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Objectives Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of diseases. Several recently identified genes highlight the overlap between peripheral neuropathies and congenital myasthenic syndromes (CMS). The beta-2 adrenergic receptor agonist salbutamol has been shown to provide symptomatic benefit in CMS, while improving structural defects at the NMJ. Based on these findings, we identified cases of motor neuropathy with NMJ dysfunction and assessed the effect of salbutamol on motor function. Methods Cases of motor neuropathy with significant NMJ dysfunction, were identified using repetitive nerve stimulation and single fibre electromyography. Oral salbutamol was administered for 12 months. Repeat neurophysiological and clinical assessments were undertaken at baseline, 6 months and 12 months. Results Significant defects of neuromuscular transmission were identified in 15 patients harbouring a range of genetic defects, including mutations in GARS1, DNM2, SYT2 and DYNC1H. No clear benefit on motor function was seen following the administration of 12 months of oral salbutamol; however, there was a significant improvement in patient reported fatigue. In addition, no clear effect on neurophysiological parameters was seen in patients treated with salbutamol. Side-effects due to off-target beta-adrenergic effects were significant in the patient cohort. Conclusion These results highlight the involvement of the NMJ in several subtypes of motor neuropathies, including subtypes of neuropathy due to deficits in mitochondrial fusion-fission, synaptic vesicle transport, calcium channels and tRNA synthetases. Whether the NMJ dysfunction is simply due to muscle reinnervation or a pathology unrelated to denervation is unknown. The involvement of the NMJ may represent a novel therapeutic target in these conditions. However, treatment regimens will need to be more targeted for patients with primary inherited defects of neuromuscular transmission.

To assess in-vivo cross-sectional and 3D morphology of human motor units in hand, forearm and lower leg muscles using magnetic resonance imaging (MRI).Diffusion weighted MRI was used with in-scanner electrical stimulation in healthy controls to image motor units at a single slice in lower leg, forearm and hand muscles (n = 6) and multiple slices in the lower leg for 3D assessment (n = 7).Motor unit cross-sectional area (CSA) and maximum Feret diameter (FDMotor unit MRI (MUMRI) can be applied to upper limb muscles, and can reveal the 3D structure of human motor units in-vivo.MUMRI provides the first in-vivo 2D images of upper limb motor units and 3D images of lower leg motor units. 3D imaging suggest a more complex human motor unit structure than previously thought.

In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource. The primary outcome was to interrogate the clinico-radiopathological correlates and prognostic indicators of stroke-like episode in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). The secondary objective was to develop a multivariable prediction model to forecast stroke-like episode risk. The most common genetic cause of stroke-like episodes was the m.3243A>G variant in MT-TL1 (n = 66), followed by recessive pathogenic POLG variants (n = 22), and 11 other rarer pathogenic mitochondrial DNA variants (n = 23). The age of first stroke-like episode was available for 105 patients [mean (SD) age: 31.8 (16.1)]; a total of 35 patients (32%) presented with their first stroke-like episode ≥40 years of age. The median interval (interquartile range) between first and second stroke-like episodes was 1.33 (2.86) years; 43% of patients developed recurrent stroke-like episodes within 12 months. Clinico-radiological, electrophysiological and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy. Patients with POLG-related stroke-like episodes demonstrated more fulminant disease trajectories than cases of m.3243A>G and other mitochondrial DNA pathogenic variants, in terms of the frequency of refractory status epilepticus, rapidity of progression and overall mortality. In multivariate analysis, baseline factors of body mass index, age-adjusted blood m.3243A>G heteroplasmy, sensorineural hearing loss and serum lactate were significantly associated with risk of stroke-like episodes in patients with the m.3243A>G variant. These factors informed the development of a prediction model to assess the risk of developing stroke-like episodes that demonstrated good overall discrimination (area under the curve = 0.87, 95% CI 0.82–0.93; c-statistic = 0.89). Significant radiological and pathological features of neurodegeneration were more evident in patients harbouring pathogenic mtDNA variants compared with POLG: brain atrophy on cranial MRI (90% versus 44%, P < 0.001) and reduced mean brain weight (SD) [1044 g (148) versus 1304 g (142), P = 0.005]. Our findings highlight the often idiosyncratic clinical, radiological and EEG characteristics of mitochondrial stroke-like episodes. Early recognition of seizures and aggressive instigation of treatment may help circumvent or slow neuronal loss and abate increasing disease burden. The risk-prediction model for the m.3243A>G variant can help inform more tailored genetic counselling and prognostication in routine clinical practice.

Background and purpose In a subset of patients with inherited peripheral neuropathies the first symptom is atrophy and weakness of the intrinsic muscles of the hands, without involvement of lower limbs until later in the disease course. The exact pathomechanisms of this phenotype are currently unknown. The aim of this study was to characterize the clinical, neurophysiological and genetic features of a group of patients with a clinical diagnosis of upper limb predominant Charcot-Marie-Tooth disease (CMT). Methods The clinical, electrophysiology and genetic data of 11 patients with upper limb predominant peripheral neuropathy selected from a single-centre cohort of 461 patients diagnosed with inherited neuropathy were analysed and the clinical, electrophysiological and genetic characteristics of these patients reported. Results An overlapping phenotype of neuropathy and myopathy was detected in two patients. Four patients carry autosomal dominant mutations in GARS and a single patient had a homozygous mutation in SH3TC2. However, the underlying genetic diagnosis could not be confirmed in six patients by gene panel sequencing. Conclusions Upper limb-onset inherited neuropathies are genetically heterogeneous and, in some cases, there is an overlapping myopathy. Autosomal dominant GARS mutations are the most common genetic cause; however, mutations in other CMT genes may also result in this phenotype in individual patients. The majority of these patients cannot be genetically diagnosed by gene panel testing of known CMT and myopathy genes, suggesting further genetic heterogeneity and highlighting the importance of further genetic investigations in these patients and families.

