological remission of the myelitis and the patient showed some improvement in her neurological function. This case illustrates the heterogeneous aetiology that LETM may have and that O-CVP may be used as therapeutic option in patients with NMOSD driven by follicular lymphoma.

Whole genome sequencing (WGS) is regarded by many as the pinnacle of contemporary molecular genetic testing, and has only been possible because of the rapid development and roll-out of next-generation sequencing technologies. It provides a phenotype-agnostic analysis of the genome and has important advantages compared to other techniques including a consistent coverage across the coding and non-coding genome, the application of high resolution homozygosity mapping and the ability to detect and highlight structural variation. Realising this potential and with a bid to sequence 100,000 genomes, the UK rolled out the 100,000 Genomes Project as a proof of concept of integrating genomics in the national health service. Participants with cancer and rare diseases enrolled in the project whose infrastructure comprises of a central national biorepository and 13 regional genomic medicine centres where clinicians, geneticists and other scientists work as part of a multidisciplinary team. Amongst participants are also patients with genetically unclassified Charcot-Marie-Tooth disease who have benefited substantially from improved diagnostic rates and many more stand to benefit as the analysis of genomic data is ongoing. WGS is an important tool as we head towards more personalised medicine and in our quest to improve public health and treat and where possible prevent disease.

SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common SARM1 intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.

ObjectiveNeurofilaments are the major scaffolding proteins for the neuronal cytoskeleton, and variants in NEFH have recently been described to cause axonal Charcot-Marie-Tooth disease type 2CC (CMT2CC).MethodsIn this large observational study, we present phenotype–genotype correlations on 30 affected and 3 asymptomatic mutation carriers from eight families.ResultsThe majority of patients presented in adulthood with motor-predominant and lower limb-predominant symptoms and the average age of onset was 31.0±15.1 years. A prominent feature was the development of proximal weakness early in the course of the disease. The disease progressed rapidly, unlike other Charcot-Marie-Tooth disease (CMT) subtypes, and half of the patients (53%) needed to use a wheelchair on average 24.1 years after symptom onset. Furthermore, 40% of patients had evidence of early ankle plantarflexion weakness, a feature which is observed in only a handful of CMT subtypes. Neurophysiological studies and MRI of the lower limbs confirmed the presence of a non-length-dependent neuropathy in the majority of patients.All families harboured heterozygous frameshift variants in the last exon of NEFH, resulting in a reading frameshift to an alternate open reading frame and the translation of approximately 42 additional amino acids from the 3' untranslated region (3′-UTR).ConclusionsThis phenotype–genotype study highlights the unusual phenotype of CMT2CC, which is more akin to spinal muscular atrophy rather than classic CMT. Furthermore, the study will enable more informative discussions on the natural history of the disease and will aid in NEFH variant interpretation in the context of the disease’s unique molecular genetics.

SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common SARM1 intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.

Charcot-Marie-Tooth disease and the related disorders hereditary motor neuropathy and hereditary sensory neuropathy, collectively termed CMT, are the commonest group of inherited neuromuscular diseases, and they exhibit wide phenotypic and genetic heterogeneity. CMT is usually characterized by distal muscle atrophy, often with foot deformity, weakness and sensory loss. In the past decade, next-generation sequencing (NGS) technologies have revolutionized genomic medicine and, as these technologies are being applied to clinical practice, they are changing our diagnostic approach to CMT. In this Review, we discuss the application of NGS technologies, including disease-specific gene panels, whole-exome sequencing, whole-genome sequencing (WGS), mitochondrial sequencing and high-throughput transcriptome sequencing, to the diagnosis of CMT. We discuss the growing challenge of variant interpretation and consider how the clinical phenotype can be combined with genetic, bioinformatic and functional evidence to assess the pathogenicity of genetic variants in patients with CMT. WGS has several advantages over the other techniques that we discuss, which include unparalleled coverage of coding, non-coding and intergenic areas of both nuclear and mitochondrial genomes, the ability to identify structural variants and the opportunity to perform genome-wide dense homozygosity mapping. We propose an algorithm for incorporating WGS into the CMT diagnostic pathway.

