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A broad mutational spectrum in the dystrophin ( DMD ) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD , adding to the diversity of mutational events that give rise to D/BMD., Competing Interests: The authors declare no conflict of interest.

Background: Chorea may occur as a manifestation of an acute stroke. Patients with vascular-related chorea typically present with an acute or subacute onset of hemichorea, contralateral to the lesion., Methods and Findings: In this clinico-pathological case, we report a 90-year-old female who presented, at age 81, with a transient episode of generalized chorea. Over the years, the patient continued to have intermittent episodes of generalized chorea or hemichorea, followed by a progressive dementia syndrome with gait and sphincter disturbance. There was no family history of chorea or dementia. Laboratory tests for paraneoplastic or autoimmune disorders and genetic testing for Huntington's disease were normal or negative. Magnetic resonance imaging showed subcortical and basal ganglia atrophy associated with ischemic leukoencephalopathy and lacunar infarcts. The post-mortem examination identified multiple lacunar infarcts (cortex, white matter, thalamus, basal ganglia) and minor Alzheimer's disease neuropathological changes., Conclusions: Vascular disease, affecting the basal ganglia, is included in most lists of causes of generalized chorea. Proven cases are difficult to find. We present a rare case of vascular pathology causing late onset generalized and intermittent chorea. We highlight the intermittent nature of the chorea that could be explained by cumulative vascular lesions or functional disconnection in a previous deficient circuit.

Introduction: Carpal tunnel syndrome (CTS) is a nonspecific manifestation of hereditary ATTR amyloidosis (ATTRm). Amyloid deposition of wild-type TTR (WT-ATTR) has been found in transverse carpal ligament (TCL) in idiopathic CTS. We retrospectively studied a group of patients with ATTRm and CTS submitted to carpal tunnel release surgery (CTRS)., Methods: From the nerve conduction studies performed in our Clinical Unit dedicated to hereditary amyloidosis between July 2009 and October 2013, we selected patients who fulfilled neurophysiological criteria for CTS, had been submitted to CTRS and whose TCL was available for pathology. Clinical registries were reviewed and amyloid detection in the ligaments was performed using Congo-red staining., Results: We included 16 patients: three males (18.8%), mean age = 46.1 years old, all with V30M mutation. At the time of surgery, four patients were considered asymptomatic and 12 symptomatic carriers, five of them late-onset ATTRm (onset age >50 years old). In all but one patient, the CTS preceded the polyneuropathy. Amyloid detection in the TCL was positive in 14 patients (87.5%)., Discussion/conclusions: In most patients, CTS preceded or was contemporary to the polyneuropathy and amyloid detection in TCL was positive. The detection of amyloid in TCL may add specificity to CTS as an early manifestation of the disease but more studies are needed.

Introduction: The association of myasthenia gravis (MG) and inflammatory myopathy is rare and often only one of the diseases is diagnosed. Thymus pathology may be in the origin of such disease association., Methods: We described four patients with both MG and inflammatory myopathy., Results: These cases correspond to 2.3% of our MG cohort. Case 1: MG, polymyositis and thymolipoma; case 2: MG and necrotizing myopathy without thymic pathology on a background of scleroderma, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia (CREST); case 3: MG and dermatomyositis without thymic pathology; case 4: MG and dermatomyositis with type C thymoma., Discussion: The recognition of these neuromuscular co-morbidities contributes to (i) understanding their pathogenic mechanisms, (ii) developing better management approaches and (iii) further improving disease outcomes., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aims: Microglia-driven neuroinflammation can play an important role in the pathophysiology of neurodegenerative disorders. In this study, we sought to characterize the distribution of microglial cell activation in 2 neurodegenerative dementias with distinct protein signatures, Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) of the TDP subtype, and to determine if there was an anatomical correlation with the phenotypes most commonly associated with these conditions., Methods: The distribution and extent of microglial cell activation was assessed semiquantitatively in the hippocampal formation, cortical gray matter, and subcortical white matter of CD68-immunostained sections of the frontal, temporal, parietal, and occipital cortices from 15 pathologically confirmed cases of AD, 13 cases of FTLD, and 18 controls., Results: Significantly higher levels of microglial cell activation occurred in the subiculum in AD and FTLD than in controls. Additionally, AD had higher microglial activation in the CA1 and FTLD in the hippocampal white matter than the controls. Microglial activation was greater in the dentate gyrus molecular layer in AD than in FTLD. In the cortical regions, the 2 pathological groups differed only in frontal white matter, with the FTLD group showing higher microglial scores. FTLD showed higher microglial activation in the white matter compared to the respective gray matter in the entorhinal, temporal, and frontal regions., Conclusions: Our work expands the knowledge of the distribution and magnitude of microglial activation in these disorders. Additionally, we found some microglial circuit-specific patterns that could help to explain some of the clinical overlap between AD and FTLD-TDP, namely in memory deficits., (© 2017 S. Karger AG, Basel.)