Highlights • A novel MRI technique capable of detecting the size, shape and distribution of human motor units is described. • Human motor units have a range of different outlines including elliptical, complex or split. • This technique demonstrates a heterogeneous remodelling of motor units with age., Objective To determine the size, shape and distribution of single human motor units in-vivo in healthy controls of different ages. Methods A novel diffusion-weighted magnetic resonance imaging (MRI) technique was used in combination with in-scanner electrical stimulation to quantify the shape, cross-sectional area, and dimensions of individual motor units in 10 healthy subjects. Results Thirty-one discrete motor units were studied. The majority were elliptical or crescent shaped, but occasional split motor units were observed. The mean motor unit cross sectional area was 26.7 ± 11.2 mm2, the mean maximum dimension was 10.7 ± 3.3 mm, and the mean minimum dimension was 4.5 ± 1.2 mm. Subjects aged over 40 had significantly larger maximum dimensions than those below this age (p

ObjectiveTo determine the prevalence of neuromuscular junction (NMJ) abnormalities in patients with mitochondrial disease.MethodsEighty patients with genetically proven mitochondrial disease were recruited from a national center for mitochondrial disease in the United Kingdom. Participants underwent detailed clinical and neurophysiologic testing including single-fiber electromyography.ResultsThe overall prevalence of neuromuscular transmission defects was 25.6%. The highest prevalence was in patients with pathogenic dominant RRM2B variants (50%), but abnormalities were found in a wide range of mitochondrial genotypes. The presence of NMJ abnormalities was strongly associated with coexistent myopathy, but not with neuropathy. Furthermore, 15% of patients with NMJ abnormality had no evidence of either myopathy or neuropathy.ConclusionsNMJ transmission defects are common in mitochondrial disease. In some patients, NMJ dysfunction occurs in the absence of obvious pre- or post-synaptic pathology, suggesting that the NMJ may be specifically affected.

Localised signal voids in diffusion‐weighted (DW) images of skeletal muscle have been postulated to occur as a result of muscle fibre contraction and relaxation. We investigated the contrast mechanism of these signal voids using a combination of modelling and experimental measurements by employing DW and phase contrast (PC) imaging sequences. The DW signal and PC signal were simulated for each time point of a theoretical muscle twitch. The model incorporated compaction (simulating actively contracting muscle fibres) and translation (simulating passively moving surrounding fibres). The model suggested that the DW signal depended on contraction time and compaction whereas the PC signal depended on contraction time, compaction and translation. In a retrospective study, we tested this model with subgroup analyses on 10 healthy participants. Electrical nerve stimulation was used to generate muscle twitches in lower leg muscles; the resulting force was measured using an MR‐compatible force transducer. At current levels causing a visible muscle twitch (~13 mA), the width of the first signal drop in the DW signal (mean ± SD: 103 ± 20 ms) was comparable with the force contraction time (93 ± 34 ms; intraclass correlation coefficient [ICC] = 0.717, P = .010). At current levels activating single motor units (~9 mA), the contraction time determined from the DW signal was 75 ± 13 ms and comparable with the PC contraction time (81 ± 15 ms; ICC = 0.925, P = .001). The maximum positive velocity was 0.55 ± 0.26 cm/s and the displacement was 0.20 ± 0.10 mm. Voxel‐wise analysis revealed localised DW changes occurring together with more widespread phase changes. In conclusion, local signal attenuations in DW images following muscle fibre activation are primarily caused by compaction. The PC sequence also detects translating muscle tissue being passively pulled. The magnitude of the changes in DW and PC images depends on the twitch's contractile properties and percentage contraction. DW imaging and PC imaging can therefore measure twitch profiles of skeletal muscle fibres., Muscle fibre contraction induces signal changes in diffusion weighted and phase contrast images, which we used to extract the twitch time profile of individual motor units with a technique called motor unit MRI (MUMRI). Using modelling and experimental data, we showed that these signal changes depend on the contractile characteristics of the muscle twitch. Furthermore, we found that the diffusion weighted signal represents the active contraction, and the phase contrast measured velocity also detects passively moving muscle fibres.

The development of hardware for neural interfacing remains a technical challenge. We introduce a flexible, transversal intraneural tungsten:titanium electrode array for acute studies. We characterize the electrochemical properties of this new combination of tungsten and titanium using cyclic voltammetry and electrochemical impedance spectroscopy. With an in-vivo rodent study, we show that the stimulation of peripheral nerves with this electrode array is possible and that more than half of the electrode contacts can yield a stimulation selectivity index of 0.75 or higher at low stimulation currents. This feasibility study paves the way for the development of future cost-effective and easy-to-fabricate neural interfacing electrodes for acute settings, which ultimately can inform the development of technologies that enable bi-directional communication with the human nervous system.

Mitochondrial diseases are a clinically diverse group of genetic disorders that often present to neurologists. Health related quality of life (HRQOL) is increasingly recognised as a fundamental patient based outcome measure in both clinical intervention and research. Generic outcome measures have been extensively validated to assess HRQOL across populations and different disease states. However, due to their inclusive construct, it is acknowledged that not all relevant aspects of a specific illness may be captured. Hence there is a need to develop disease specific HRQOL measures that centre on symptoms characteristic of a specific disease or condition and their impact. This study presents the initial conceptualisation, development and preliminary psychometric assessment (validity and reliability) of a mitochondrial disease specific HRQOL measure (Newcastle Mitochondrial Quality of life measure (NMQ)). NMQ is a valuable assessment tool and consists of 63 items within 16 unidimensional domains, each demonstrating good internal reliability (Cronbach’s α⩾0.83) and construct validity.

Background Congenital myasthenic syndrome with episodic apnoea (CMS-EA) is a rare but potentially treatable cause of apparent life-threatening events in infancy. The underlying mechanisms for sudden and recurrent episodes of respiratory arrest in these patients are unclear. Whilst CMS-EA is most commonly caused by mutations in CHAT, the list of associated genotypes is expanding. Methods We reviewed clinical information from 19 patients with CMS-EA, including patients with mutations in CHAT, SLC5A7 and RAPSN, and patients lacking a genetic diagnosis. Results Lack of genetic diagnosis was more common in CMS-EA than in CMS without EA (56% n = 18, compared to 7% n = 97). Most patients manifested intermittent apnoea in the first 4 months of life (74%, n = 14). A degree of clinical improvement with medication was observed in most patients (74%, n = 14), but the majority of cases also showed a tendency towards complete remission of apnoeic events with age (mean age of resolution 2 years 5 months). Signs of impaired neuromuscular transmission were detected on neurophysiology studies in 79% (n = 15) of cases, but in six cases, this was only apparent following specific neurophysiological testing protocols (prolonged high-frequency stimulation). Conclusions A relatively large proportion of CMS-EA remains genetically undiagnosed, which suggests the existence of novel causative CMS genes which remain uncharacterised. In light of the potential for recurrent life-threatening apnoeas in early life and the positive response to therapy, early diagnostic consideration of CMS-EA is critical, but without specific neurophysiology tests, it may go overlooked.