Charcot-Marie-Tooth (CMT) disease and related disorders are the commonest group of inherited neuromuscular diseases and represent a heterogeneous group of disorders. This review will cover recent advances in genetic diagnosis and the evolving genetic and phenotype landscape of this disease group. We will review recent evidence of the increasingly recognized phenotypic overlap with other neurodegenerative conditions including hereditary spastic paraplegia, hereditary ataxias and mitochondrial diseases and highlight the importance of deep phenotyping to inform genetic diagnosis and prognosis.Through whole exome sequencing and multicentre collaboration new genes are being identified as causal for CMT expanding the genetic heterogeneity of this condition. In addition, an increasing number of variants have been identified in genes known to cause complex inherited diseases in which the peripheral neuropathy is part of the disorder and may be the presenting feature. The recent discovery of a repeat expansion in the RFC1 gene in cerebellar ataxia, neuropathy, vestibular areflexia syndrome highlights the prevalence of late-onset recessive conditions which have historically been considered to cause early-onset disease.CMT is an evolving field with considerable phenotypic and genetic heterogeneity and deep phenotyping remains a cornerstone in contemporary CMT diagnostics.

Neurofilaments are the major scaffolding proteins for the neuronal cytoskeleton, and variants inIn this large observational study, we present phenotype-genotype correlations on 30 affected and 3 asymptomatic mutation carriers from eight families.The majority of patients presented in adulthood with motor-predominant and lower limb-predominant symptoms and the average age of onset was 31.0±15.1 years. A prominent feature was the development of proximal weakness early in the course of the disease. The disease progressed rapidly, unlike other Charcot-Marie-Tooth disease (CMT) subtypes, and half of the patients (53%) needed to use a wheelchair on average 24.1 years after symptom onset. Furthermore, 40% of patients had evidence of early ankle plantarflexion weakness, a feature which is observed in only a handful of CMT subtypes. Neurophysiological studies and MRI of the lower limbs confirmed the presence of a non-length-dependent neuropathy in the majority of patients.All families harboured heterozygous frameshift variants in the last exon ofThis phenotype-genotype study highlights the unusual phenotype of CMT2CC, which is more akin to spinal muscular atrophy rather than classic CMT. Furthermore, the study will enable more informative discussions on the natural history of the disease and will aid in

Reports of Guillain-Barré syndrome (GBS) have emerged during the Coronavirus disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS. The epidemiology of GBS cases reported to the UK National Immunoglobulin Database was studied from 2016 to 2019 and compared to cases reported during the COVID-19 pandemic. Data were stratified by hospital trust and region, with numbers of reported cases per month. UK population data for COVID-19 infection were collated from UK public health bodies. In parallel, but separately, members of the British Peripheral Nerve Society prospectively reported incident cases of GBS during the pandemic at their hospitals to a central register. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases in this cohort were compared. The incidence of GBS treated in UK hospitals from 2016 to 2019 was 1.65–1.88 per 100 000 individuals per year. GBS incidence fell between March and May 2020 compared to the same months of 2016–19. GBS and COVID-19 incidences during the pandemic also varied between regions and did not correlate with one another (r = 0.06, 95% confidence interval: −0.56 to 0.63, P = 0.86). In the independent cohort study, 47 GBS cases were reported (COVID-19 status: 13 definite, 12 probable, 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome between these groups. Intubation was more frequent in the COVID-19 affected cohort (7/13, 54% versus 5/22, 23% in COVID-19-negative) attributed to COVID-19 pulmonary involvement. Although it is not possible to entirely rule out the possibility of a link, this study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic, which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.

