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Background: Investigation of atrophy data from a pivotal natalizumab trial has demonstrated an increased rate of volume loss, compared to placebo, after the first year of therapy. It was considered to be probably due to a pseudoatrophy effect. Objective: To assess grey and white matter volume changes and their relation to global brain volume changes and to baseline inflammation, for patients under natalizumab therapy. Methods: We selected 45 patients on natalizumab therapy for at least 24 months, with magnetic resonance imaging (MRI) scans at baseline, 12 and 24 months. We calculated the percentage brain volume change (PBVC) for the first and second year, using SIENA software. Grey and white matter fractions (GMF and WMF, respectively) for the first year were calculated with SPM5, using lesion masks. After quality checks, six patients were excluded. We studied the predictive variables of change in brain volumes. Results: The PBVC decrease was faster during the first year (−1.10% ± 1.43%), as compared to the second (−0.51% ± 0.96%) (p = 0.037). These differences were more marked in patients with baseline gadolinium-enhancing lesions (p = 0.005). Mean GMF and WMF changes during the first year of treatment were +1.15% (n.s.) and −1.72% (p = 0.017), respectively. The presence of active lesions at baseline MRI predicted PBVC (p = 0.022) and WMF change (p = 0.026) during the first year of treatment, after adjusting for age and corticosteroid treatment. No predictors were found for GMF volume changes. Conclusion: Early brain volume loss during natalizumab therapy is mainly due to WMF volume loss and it is related to the inflammatory activity present at the onset of therapy. We found that the pseudoatrophy effect is mostly due to white matter volume changes.

Mutations in nuclear-encoded protein subunits of the mitochondrial ribosome are an increasingly recognised cause of oxidative phosphorylation system (OXPHOS) disorders. Among them, mutations in the MRPL44 gene, encoding a structural protein of the large subunit of the mitochondrial ribosome, have been identified in four patients with OXPHOS defects and early-onset hypertrophic cardiomyopathy with or without additional clinical features. A 23-year-old individual with cardiac and skeletal myopathy, neurological involvement, and combined deficiency of OXPHOS complexes in skeletal muscle was clinically and genetically investigated. Analysis of whole-exome sequencing data revealed a homozygous mutation in MRPL44 (c.467 T > G), which was not present in the biological father, and a region of homozygosity involving most of chromosome 2, raising the possibility of uniparental disomy. Short-tandem repeat and genome-wide SNP microarray analyses of the family trio confirmed complete maternal uniparental isodisomy of chromosome 2. Mitochondrial ribosome assembly and mitochondrial translation were assessed in patient derived-fibroblasts. These studies confirmed that c.467 T > G affects the stability or assembly of the large subunit of the mitochondrial ribosome, leading to impaired mitochondrial protein synthesis and decreased levels of multiple OXPHOS components. This study provides evidence of complete maternal uniparental isodisomy of chromosome 2 in a patient with MRPL44 -related disease, and confirms that MRLP44 mutations cause a mitochondrial translation defect that may present as a multisystem disorder with neurological involvement.

FTY720 (fingolimod) is a structural analogue of sphingosine, an endogenous lysophospholipid, which targets sphingosine-1-phosphate receptors after biotransformation to FTY720-phosphate. The immunomodulatory properties of this agent are mainly related to its ability to entrap lymphocytes in secondary lymphoid organs, reducing their availability for cell-mediated immune responses. Emerging evidence suggests that FTY720 also exerts direct actions on glial and precursor cells of the CNS which may be relevant for the process of tissue repair after injury. The therapeutic effects of the drug observed in animal models of human multiple sclerosis have provided the experimental basis for its clinical application. A recent Phase II study has demonstrated that oral FTY720 is effective in reducing disease activity in relapsing multiple sclerosis with a favorable adverse-effect profile. These results are awaiting confirmation in the three ongoing Phase III clinical trials evaluating FTY720 for relapsing-remitting multiple sclerosis.

Background Functional Neurological Disorders (FND) are common in clinical practice. It is recognized that FND may present at onset or during the course of other neurological diseases ( functional comorbidity ). Cases We report a clinical series of three patients who initially presented positive signs of a functional movement disorder (FMD) and were later diagnosed with a Creutzfeldt-Jakob disease (CJD). All patients presented with unilateral functional tremor, two patients also had functional limb weakness. All patients progressed to an asymmetric corticobasal syndrome, fulfilling clinical criteria of CJD. They had a rapid progression and died within 2–3 months. Conclusions FND may be the initial clinical presentation of neurodegenerative diseases reflecting a dysfunction across brain circuits that are involved in the pathophysiology of FND. A positive diagnosis of FND is essential as it is an adequate examination and a close follow-up of these patients in neurology clinics.