BACKGROUND Clinical nerve conduction studies (NCS) are often used as a secondary outcome measure in therapeutic trials, but show a high degree of inter-trial variability even when technical factors known to affect the recorded responses are minimised. This raises the intriguing possibility that some of the observed variability may reflect true changes in nerve activity. OBJECTIVES Our aim was determine how much variability these factors might produce, and how this might affect the results of commonly used neuropathy rating scales. METHODS A standardised protocol was repeated over forty consecutive trials by the same operators in two healthy subjects. The protocol included recordings that shared either a stimulating or a recording electrode position, such that changes due to electrode position could be excluded, and hand temperature was closely controlled. RESULTS Despite controlling for inter-operator differences, electrode position, and hand temperature, the variability in sensory nerve action potential (SNAP) amplitude was extremely high (Range 23 μV, CoV = 10.7-18.8). This variability was greater than the change in amplitude needed to move a subject from point 0 to point 4 on the CMT neuropathy rating scale. Neither temperature or electrode position accounted for all of this variability, suggesting that additional as yet unidentified factors are responsible. CONCLUSION Even under closely controlled conditions and sophisticated laboratory methods, test-to-test variability can be significant. The factors responsible for this variability may be difficult to control, limiting the utility of single nerve recordings as a trial outcome measure.

Purpose Most people with epilepsy (PWE) in low-income countries are not treated. We identified risk factors for the epilepsy treatment gap in rural Tanzania. Methods We identified adult PWE in a community-based prevalence study. Factors associated with failure to access or default from medical care were identified using logistic regression modelling. Results A total of 291 PWE were included, of whom 253 (86.9%) had presented to medical services. Failure to present was positively associated with using alcohol (odds ratio (OR) 4.20; 95% confidence interval (CI) 1.63 to 10.82) or attending traditional healers (OR 2.62; CI 1.00 to 6.83) and inversely associated with having completed primary education (OR 0.33; CI 0.11 to 0.96). Default from treatment was associated with being male (OR 3.35; CI 1.39 to 8.09), having a seizure-related injury (OR 2.64; CI 1.12 to 6.19), believing in a supernatural cause for epilepsy (OR 5.44; CI 1.48 to 19.94) or having no expressed knowledge of cause (OR 5.29; CI 1.60 to 17.52). Cases less likely to default had a duration of epilepsy greater than 10 years (OR 0.28; CI 0.09 to 0.90) or had previously received a seizure-related diagnosis (OR 0.25; CI 0.09 to 0.65). Of all 291 PWE included, 118 denied taking AEDs; the epilepsy treatment gap in this population was therefore 40.5% (95% CI 34.9 to 46.2). Conclusion Interventions to improve access to education and to support formal diagnoses may promote access to, and retention under, medical care for PWE in rural Tanzania and in other low-income countries.

Objective The aim of this work was to determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease. Methods We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between January 1, 2005 and January 1, 2008. We then followed this cohort over a 7‐year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke‐like episode, and death. Results Overall prevalence of epilepsy in the cohort was 23.1%. Mean age of epilepsy onset was 29.4 years. Prevalence varied widely between genotypes, with several genotypes having no cases of epilepsy, a prevalence of 34.9% in the most common genotype (m.3243A>G mutation), and 92.3% in the m.8344A>G mutation. Among the cohort as a whole, focal seizures, with or without progression to bilateral convulsive seizures, was the most common seizure type. Conversely, all of the patients with the m.8344A>G mutation and epilepsy experienced myoclonic seizures. Patients with the m.3243A>G mutation remain at high risk of developing stroke‐like episodes (1.16% per year). However, although the standardized mortality ratio for the entire cohort was high (2.86), this ratio did not differ significantly between patients with epilepsy (2.96) and those without (2.83). Interpretation Epilepsy is a common manifestation of mitochondrial disease. It develops early in the disease and, in the case of the m.3243A>G mutation, often presents in the context of a stroke‐like episode or status epilepticus. However, epilepsy does not itself appear to contribute to the increased mortality in mitochondrial disease. Ann Neurol 2015;78:949–957

Objectives: To describe the clinical and electrophysiologic features of synaptotagmin II (SYT2) mutations, a novel neuromuscular syndrome characterized by foot deformities and fatigable ocular and lower limb weakness, and the response to modulators of acetylcholine release. Methods: We performed detailed clinical and neurophysiologic assessment in 2 multigenerational families with dominant SYT2 mutations (c.920T>G [p.Asp307Ala] and c.923G>A [p.Pro308Leu]). Serial clinical and electrophysiologic assessments were performed in members of one family treated first with pyridostigmine and then with 3,4-diaminopyridine. Results: Electrophysiologic testing revealed features indicative of a presynaptic deficit in neurotransmitter release with posttetanic potentiation lasting up to 60 minutes. Treatment with 3,4-diaminopyridine produced both a clinical benefit and an improvement in neuromuscular transmission. Conclusion: SYT2 mutations cause a novel and potentially treatable complex presynaptic congenital myasthenic syndrome characterized by motor neuropathy causing lower limb wasting and foot deformities, with reflex potentiation following exercise and a uniquely prolonged period of posttetanic potentiation.

Objective To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog (PTEN), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases. Methods We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patient's fibroblasts. Results The predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) PTEN variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN-deficient mice. Conclusion We describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway.