Differentiating between an acquired and genetic aetiology of peripheral neuropathy poses a challenge to the neurologist. Contributing factors to this include a lack of family history of neuropathy, a rapid progres- sion of the clinical syndrome and/or the presence of features that are considered atypical for inherited neuropathies such as non-length dependent weakness and denervation.We present 6 patients with genetically confirmed CMT (2 NEFH, 3 MME and 1 TFG), who presented in adulthood with a rapid course of disease progression. The mean age of symptom onset was 37.8yrs (range 33–49) and despite an average disease duration of only 12.8yrs (range 7–16), 50% of patients (3/6) required a wheelchair or stick for mobility. All patients developed significant proximal involvement early on in the course of their disease with half of them having persistent evidence of non-length dependent weakness and denervation. All sporadic cases had CSF examinations and investigations for inflammatory causes of neuropathy, 1 patient had 2 courses of IVIG and another was considered for a nerve biopsy prior to achieving a genetic diagnosis.Certain adult onset CMT subtypes may mimic acquired neuropathies and in order to avoid missing treatable causes, the pursuit of both diagnostic avenues is often necessary.m.pipis@ucl.ac.uk

BackgroundThe association of CMT1X with white matter abnormalities and “stroke like episodes” has long been recognised, and a recent review of the 133 patients with CMT1X in our cohort found that 10/26 MRI brain scans showed white matter abnormalities.(1) The literature describes very occasional patients who have any type of CMT and hydrocephalus.CasesA pair of monozygotic twins have the p.Trp24Cys GJB1 mutation which segregates with CMT in their family, with recognised phenotypic variability in the women, attributable to X-inactivation. One of the twins presented in their 20’s with headache and visual obscurations due to hydrocephalus resulting from decompensation of a previously diagnosed aqueductal stenosis. The second twin had migraine at age 27, an MRI identified lateral and third ventricular dilatation due to focal narrowing with an aqueductal web. An endoscopic third ventriculocysternostomy was performed. An affected cousin with the family GJB1 mutation has normal brain imaging.DiscussionDespite the finding of hydrocephalus in both affected twins, further family evaluation confirmed the hydrocephalous not to segregate with the GJB1 mutation. This highlights the importance of detailed phenotype segregation studies before diagnosing an atypical phenotype with genetic diseases. Alterna- tive genetic causes for the hydrocephalus are being sought.1) Vivekanandam V, Hoskote C, Rossor AM, Reilly MM. CNS phenotype in X linked Charcot- Marie-Tooth disease. J Neurol Neurosurg Psychiatry 2018 Dec 5;90(9).carolynnedoherty@doctors.org.uk|NIHR Bursary93

BackgroundA problem frequently faced by neurologists is the interpretation of genetic variants of unknown significance(VUS). Unlike in many muscle diseases, specific patterns of muscle involvement are not typically demonstrated on muscle MRI of inherited neuropathy patients. Imaging muscle involvement can be of assistance when assessing VUS.Case ExamplesTwo unrelated individuals with axonal CMT were identified to have a novel p.Lys554Glu DNM2 mutation. Neuromuscular MRI was consistent with the clinical findings and similar to literature descriptions, supporting the pathogenicity of this variant.Spinal Muscular Atrophy Lower Extremity Dominant (SMA-LED) due to DYNC1H1 mutations can be associ- ated with sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, with diffuse involvement at the calf level, sparing the anterior-medial muscles1 on MRI. These features were demonstrated in the imaging of a proband with SMA-LED has two mutations in DYNC1H1, one of which is novel. The novel p.His75Pro mutation was also found in his mother who has normal clinical examination and neuromuscular MRI, suggesting that the previously described p.Arg251His mutation2 was the cause of the neuromuscular phenotype in the proband.DiscussionMRI has a role supporting the diagnosis of inherited neuropathies, and in evaluating VUS.Scoto et al. Novel mutations expand the clinical spectrum of DYNC1H1-associated SMA. Neurology.2015Feb17;84:668–679Antoniadi et al. Application of targeted multi-gene panel testing for the diagnosis of inherited peripheral neuropathy provides high diagnostic yield.BMCMedGenet.2015Sep21;16:84.c.doherty@ucl.ac.uk

BackgroundA 22-year-old woman was initially assessed in the context of a family history of distal wasting and weakness, typically with upper limb onset, then lower limb involvement. When assessed as a child her phenotype was recognised to be atypical compared to her sister, but she was thought to be affected. Ultimately the family was diagnosed with distal hereditary motor neuropathy due to a GARS mutation. However, this patient did not carry the mutation, prompting further evaluation.CaseAt age 11 the left foot was smaller with some toe clawing and cavus deformity. Left sided wasting of tibialis anterior and the posterior compartment was seen, ankle dorsiflexors were grade 3.ResultsNerve conduction studies and EMG were normal in the right leg and arms. Chronic denervation was identified in L4, L5 and S1. MRI of lumbar spine was normal. However, 2 areas of marked thickening and enhancement were seen in the left sciatic nerve in the upper thigh and a further lesion in the mid- thigh. Fascicular preservation of the nerve was felt to be strongly suggestive of a perineurioma.DiscussionThis case highlights the importance of careful phenotyping when validating novel variants in potentially causative genes.c.doherty@ucl.ac.uk