Background: Pathogenic variants in ryanodine receptor type 1 (RYR1) gene are an important cause of congenital myopathy. The clinical, histopathologic and genetic spectrum is wide., Objective: Review a group of the patients diagnosed with ryanodinopathy in a tertiary centre from North Portugal, as an attempt to define some phenotypical patterns that may help guiding future diagnosis., Methods: Patients were identified from the database of the reference centre for Neuromuscular Disorders in North Portugal. Their data (clinical, histological and genetic) was retrospectively accessed., Results: Seventeen RYR1-related patients (including 4 familial cases) were identified. They were divided in groups according to three distinctive clinical characteristics: extraocular muscle (EOM) weakness (N = 6), disproportionate axial muscle weakness (N = 2) and joint laxity (N = 5). The fourth phenotype includes patients with mild tetraparesis and no distinctive clinical features (N = 4). Four different histopathological patterns were found: centronuclear (N = 5), central core (N = 4), type 1 fibres predominance (N = 4) and congenital fibre type disproportion (N = 1) myopathies. Each index case, except two patients, had a different RYR1 variant. Four new genetic variants were identified. All centronuclear myopathies were associated with autosomal recessive inheritance and EOM weakness. All central core myopathies were caused by pathogenic variants in hotspot 3 with autosomal dominant inheritance. Three genetic variants were reported to be associated to malignant hyperthermia susceptibility., Conclusions: Distinctive clinical features were recognized as diagnostically relevant: extraocular muscle weakness (and centronuclear pattern on muscle biopsy), severe axial weakness disproportionate to the ambulatory state and mild tetraparesis associated with (proximal) joint laxity. There was a striking genetic heterogeneity, including four new RYR1 variants.

Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) manifests by migraine with aura, cerebral ischemic events, mood disturbances and dementia. Brain MRI lesions typically precede the symptoms from 10 to 15 years and previous evidence showed all CADASIL patients above 35 years old have an abnormal MRI, supporting the clinical diagnosis. Case results We present a 37-year-old female patient with migraine without aura, a family history of CADASIL, normal brain 3-Tesla MRI and normal skin biopsy, even though a pathogenic NOTCH3 gene mutation (allele 2, exon 11, c.1672 C\gtT, p.Arg558Cys) was detected. Conclusions When CADASIL is strongly suspected, a normal brain MRI, even in the fourth decade of life, does not rule out the diagnosis and should not discourage the genetic test.

Background: Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease., Discussion: Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimer's disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimer's disease, vascular dementia and mixed Alzheimer's disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue., Conclusion: Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses.

Mutations in DJ-1 (encoded by PARK7) are a very rare cause of early-onset recessive Parkinson's disease. We describe a patient with early-onset parkinsonism, starting at the age of 22, with poor response to levodopa and additional features in progression (dystonia, pyramidal signs and dementia), who died when he was 49 years old. The neuropathological study showed severe substantia nigra and locus coeruleus neuronal loss, with diffuse Lewy body pathology (Lewy bodies, aberrant neurites, grain-like structures, spheroids and scattered glial pathology). Genetic analysis revealed a novel c.515T > A; p.L172Q mutation in the PARK7 gene. To evaluate the pathogenicity of this new mutation we explored DJ-1 expression levels in vitro showing a massive reduction in DJ-1 protein levels due to a highly unstable and rapidly degraded L172Q mutant. DJ-1 immunohistochemistry of brain tissue revealed no staining in our case. This is the first neuropathological report of a brain from DJ-1-linked parkinsonism that, although based on a single case study, suggests that DJ-1 mutations are causative of α-synucleinopathy. These results can help in the understanding of Parkinson's disease pathophysiology, promote research studies to increase the knowledge on the pathways involved in the neurodegeneration process, and pave the way for new therapeutic interventions., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Congenital myopathies (CMs) are a heterogeneous group of muscle diseases characterized by hypotonia, delayed motor skills and muscle weakness with onset during the first years of life. The diagnostic workup of CM is highly dependent on the interpretation of the muscle histology, where typical pathognomonic findings are suggestive of a CM but are not necessarily gene specific. Over 20 loci have been linked to these myopathies, including three exceptionally large genes (TTN, NEB and RYR1), which are a challenge for molecular diagnosis. We developed a new approach using massive parallel sequencing (MPS) technology to simultaneously analyze 20 genes linked to CMs. Assay design was based on the Ion AmpliSeq strategy and sequencing runs were performed on an Ion PGM system. A total of 12 patients were analyzed in this study. Among the 2534 variants detected, 14 pathogenic mutations were successfully identified in the DNM2, NEB, RYR1, SEPN1 and TTN genes. Most of these had not been documented and/or fully characterized, hereby contributing to expand the CM mutational spectrum. The utility of this approach was demonstrated by the identification of mutations in 70% of the patients included in this study, which is relevant for CMs especially considering its wide phenotypic and genetic heterogeneity.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and is the most common cause of dementia worldwide. Cumulative data suggests that neuroinflammation plays a prominent and early role in AD, and there is compelling data from different research groups of age-associated dysregulation of the neuroimmune system. From the clinical point of view, despite clinical resemblance and neuropathological findings, there are important differences between the group of patients with sporadic early-onset (<65 years old) and late-onset AD (>65 years old). Thus, it seems important to understand the age-dependent relationship between neuroinflammation and the underlying biology of AD in order to identify potential explanations for clinical heterogeneity, interpret biomarkers, and promote the best treatment to different clinical AD phenotypes. The study of the delicate balance between pro-inflammatory or anti-inflammatory sides of immune players in the different ages of onset of AD would be important to understand treatment efficacy in clinical trials and eventually, not only direct treatment to early disease stages, but also the possibility of establishing different treatment approaches depending on the age of the patient. In this review, we would like to summarize what is currently known about the interplay between "normal" age associated inflammatory changes and AD pathological mechanisms, and also the potential differences between early-onset and late-onset AD taking into account the age-related neuroimmune background at disease onset.