Lentiviral vectors are increasingly the gene transfer tool of choice for gene or cell therapies, with multiple clinical investigations showing promise for this viral vector in terms of both safety and efficacy. The third-generation vector system is well characterized, effectively delivers genetic material and maintains long-term stable expression in target cells, delivers larger amounts of genetic material than other methods, is nonpathogenic, and does not cause an inflammatory response in the recipient. This report aims to help academic scientists and regulatory managers negotiate the governance framework to achieve successful translation of a lentiviral vector-based gene therapy. The focus is on European regulations and how they are administered in the United Kingdom, although many of the principles will be similar for other regions, including the United States. The report justifies the rationale for using third-generation lentiviral vectors to achieve gene delivery for in vivo and ex vivo applications; briefly summarizes the extant regulatory guidance for gene therapies, categorized as advanced therapeutic medicinal products (ATMPs); provides guidance on specific regulatory issues regarding gene therapies; presents an overview of the key stakeholders to be approached when pursuing clinical trials authorization for an ATMP; and includes a brief catalogue of the documentation required to submit an application for regulatory approval of a new gene therapy.

Objective:To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England.Methods:Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients).Results:The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62–2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy.Conclusions:Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies.

Purpose Many patients report being able to predict their own seizures, and yet most seizures appear to strike out of the blue. This inherent contradiction makes the topic of seizure self-prediction controversial as well as difficult to study. Here we review the evidence for whether this ability exists, how many patients are capable of self-prediction and the nature of this capability, and whether this could provide a target for intervention. Methods Systematic searches of bibliographic databases including MEDLINE, EMBASE and PsycINFO through OVID were performed to identify relevant papers which were then screened by the study authors for inclusion in the study. 18 papers were selected for inclusion as the focus of this review. Results On the basis of two studies, between 17% and 41% of patients demonstrate a significantly greater than chance ability to predict an upcoming seizure in the following 12-h time window. This risk is correlated with self-reported anxiety, stress, sleep deprivation, mood and certain prodromal symptoms. However, there is no evidence for any subjective experience which directly heralds an imminent seizure. Thus, while patients may be aware of seizure risk, and have some ability to predict seizure occurrence over a wide time window, they are unable to subjectively recognise seizure onset in advance. Conclusion Utilising subjectively acquired knowledge of seizure risk may provide a widely implementable tool for targeted intervention. The risk fluctuates over a time course appropriate for pharmacotherapy which may improve seizure control and the side-effect profile of anti-epileptic medication.

BACKGROUND:\ud \ud Miller Fisher syndrome is a regional variant of Guillain-Barre syndrome with a characteristic clinical triad of ophthalmoplegia, areflexia and ataxia and occasionally distal limb sensory loss. 90% of patients have associated antibodies to the GQ1b ganglioside. The pathophysiology of antibody-mediated peripheral nerve impairment remains uncertain. This report includes the first description of a peripheral sensory nerve biopsy in Miller Fisher syndrome.\ud \ud RESULTS:\ud \ud A single case report is described of a 46 year old woman who presented with 2 weeks of distal glove and stocking sensory loss to both deep and superficial sensory modalities, areflexia and weight loss. This was followed by rapid onset of ataxia, ophthalmoplegia, and bulbar impairment. Peripheral neurophysiology showed reduced sensory nerve amplitudes with preserved conduction velocities in keeping with an axonal pattern of impairment. Clinical concerns of a systemic inflammatory disorder led to a diagnostic peripheral nerve biopsy from the sensory branch of the radial nerve. However she subsequently made a complete recovery over 5 weeks. Combinatorial glycoarrays confirmed restricted serum binding for GQ1b in acute serum which later resolved in a convalescent sample. The nerve biopsy showed lengthening of nodes of Ranvier, myelin splitting and macrophage internodal axonal invasion without any features of demyelination.\ud \ud CONCLUSIONS:\ud \ud The pathological features were strikingly similar to those found in acute motor axonal neuropathy and indicate the region of the node of Ranvier to be a primary focus of GQ1b induced damage in Miller Fisher syndrome, at least in this particular overlap syndrome with prominent sensory nerve involvement.

Fast ripples (FRs) are network oscillations, defined variously as having frequencies of > 150 to > 250 Hz, with a controversial mechanism. FRs appear to indicate a propensity of cortical tissue to originate seizures. Here, we demonstrate field oscillations, at up to 400 Hz, in spontaneously epileptic human cortical tissue in vitro, and present a network model that could explain FRs themselves, and their relation to ‘ordinary’ (slower) ripples. We performed network simulations with model pyramidal neurons, having axons electrically coupled. Ripples (< 250 Hz) were favored when conduction of action potentials, axon to axon, was reliable. Whereas ripple population activity was periodic, firing of individual axons varied in relative phase. A switch from ripples to FRs took place when an ectopic spike occurred in a cell coupled to another cell, itself multiply coupled to others. Propagation could then start in one direction only, a condition suitable for re-entry. The resulting oscillations were > 250 Hz, were sustained or interrupted, and had little jitter in the firing of individual axons. The form of model FR was similar to spontaneously occurring FRs in excised human epileptic tissue. In vitro, FRs were suppressed by a gap junction blocker. Our data suggest that a given network can produce ripples, FRs, or both, via gap junctions, and that FRs are favored by clusters of axonal gap junctions. If axonal gap junctions indeed occur in epileptic tissue, and are mediated by connexin 26 (recently shown to mediate coupling between immature neocortical pyramidal cells), then this prediction is testable.

During chemical transmission, the function of synaptic proteins must be coordinated to efficiently release neurotransmitter. Synaptotagmin 2, the Ca2+ sensor for fast, synchronized neurotransmitter release at the human neuromuscular junction, has recently been implicated in a dominantly inherited congenital myasthenic syndrome associated with a non-progressive motor neuropathy. In one family, a proline residue within the C2B Ca2+-binding pocket of synaptotagmin is replaced by a leucine. The functional significance of this residue has not been investigated previously. Here we show that in silico modeling predicts disruption of the C2B Ca2+-binding pocket, and we examine the in vivo effects of the homologous mutation in Drosophila. When expressed in the absence of native synaptotagmin, this mutation is lethal, demonstrating for the first time that this residue plays a critical role in synaptotagmin function. To achieve expression similar to human patients, the mutation is expressed in flies carrying one copy of the wild type synaptotagmin gene. We now show that Drosophila carrying this mutation developed neurological and behavioral manifestations similar to those of human patients and provide insight into the mechanisms underlying these deficits. Our Drosophila studies support a role for this synaptotagmin point mutation in disease etiology.