IntroductionSORD is a newly described autosomal recessive gene that is emerging as the commonest cause of autosomal recessive CMT (Charcot-Marie-Tooth disease) and hereditary motor neuropathy (HMN).MethodsWe present nine cases of SORD-related neuropathy.ResultsNine unrelated patients were found to have biallelic mutations in SORD. Eight were male (89%) and median age of assessment was 34 years (range 18–55 years). Median age of symptom onset was 15 years (range 12–18 years) and all patients initially presented with difficulty walking and/or problems involving distal lower limbs. Only one patient (11%) had sensory symptoms. 5/9 (56%) had distal upper limb weakness and all had distal lower limb weakness. Sensory examination was abnormal to at least one modality in 7/9 cases (78%). The median CMT Examination and CMT Neuropathy Scores were 6 (range 2–12) and 7.5 (range 3–14) respectively. Neurophysiology showed conduction velocities in the axonal or intermediate ranges in all cases. Clinical diagnosis was distal HMN in 5/9 (56%), CMT2 in 2/9 (22%) and CMT intermediate in 2/9 (22%).ConclusionsThe SORD phenotype is typically a slowly progressive, length-dependent motor neuropathy of onset during the second decade. Sensory symptoms are rare and sensory signs minimal.chris.record@ucl.ac.uk

BackgroundReports of Guillain-Barré Syndrome (GBS) have emerged during the Coronavirus Disease 2019 (COVID-19) pandemic. This epidemiological and cohort study sought to investigate any causative association between COVID-19 infection and GBS.MethodsThe epidemiology of GBS cases reported via the UK National Immunoglobulin Database were studied from 2016-2019 and compared to cases reported during the COVID-19 pandemic. For the cohort study, members of the British Peripheral Nerve Society reported all cases of GBS during the pandemic. The clinical features, investigation findings and outcomes of COVID-19 (definite or probable) and non-COVID-19 associated GBS cases were compared.ResultsThe UK GBS incidence from 2016-2019 was 1.65-1.88 per 100,000 people per year. GBS and COVID-19 incidence varied between regions and did not correlate (r = 0.06, 95% CI −0.56 to 0.63, p=0.86). GBS incidence fell between March and May 2020 compared to the same months of 2016-2019. Forty-seven GBS cases were included in the cohort study (13 definite, 12 probable COVID-19 and 22 non-COVID-19). There were no significant differences in the pattern of weakness, time to nadir, neurophysiology, CSF findings or outcome. Intubation was more frequent in the COVID-19+ve cohort (7/13, 54% vs 5/22, 23% in COVID negative) thought to be related directly to COVID-19 pulmonary involvement.ConclusionsThis study finds no epidemiological or phenotypic clues of SARS-CoV-2 being causative of GBS. GBS incidence has fallen during the pandemic which may be the influence of lockdown measures reducing transmission of GBS inducing pathogens such as Campylobacter jejuni and respiratory viruses.