ObjectivesTo analyse and describe the clinical and genetic spectrum of Charcot-Marie-Tooth disease (CMT) caused by mutations in the neurofilament light polypeptide gene (NEFL).MethodsCombined analysis of newly identified patients with NEFL-related CMT and all previously reported cases from the literature.ResultsFive new unrelated patients with CMT carrying the NEFL mutations P8R and N98S and the novel variant L311P were identified. Combined data from these cases and 62 kindreds from the literature revealed four common mutations (P8R, P22S, N98S and E396K) and three mutational hotspots accounting for 37 (55%) and 50 (75%) kindreds, respectively. Eight patients had de novo mutations. Loss of large-myelinated fibres was a uniform feature in a total of 21 sural nerve biopsies and ‘onion bulb’ formations and/or thin myelin sheaths were observed in 14 (67%) of them. The neurophysiological phenotype was broad but most patients with E90K and N98S had upper limb motor conduction velocities <38 m/s. Age of onset was ≤3 years in 25 cases. Pyramidal tract signs were described in 13 patients and 7 patients were initially diagnosed with or tested for inherited ataxia. Patients with E90K and N98S frequently presented before age 3 years and developed hearing loss or other neurological features including ataxia and/or cerebellar atrophy on brain MRI.Conclusions NEFL-related CMT is clinically and genetically heterogeneous. Based on this study, however, we propose mutational hotspots and relevant clinical–genetic associations that may be helpful in the evaluation of NEFL sequence variants and the differential diagnosis with other forms of CMT.

Pyruvate dehydrogenase complex (PDC) deficiency caused by mutations in the X-linked PDHA1 gene has a broad clinical presentation, and the pattern of X-chromosome inactivation has been proposed as a major factor contributing to its variable expressivity in heterozygous females. Here, we report the first set of monozygotic twin females with PDC deficiency, caused by a novel, de novo heterozygous missense mutation in exon 11 of PDHA1 (NM_000284.3: c.1100A>T). Both twins presented in infancy with a similar clinical phenotype including developmental delay, episodes of hypotonia or encephalopathy, epilepsy, and slowly progressive motor impairment due to pyramidal, extrapyramidal, and cerebellar involvement. However, they exhibited clear differences in disease severity that correlated well with residual PDC activities (approximately 60% and 20% of mean control values, respectively) and levels of immunoreactive E1α subunit in cultured skin fibroblasts. To address whether the observed clinical and biochemical differences could be explained by the pattern of X-chromosome inactivation, we undertook an androgen receptor assay in peripheral blood. In the less severely affected twin, a significant bias in the relative activity of the two X chromosomes with a ratio of approximately 75:25 was detected, while the ratio was close to 50:50 in the other twin. Although it may be difficult to extrapolate these results to other tissues, our observation provides further support to the hypothesis that the pattern of X-chromosome inactivation may influence the phenotypic expression of the same mutation in heterozygous females and broadens the clinical and genetic spectrum of PDC deficiency.

Paramyotonia congenita (PMC) and sodium channel myotonia (SCM) have been considered as phenotypically distinct diseases since the potassium aggravated myotonias were first described. They are marked by the presence and absence of weakness and thought to have distinctive neurophysiology patterns. However there is little phenotypic data published comparing large groups of these patients. We investigated a large cohort of 137 patients with mutations in the sodium channel, SCN4A, to identify phenotypic differences between these groups. We found that, whilst there were distinct differences between those patients with Hyperkalaemic periodic paralysis and PMC/SCM, there were no significant phenotypic differences between PMC and SCM patients. This was both when comparing patients with and without episodes of weakness and comparing those with distinct neurophysiology patterns. We therefore propose that PMC and SCM, whilst being separate from Hyperkalaemic periodic paralysis, are part of a spectrum of the same disease and that patients are more likely to lie at a particular point on that spectrum depending on their specific genotype.

Biallelic mutations in the SBF1 gene have been identified in one family with demyelinating Charcot-Marie-Tooth disease (CMT4B3) and two families with axonal neuropathy and additional neurological and skeletal features. Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209_2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features. Pathogenicity of these variants is supported by co-segregation and in silico analyses and evolutionary conservation. Our findings suggest that SBF1 mutations may cause a syndromic form of autosomal recessive axonal neuropathy (AR-CMT2) in addition to CMT4B3.

Biallelic mutations in the HINT1 gene were recently identified as the cause of axonal neuropathy with neuromyotonia. It has been suggested that HINT1 mutations may indeed account for 11 % of all inherited neuropathies with autosomal recessive inheritance. However, 81 % of patients HINT 1-related neuropathies reported to date are originally from five European countries and the global prevalence of the disorder is still unknown. In our study, we aimed to determine the frequency of HINT1 mutations by direct sequencing in a cohort of 152 patients with inherited neuropathies from the UK and Spain, where no cases have been described to date. We failed to identify patients with clinical myotonia, neuromyotonia or pathogenic mutations in HINT1 . Our results support that HINT1 -related neuropathies are not homogeneously distributed among European populations, which may be explained by founder effects. This geographical variability also underlines the importance of considering the ethnic background when screening for mutations in neuropathy-related genes.