Purpose To estimate the prevalence of active epilepsy in adults in an established demographic surveillance site in rural Tanzania. To describe the clinical characteristics of epilepsy and to estimate the treatment gap in this population. Methods A pilot study established that a previously validated screening questionnaire was sensitive for detecting cases of epilepsy in a Kiswahili-speaking Tanzanian population. A door-to-door census of the adult population (total 103,026) used the screening questionnaire to identify possible cases of epilepsy, who were then assessed by a research doctor to establish a diagnosis of epilepsy or otherwise. The prevalence of active epilepsy in this population was estimated with age-standardisation to the WHO standard population. Seizure types and epilepsies were classified according to current recommendations of the International League Against Epilepsy. The treatment gap for epilepsy was estimated based on antiepileptic drug use as reported by cases. Results Two hundred and ninety-one cases of active epilepsy, all with convulsive seizures, were identified. The age-standardised prevalence was 2.91/1000 adults (95% CI 2.58–3.24); the crude prevalence adjusted for non-response was 3.84/1000 adults (95% CI 3.45–4.20). Focal-onset seizures accounted for 71.5% of all cases identified. The treatment gap was 68.4% (95% CI 63.0–73.7). Conclusions This is one of the largest community-based studies of the prevalence of epilepsy in adults conducted in sub-Saharan Africa to date. We identified a lower prevalence than has previously been described in this region. The high proportion of focal onset seizures points to a large burden of acquired, and possibly preventable, epilepsy in this population. A treatment gap of 68.4% confirms that interventions to raise awareness of the treatable nature of epilepsy are warranted in this and similar populations.

Mutations affecting the nuclear gene encoding the mitochondrial OPA1 protein are the commonest causes of autosomal dominant optic atrophy (DOA). More recently OPA1 mutations have been shown to cause a disorder of mitochondrial DNA (mtDNA) maintenance, thus explaining the extraocular features observed in ∼20% of OPA1 mutation carriers with “DOA+,” which include deafness, progressive external ophthalmoplegia (PEO), myopathy, ataxia, neuropathy, and spastic paraplegia.1,2 However, it remains puzzling why, unlike other hereditary mtDNA maintenance disorders (e.g., POLG1 3), most OPA1 mutation carriers only appear to develop isolated optic neuropathy. To determine whether this is actually the case, we looked for electrophysiologic evidence of subclinical multisystem disease in a sample of patients with clinically “pure” DOA. Because spasticity is an unusual clinical finding in mitochondrial disease, we were particularly interested to look for evidence of subclinical corticospinal tract (CST) disease in this clinically asymptomatic group, specifically to gain insight into the role of mitochondrial dysfunction in other more common neurodegenerative motor disorders. ### Methods. Fourteen patients with confirmed pathogenic OPA1 mutations were recruited prospectively: 1) 13 patients with bilateral optic atrophy and no evidence of any neurologic deficit, classified as “pure” DOA; and 2) 1 visually asymptomatic OPA1 mutation carrier (c.1294A>G) with no clinical or electrophysiologic evidence of optic nerve dysfunction. MRI was performed as part of the patients' initial diagnostic workup for their unexplained bilateral optic neuropathy. All patients had nerve conduction studies (NCS), needle EMG, and transcranial magnetic stimulation (TMS) was used to obtain motor evoked potentials …

Inherited and acquired mutations of mtDNA cause an extraordinary group of diseases that are associated with a diverse panoply of neurological and non-neurological features. These diseases are surprisingly common and are often severely debilitating and readily transmitted through families. Remarkable advances in understanding molecular mechanisms have been made since the first pathogenic mtDNA mutations were identified in 1988, and while widely available genetic techniques have facilitated diagnosis, the complexities of mitochondrial genetics leave the neurologist facing important challenges in recognizing, managing and counseling patients with mtDNA mutations. In this article, we will discuss the clinical phenotypes associated with mtDNA disease, current diagnostic strategies, disease management and genetic counseling, as well as presenting new developments in preventing disease transmission and secondary complications.

Very fast oscillations (VFOs, >80 Hz) are important for physiological brain processes and, in excess, with certain epilepsies. Putative mechanisms for VFO include interneuron spiking and network activity in coupled pyramidal cell axons. It is not known whether either, or both, of these apply in pathophysiological conditions. Spontaneously occurring interictal discharges occur in human tissue in vitro, resected from neocortical epileptic foci. VFO associated with these discharges was manifest in both field potential and, with phase delay, in excitatory synaptic inputs to fast spiking interneurons. Recruitment of somatic pyramidal cell and interneuron spiking was low, with no correlation between VFO power and synaptic inputs to principal cells. Reducing synaptic inhibition failed to affect VFO occurrence, but they were abolished by reduced gap junction conductance. These data suggest a lack of a causal role for interneurons, and favor a nonsynaptic pyramidal cell network origin for VFO in epileptic human neocortex.

Many types of electrographic seizures are readily identifiable by direct visual examination of electroencephalographic or electrocorticographic recordings. This process can, however, be painstakingly slow, and much effort has been expended to automate the process using various dynamic properties of epileptiform waveforms. As methods have become more subtle and powerful they have been used for seizure subclassification, seizure prediction, and seizure onset identification and localization. Here we concentrate on the last, with reference to seizures of neocortical origin. We briefly review some of the methods used and introduce preliminary results from a very simple dynamic model based on key electrophysiological properties found in some seizure types: occurrence of very fast oscillations (sometimes called ripples), excess gamma frequency oscillations, electroencephalographic/electrocorticographic flattening, and changes in global synchrony. We show how this multiscale analysis may reveal features unique to seizure onset and speculate on the underlying cellular and network phenomena responsible.

We investigated whether the benefit of slow wave sleep (SWS) for memory consolidation typically observed in healthy individuals is disrupted in people with accelerated long-term forgetting (ALF) due to epilepsy. SWS is thought to play an active role in declarative memory in healthy individuals and, furthermore, electrographic epileptiform activity is often more prevalent during SWS than during wakefulness or other sleep stages. We studied the relationship between SWS and the benefit of sleep for memory retention using a word-pair associates task. In both the ALF and the healthy control groups, sleep conferred a memory benefit. However, the relationship between the amount of SWS and sleep-related memory benefits differed significantly between the groups. In healthy participants, the amount of SWS correlated positively with sleep-related memory benefits. In stark contrast, the more SWS, the smaller the sleep-related memory benefit in the ALF group. Therefore, contrary to its role in healthy people, SWS-associated brain activity appears to be deleterious for memory in patients with ALF.