BACKGROUND AND AIMS: The CMT-FOM is a 13-item clinical outcome assessment (COA) that measures physical ability in adults with Charcot-Marie-Tooth disease (CMT). Test-retest reliability, internal consistency and convergent validity have been established for the CMT-FOM. This current study sought to establish inter-rater reliability. METHODS: Following an in-person training of six international clinical evaluators we recruited 10 participants with genetically diagnosed CMT1A, (aged 18-74 years, 6 female). Participants were evaluated using the CMT-FOM over 2 days. Participants were given at least a 3 hour rest between evaluations, and were assessed twice each day. RESULTS: Following the provision of training by master trainers, all 13 items of the CMT-FOM exhibited excellent inter-rater reliability for raw scores (ICC(1,1) 0.825 to 0.989) and z-scores (ICC(1,1) 0.762 to 0.969). Reliability of the CMT-FOM total score was excellent (ICC(1,1) 0.983, 95% CI 0.958-0.995). INTERPRETATION: The CMT-FOM is a reliable COA used by clinical evaluators internationally. The next steps are to establish further validation through psychometric evaluation of the CMT-FOM in the Accelerate Clinical Trials in CMT (ACT-CMT) study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Here we demonstrate biallelic mutations in sorbitol dehydrogenase (SORD) as the most frequent recessive form of hereditary neuropathies. We identified 45 cases from 38 families across multiple ethnicities, carrying a particular nonsense mutation in SORD, c.753delG; p.Ala253GlnfsTer27, either in homozygous or compound heterozygous state with a second variant. With an allele frequency of 0.004 in healthy controls, the p.Ala253GlnfsTer27 variant represents one of the most common pathogenic alleles in humans. SORD is an enzyme that converts sorbitol into fructose, in the two-step polyol pathway that has been implicated in diabetic neuropathy. In patient-derived fibroblasts, we find a complete loss of SORD protein as well as increased intracellular sorbitol. Also, serum fasting sorbitol level was over 100 times higher in patients homozygous for the p.Ala253GlnfsTer27 mutation compared to healthy individuals. In Drosophila, we show that loss of SORD orthologues causes synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a potentially treatable cause in a significant fraction of patients with inherited neuropathies and may contribute to a better understanding of the pathophysiology of diabetic neuropathy.

Charcot-Marie-Tooth disease and the related disorders hereditary motor neuropathy and hereditary sensory neuropathy, collectively termed CMT, are the commonest group of inherited neuromuscular diseases, and they exhibit wide phenotypic and genetic heterogeneity. CMT is usually characterized by distal muscle atrophy, often with foot deformity, weakness and sensory loss. In the past decade, next-generation sequencing (NGS) technologies have revolutionized genomic medicine and, as these technologies are being applied to clinical practice, they are changing our diagnostic approach to CMT. In this Review, we discuss the application of NGS technologies, including disease-specific gene panels, whole-exome sequencing, whole-genome sequencing (WGS), mitochondrial sequencing and high-throughput transcriptome sequencing, to the diagnosis of CMT. We discuss the growing challenge of variant interpretation and consider how the clinical phenotype can be combined with genetic, bioinformatic and functional evidence to assess the pathogenicity of genetic variants in patients with CMT. WGS has several advantages over the other techniques that we discuss, which include unparalleled coverage of coding, non-coding and intergenic areas of both nuclear and mitochondrial genomes, the ability to identify structural variants and the opportunity to perform genome-wide dense homozygosity mapping. We propose an algorithm for incorporating WGS into the CMT diagnostic pathway.

See Paisán-Ruiz and Jen (doi:10.1093/brain/awaa015) for a scientific commentary on this article. Cortese et al. describe the full disease phenotype, including progression of ataxia, in 100 confirmed carriers of RFC1 repeat expansions. RFC1 repeat expansion should be considered in all cases of sensory ataxic neuropathy, particularly if cerebellar dysfunction, vestibular involvement and cough coexist., 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.

CaseA 20-year-old female had symptom onset age 7 of bilateral foot drop and distal lower limb atrophy. Nerve conduction studies demonstrated a length dependent axonal motor and sensory neuropathy. At 16 her vision deteriorated to 3/36 right, 6/60 left. Visual evoked potentials were borderline compatible with bilateral optic atrophy. Metabolic and structural causes were excluded.ExaminationAt age 18 examination demonstrated bilateral foot drop and a positive knee bob sign. There was asymmetrical distal limb atrophy. Fundi were pale. Reflexes were brisk in upper limbs and knees with absent ankles and mute plantars.ResultsThe 56-gene Bristol axonal neuropathy panel revealed a non-pathogenic TRPV4 mutation. Mutations in OPA1, OPA3, POLG, ATPase 6 and 8 were not identified. Exome sequencing in the research setting demonstrated compound heterozygous SLC25A46 mutations. One mutation was confirmed in each of her parents.DiscussionMutations in SLC25A46 are associated with spectrum of disorders encompassing pontocerebellar hypoplasia (including lethal congenital cases), Leigh Syndrome, Progressive myoclonic ataxia with optic atrophy and neuropathy, and hereditary motor and sensory neuropathy type 6B, sometimes with associated features such as cerebellar ataxia and spasticity. We present a case of CMT2 with optic atrophy due to heterozygous mutations and discuss the literature.