Increasingly, neuroscientists are taking the opportunity to use live human tissue obtained from elective neurosurgical procedures for electrophysiological studies in vitro. Access to this valuable resource permits unique studies into the network dynamics that contribute to the generation of pathological electrical activity in the human epileptic brain. Whilst this approach has provided insights into the mechanistic features of electrophysiological patterns associated with human epilepsy, it is not without technical and methodological challenges. This review outlines the main difficulties associated with working with epileptic human brain slices from the point of collection, through the stages of preparation, storage and recording. Moreover, it outlines the limitations, in terms of the nature of epileptic activity that can be observed in such tissue, in particular, the rarity of spontaneous ictal discharges, We discuss manipulations that can be utilised to induce such activity. In addition to discussing conventional electrophysiological techniques that are routinely employed in epileptic human brain slices, we review how imaging and multielectrode array recordings could provide novel insights into the network dynamics of human epileptogenesis. Acute studies in human brain slices are ultimately limited by the lifetime of the tissue so overcoming this issue provides increased opportunity for information gain. We review the literature with respect to organotypic culture techniques that may hold the key to prolonging the viability of this material. A combination of long-term culture techniques, viral transduction approaches and electrophysiology in human brain slices promotes the possibility of large scale monitoring and manipulation of neuronal activity in epileptic microcircuits.

Symmetrical polyneuropathy is a common feature of mitochondrial disease. Both axonal and demyelinating types are described, with Schwann cell abnormalities demonstrated on nerve biopsy. Some authors have also suggested an increased incidence of entrapment neuropathy. We identified 738 adult patients with proven mitochondrial disease seen in our centre in the past 25 years. One-hundred sixty seven of these patients had undergone nerve conduction studies as part of their routine clinical care, and the results of these studies were reviewed. We found an incidence rate of carpal tunnel syndrome (CTS) of 50.7 per 100,000 person-years; 32.5 per 100,000 person-years for men and 65.3 per 100,000 person-years for women. One other patient had evidence of ulnar neuropathy at the elbow. The incidence of CTS in mitochondrial disease is similar to published rates for the UK general population. We found no evidence that mitochondrial disease per se increases the risk of entrapment neuropathy. We suggest that the pathophysiological mechanisms for the development of polyneuropathy in mitochondrial disease are quite distinct from the pathophysiology of CTS. Furthermore, it is essential that patients with mitochondrial disease who present with upper limb paraesthesia be referred for neurophysiological testing, so that treatable CTS is not missed.

Powerful endogenous inhibitory mechanisms are thought to restrict the spread of epileptic discharges in cortical networks. Similar inhibitory mechanisms also influence physiological processing. We reasoned, therefore, that useful information about the quality of inhibitory restraint in individuals with epilepsy may be gleaned from psychophysical assays of these physiological processes. We derived a psychophysical measure of cortical inhibition, the motion surround suppression index (SSI), in 54 patients with epilepsy and 146 control subjects. Multivariate regression analyses showed that SSI was predicted strongly by age and seizure type, but not by seizure frequency. Specifically, we found that patients with exclusively focal epilepsy, and no history of generalization, showed significantly stronger cortical inhibition as measured by the SSI compared to all other groups, including controls. In contrast, patients with focal seizures evolving into generalized seizures, and patients with generalized genetic epilepsy, showed similar levels of cortical inhibition to controls. The presumptive focus, when one could be identified, was rarely found in visual cortex, meaning that the relationship with the epilepsy subtype is likely to reflect some global difference in inhibition in these subjects. This is the first reported instance of raised SSI in any patient cohort, and appears to differentiate between patients with respect to the likelihood of their experiencing generalization of their seizures. These results suggest that such simple psychophysical assays may provide useful aids to clinical management, particularly at the time of diagnosis.

Synaptotagmin 2 is a synaptic vesicle protein that functions as a calcium sensor for neurotransmission but has not been previously associated with human disease. Via whole-exome sequencing, we identified heterozygous missense mutations in the C2B calcium-binding domain of the gene encoding Synaptotagmin 2 in two multigenerational families presenting with peripheral motor neuron syndromes. An essential calcium-binding aspartate residue, Asp307Ala, was disrupted by a c.920A>C change in one family that presented with an autosomal-dominant presynaptic neuromuscular junction disorder resembling Lambert-Eaton myasthenic syndrome. A c.923C>T variant affecting an adjacent residue (p.Pro308Leu) produced a presynaptic neuromuscular junction defect and a dominant hereditary motor neuropathy in a second family. Characterization of the mutation homologous to the human c.920A>C variant in Drosophila Synaptotagmin revealed a dominant disruption of synaptic vesicle exocytosis using this transgenic model. These findings indicate that Synaptotagmin 2 regulates neurotransmitter release at human peripheral motor nerve terminals. In addition, mutations in the Synaptotagmin 2 C2B domain represent an important cause of presynaptic congenital myasthenic syndromes and link them with hereditary motor axonopathies., National Institutes of Health (U.S.) (NIH Grant NS40296), Picower Institute for Learning and Memory (Picower Neurological Disease Research Fund), JPB Foundation

A 39-year-old lawyer presented with intermittent spasms and pain in his abdominal muscles, particularly the right upper quadrant. These had occurred since his mid-20s and there had been long asymptomatic periods, including 8 years prior to the most recent 4-month exacerbation. Trivial movement triggered a spasm of the abdominal muscles, leading to severe pain, which made breathing uncomfortable and interfered with sleep. The symptoms subsided spontaneously after 4 to 5 days, leaving him with a sore abdomen for several weeks. Past attacks had also been precipitated by specific forms of repetitive exercise such as jogging. He described ill-defined numbness in the left leg, but denied any muscle twitching, weakness, back pain, or sphincter disturbance. There was no significant past medical or family history.

A 2-month-old baby presented with variable right-sided ptosis (without fatigability or maternal myasthenia) and recurrent unexplained central apneas since birth. On sucking, there was a right Marcus Gunn phenomenon with temporary left-sided ptosis (figure; video on the Neurology ® Web site at [www.

Purpose: To define the prevalence and risk factors for epilepsy in children in a rural district of Tanzania by conducting a community-based case - control study. Methods: Children aged 6-14 years with active epilepsy (at least two unprovoked seizures in the last 5 years) were identified in a cross-sectional survey in Tanzania. Cases were compared with age-matched controls. Key Findings: Overall 112 children with epilepsy (CWE) were identified; the unadjusted prevalence of epilepsy was 2.91 per 1,000 (95% confidence interval [95% CI] 2.4-3.5). The main seizure types were focal motor with secondary generalization in 73 (65.2%) of 112 and generalized convulsive seizures in 19 (16.9%) of 112. Adverse perinatal events were present in 16 (14%) of 112 cases but in no controls. In multivariate analysis, epilepsy was associated with number of parents who were resident at home (odds ratio [OR] 6.2 for none vs. both resident, 95% CI 1.5-25.5), history of adverse perinatal events (OR 14.9, 95% CI 1.4-151.3), family history of afebrile seizures (OR 5.7, 95% CI 1.0-27.5), and poor scholastic attainment (OR 8.6, 95% CI 4.0-18.4). Electroencephalography (EEG) and computed tomography (CT) scans were abnormal in 44 (44%) of 101 and 26 (29%) of 90 cases, respectively. Overall, 98 (88%) of 112 cases had focal features on assessment. Significance: In this study from sub-Saharan Africa, CWE predominantly had focal features that support the suggestion that most epilepsy in this region has a symptomatic etiology. Adverse perinatal events were strongly associated with epilepsy. Genetic and social factors may also be important. Epilepsy may be preventable in a significant proportion of children with better antenatal and perinatal care. ©2012 International League Against Epilepsy.

Defects in the mitochondrial DNA replication enzyme, polymerase γ, are an important cause of mitochondrial disease with ∼25% of all adult diagnoses attributed to mutations in the POLG gene. Peripheral neuronopathy is often part of the clinical syndrome and can represent the most disabling feature. In spite of this, the molecular mechanisms underlying the neuronopathy remain to be elucidated and treatment strategies are limited. In the present study, we use a combined approach comprising clinical, electrophysiological, neuropathological and molecular genetic investigations to unravel the mechanisms underpinning peripheral neuronopathy in autosomal recessive polymerase γ-related disease. Electrophysiological assessments documented a dorsal root ganglionopathy in all 11 cases. Of the 11 cases, eight also showed changes consistent with motor fibre loss. Detailed neuropathological investigation of two patients confirmed the electrophysiological findings, revealing atrophy of posterior columns and striking neuronal cell loss from the dorsal root ganglia, which was accompanied by severe mitochondrial biochemical abnormalities involving respiratory chain complexes I and IV due to clonally-expanded mitochondrial DNA deletions and a significant reduction in mitochondrial DNA copy number in affected neurons. We propose that the respiratory chain defects, secondary to mitochondrial DNA deletion and depletion, are likely to be responsible for pathology observed in the dorsal root ganglion and the sensory ganglionopathy documented electrophysiologically.

Mitochondrial diseases are heterogeneous in clinical presentation and genotype. The incidence of known pathogenic mitochondrial DNA mutations in the general population is 1 in 500. Little is known about the implications of pregnancy for women with mitochondrial disease. We undertook a systematic review of the literature on mitochondrial disease in pregnancy. Ten case reports were identified. The most common complications were threatened preterm labour (5 women) and preeclampsia (4 women). Two women experienced magnesium sulphate toxicity. Pregnancy had a varied effect on mitochondrial disease with some women being asymptomatic; others developing mild symptoms such as exercise intolerance or muscle weakness which resolved postnatally; and others developed more serious, persistent symptoms such as symptomatic Wolff–Parkinson–White syndrome, persistent paraesthesia and focal segmental glomerulosclerosis. Women with mitochondrial disease appear to be at increased risk of complications during pregnancy and labour but further prospective cohort studies are needed.

Purpose: To define the prevalence and associations of co-morbidity and school attendance in older children with epilepsy (CWE) from a rural district of Tanzania by conducting a community-based case-control study. Methods: Children aged 6-14 years old with active epilepsy (at least two unprovoked seizures in the last five years) were identified in a cross-sectional survey in Tanzania. Co-morbidities were assessed and cases were compared with age-matched controls. Results: Co-morbidity was very common amongst cases (95/112, 85%), with 62/112 (55%) having multiple co-morbidities. Co-morbidities consisted of cognitive impairment (72/112, 64%), behaviour disorder 68/112 (61%), motor difficulties 29/112 (26%), burns and other previous injuries (29/112, 26%). These complications were significantly more common in cases than in controls (odds ratio 14.8, 95%CI 7.6-28.6, p < 0.001). Co-morbidity in CWE was associated with structural cause, abnormal electroencephalogram and early onset seizures. Cognitive impairment was very common in CWE (64%) and was not associated with Phenobarbital use but was associated with motor difficulties, early onset and recurrent seizures. Poor school attendance was found in 56/112 (50%) of CWE, but not in the controls: it was associated with the presence of multiple co-morbidities, especially with motor difficulties in CWE. Conclusion: Children with epilepsy in a rural area of sub-Saharan Africa had a high level of co-morbidity. Cognitive impairment and poor school attendance were very common. These associated difficulties in CWE in the region need to be addressed to reduce the negative impact of epilepsy on these children. Crown Copyright © 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

A 40-year-old man presented with a 25-year history of cramps affecting the abdomen, neck, and limbs. Examination revealed fasciculation in the forearms, abdomen, and chin (video on the Neurology ® Web site at [Neurology.org][1]). There was shoulder girdle wasting with bilateral mastectomy scars (figure, B and C). Creatine kinase (CK) was 1,650 U/L (normal < 310 U/L). Electrodiagnostic studies revealed sensory neuronopathy with neurogenic changes on EMG. Genetic testing demonstrated excess CAG repeats in the androgen receptor gene, confirming Kennedy disease.1 This X-linked disorder is the most common adult-onset spinal muscular atrophy. CK can be markedly raised.2 Gynecomastia results from androgen insufficiency and can precede the development of neurologic symptoms. [1]: http://www.neurology.org/