Charcot-Marie-Tooth (CMT) disease and related disorders encompass a phenotypically and genetically heterogeneous group of disorders. Our diagnostic approach to CMT has been revolutionised by the advent and use of next-generation sequencing (NGS) technologies with applications in CMT gene panels, whole exome and whole genome sequencing, mitochondrial sequencing and high-throughput transcriptome sequencing.We present the up to date evidence pertaining to the application of these technologies in CMT diagnostics and also discuss what challenges they bring in relation to variant interpretation. Phenotypic, genetic and bioinformatic evidence should be used to overcome these challenges, and we discuss how setting a maximum credible population allele frequency for pathogenic variants in dominant and recessive CMT genes is crucial in filtering efficiently NGS-derived variants.Whole genome sequencing as a single molecular genetic test is very appealing and, in the context of the 100,000 Genome Project, we suggest how its application into CMT clinical practice can happen with a balance between improved diagnostic yield and burden of variant analysis.

Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous haematological malignancies that can rarely develop first in the peripheral nervous system, or more commonly, invade nerves from more usual primary locations. Patients with PTCLs usually respond poorly to treatment and have a poor clinical outcome.We report a patient with multiple skin lesions, multifocal mononeuropathies and constitutional symptoms all suggestive of a lymphoproliferative disorder, in whom repeat skin biopsies and clonality studies failed to achieve a diagnosis. Neurophysiological studies confirmed severe post-ganglionic lesions in the lower limbs including the sciatic, femoral, obturator, tibial and sural territories. Based on this neurotropic presentation we undertook a sural nerve biopsy, despite the clinical and neurophysiological presence of a nerve lesion more proximal to the biopsy site, and this allowed us to establish a final diagnosis of PTCL. The patient was treated successfully with chemotherapy and an autologous stem cell transplant.In our case PET imaging and MR neurography provided radiological evidence of widespread lesions in the subcutaneous and nerve tissues, and there is emerging evidence for the importance of PET imaging in the diagnostic work-up of PTCLs. Furthermore, a post-treatment PET scan confirmed the complete metabolic remission, highlighting its usefulness as a surveillance tool.

Neurologists are often asked to review patients with presumed meningoencephalitis and depending on the clinical presentation, foreign travel and demographics of the patient a variety of infectious causes are considered in the differential diagoses. We present the case of a middle-aged woman who originates from Nigeria and who initially presented in February 2016 with malaise and generalised weakness. Over the next six months she developed worsening ataxia, a disturbed sleep cycle, upper limb myoclonic jerks with myoclonic tremor and intermittent mild pyrexia. In the later stages of her illness she became increasingly encephalopathic and drowsy. Serology for Trypanosoma brucei Gambiense was found to be positive both in the serum and cerebrospinal fluid. She was diagnosed with Human African Trypanosomiasis (second stage) and treated with Nifurtimox and Eflornithine combination therapy. She made a rapid and near-complete recovery including her myoclonus which resolved (videos pre- and post-treatment show the remarkable improvement and are available to display; appropriate consent taken).

This case provides the background for a discussion of post-stroke movement disorders. Hyperkinetic movement disorders are rare after cerebral infarction, the most common being chorea and ballismus. The role of the basal ganglia is more easily understood if one studies the clinical manifestations of neurological disorders of the basal ganglia. Strategic lesions of the basal ganglia and occasionally other brain structures, which may be vascular, structural, infective, traumatic or hypoxic in origin, can all result in secondary movement disorders. However, movement disorders of a vascular origin differ in their clinical presentation, natural history, prognosis and treatment. Haemorrhagic or ischaemic strokes may account for approximately 25 % of secondary movement disorders and can occur immediately after a stroke or have a delayed presentation.