Purpose: Single large-scale mitochondrial DNA deletions account for a quarter of mitochondrial disease cases and occur sporadically with unknown risk factors. Mitochondrial DNA deletions accumulate with age in many tissues. Primordial germ cells, the precursors of oocytes are made by our grandmothers, therefore we wanted to determine whether age of maternal grandmother is a risk factor for sporadic mitochondrial DNA deletions. Methods: Twenty-nine patients with sporadic single mitochondrial DNA deletions from the Newcastle UK cohort provided dates of birth for mothers and maternal grandmothers plus father and paternal grandmother (healthy controls). Results: Mean age for grandmothers at birth of a mother of an affected patient was 28.5 years (SD ± 6.9) for single mitochondrial DNA deletions maternal grandmothers and 28.2 years (SD ± 6.1) for healthy control paternal grandmothers. Conclusion: Maternal grandmother age is not a risk factor for sporadic mitochondrial DNA deletions, an important observation in a population where many women are delaying reproduction.

International audience; Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal ‘dominant optic atrophy plus’ variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44–6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08–4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.

The m.3243 A>G point mutation in the mitochondrial-encoded MTTL1 gene is the single most common cause of mitochondrial disease.1 The range of clinical phenotypes is highly variable, from isolated diabetes and deafness to the devastating mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Mitochondria contain multiple copies of mtDNA, and both wild-type and mutated mtDNA molecules can coexist in the same cell, a condition referred to as heteroplasmy. The expression of different clinical phenotypes is presumed to relate to different heteroplasmy levels within affected tissues.2 Being able to predict which patients are likely to develop complications of mitochondrial disease is essential for optimal clinical management. An important question therefore is which of the tissues which are suitable for analysis best reflect the level of mutation in clinically affected tissues, and hence are likely to best predict clinical outcome. Although the m.3243A>G mutation is readily measurable in blood leukocytes, the level of mutation declines over time.3 Thus even in severely affected patients presenting with MELAS, the level of m.3243A>G mutation may be very low, or even escape detection. Muscle biopsy is the current gold standard for the measurement of heteroplasmy to predict the incidence of specific clinical features. However, …

The hallmarks of the myoclonic epilepsy with ragged red fibers (MERRF) syndrome are myoclonic epilepsy, ataxia and ragged red fibres detected on muscle biopsy. We present a case of a 25-year-old male who first presented to his general practitioner at the age of 22 years with myoclonic jerks affecting the arms and legs, fatigue and mild ataxia. He was found to carry an A>G transition at nucleotide 8344 in mitochondrial DNA. This mutation is the most common cause of the MERRF syndrome, found in more than 80% of affected patients. Our patient had the diagnosis tattooed on his arm, both out of frustration at how few people had heard of it, and as a way of accepting that his condition was a part of who he was. Although the MERRF syndrome is one of the more common forms of mitochondrial encephalomyopathy, with a prevalence estimated at between 0.25 and 0.39 per 100,000, it is still a rare disorder. We are always striving to increase the public’s understanding of these important conditions. Our patient has perhaps helped more than most towards this aspiration.

Objective Diverse and variable clinical features, a loose genotype–phenotype relationship, and presentation to different medical specialties have all hindered attempts to gauge the epidemiological impact of mitochondrial DNA (mtDNA) disease. Nevertheless, a clear understanding of its prevalence remains an important goal, particularly about planning appropriate clinical services. Consequently, the aim of this study was to accurately define the prevalence of mtDNA disease (primary mutation occurs in mtDNA) in the working-age population of the North East of England. Methods Adults with suspected mitochondrial disease in the North East of England were referred to a single neurology center for investigation from 1990 to 2004. Those with pathogenic mtDNA mutations were identified and pedigree analysis performed. For the midyear period of 2001, we calculated the minimum point prevalence of mtDNA disease for adults of working age (>16 and

The aims of this study were (1) to determine the prevalence and rate of progression in diabetes secondary to mitochondrial DNA (mtDNA) mutations; and (2) to determine whether percentage heteroplasmy predicts clinical outcome in patients carrying the m.3243A>G mutation. We prospectively assessed 242 patients attending a specialist neuromuscular clinic using a validated mitochondrial disease rating scale. Retrospective clinical data on these patients from up to 25 years of follow-up were also included. Percentage heteroplasmy in blood, urine and muscle was determined for the m.3243A>G group and correlated against clinical features. Patients carrying the m.3243A>G mutation formed the largest group of patients with diabetes (31/81 patients). The highest prevalence of diabetes was in the m.12258C>A group (2/2 patients), the lowest in the multiple mtDNA deletions group (3/43 patients). The earliest age of onset was in the m.3243A>G group (37.9 years) with the highest age of presentation in the multiple deletion group (56.3 years). Of patients presenting with m.3243A>G, 12.9% required insulin; an additional 32.3% progressed to insulin requirement over a mean of 4.2 years after presentation. Percentage heteroplasmy in blood, urine or muscle did not predict progression of diabetes or risk of developing complications. Early age of presentation with diabetes did predict poor clinical outcome. Although patients carrying the m.3243A>G mutation account for the majority of cases of diabetes secondary to mtDNA mutations, several other genotypes are also associated with the development of diabetes, some with high penetrance. All show a gradual progression to insulin requirement. Percentage heteroplasmy is a poor predictor of severity of diabetes in the m.3243A>G group.

A well-studied paradox of motion perception is that, in order to correctly judge direction in high-contrast stimuli, subjects need to observe motion for longer in large stimuli than in small stimuli. This effect is one of several perceptual effects known generally as "surround suppression." It is usually attributed to center-surround antagonism between neurons in visual cortex, believed to be mediated by GABA-ergic inhibition. Accordingly, several studies have reported that this index of surround suppression is reduced in groups known to have reduced GABA-ergic inhibition, including older people and people with schizophrenia and major depressive disorder. In this study, we examined the effect on this index of moderate amounts of ethanol alcohol. Among its many effects on the nervous system, alcohol potentiates GABA-ergic transmission. We therefore hypothesized that it should further impair the perception of motion in large stimuli, resulting in a stronger surround-suppression index. This prediction was not borne out. Alcohol consumption slightly worsened duration thresholds for both large and small stimuli, but their ratio did not change significantly.