Cytomegalovirus (CMV) is the most common congenital viral infection, causing hearing, visual and psychomotor impairment. Preexisting maternal CMV immunity substantially reduces, but not eliminates, the risk of fetal infection and affectation. This article is about a case of nonprimary maternal CMV infection during pregnancy, with vertical transmission, resulting in severe fetal affectation. Preconceptional analysis indicated maternal CMV past infection. Pregnancy progressed uneventfully until the 20th week ultrasound (US), which revealed cerebral abnormalities: thin and hyperechogenic cerebral cortex with prominent lateral ventricles, bilateral periventricular hyperechogenicities, cerebellar vermis hypoplasia and absent corpus callosum. The MRI suggested these findings were compatible with congenital infection rather than primary brain malformation.The fetal karyotype was normal. The title of CMV's IgG antibodies almost tripled. Since the first semester, analysis of the polymerase chain reaction (PCR) for CMV DNA in the amniotic fluid was negative. The pregnancy was terminated at 23 weeks. Neuropathological findings at autopsy showed severe brain lesions associated with CMV infection., (Thieme Publicações Ltda Rio de Janeiro, Brazil.)

Background: Alpha-synuclein (α-Syn) is particularly abundant in the vermiform appendix, which makes this structure an anatomical candidate for the initiation of Parkinson's disease (PD) pathology. We hypothesized that history of appendectomy might affect PD clinical onset., Methods: A total of 295 PD patients enrolled in a comprehensive observational study were asked about past history of appendectomy. Cox's regression, with a time-dependent covariate, explored the effects of appendectomy on age at PD onset., Results: Thirty-four patients (11.5%) had appendectomy before PD onset. There was no significant effect of appendectomy on age at PD onset for the entire cohort (P = 0.153). However, among patients with late onset (≥55 years), we found evidence that those with past appendectomy had more years of life without PD symptoms than patients without appendectomy (P = 0.040). No association was found for the young-onset group (P = 0.663)., Conclusions: An apparent relationship was observed between appendectomy and PD onset in the late PD cohort., (© 2015 International Parkinson and Movement Disorder Society.)

Muscular dystrophies (MDs) are a group of hereditary muscle disorders that include two particularly heterogeneous subgroups: limb-girdle MD and congenital MD, linked to 52 different genes (seven common to both subgroups). Massive parallel sequencing technology may avoid the usual stepwise gene-by-gene analysis. We report the whole-exome sequencing (WES) analysis of a patient with childhood-onset progressive MD, also presenting mental retardation and dilated cardiomyopathy. Conventional sequencing had excluded eight candidate genes. WES of the trio (patient and parents) was performed using the ion proton sequencing system. Data analysis resorted to filtering steps using the GEMINI software revealed a novel silent variant in the choline kinase beta (CHKB) gene. Inspection of sequence alignments ultimately identified the causal variant (CHKB:c.1031+3G>C). This splice site mutation was confirmed using Sanger sequencing and its effect was further evaluated with gene expression analysis. On reassessment of the muscle biopsy, typical abnormal mitochondrial oxidative changes were observed. Mutations in CHKB have been shown to cause phosphatidylcholine deficiency in myofibers, causing a rare form of CMD (only 21 patients reported). Notwithstanding interpretative difficulties that need to be overcome before the integration of WES in the diagnostic workflow, this work corroborates its utility in solving cases from highly heterogeneous groups of diseases, in which conventional diagnostic approaches fail to provide a definitive diagnosis.

Introduction: Leprosy is still one of the most frequent causes of peripheral neuropathy. Although regarded as eradicated in Portugal, is still documented in neuropathological study of patients with clinical peripheral neuropathy without proper diagnosis., Material and Methods: Review of the cases of Hansen disease neuropathy diagnosed in Neuropathology Unit of Centro Hospitalar do Porto between 1978 and 2013, atending to gender, age, clinical manifestations and neuropathological findings., Results: Twenty one patients were identified with neuropathological diagnosis of Hansenâs disease neuropathy, predominantly male. The mean age at diagnosis was 52 years, and sensory symptoms predominate as neurological manifestation of disease. Interval between symptoms and diagnosis was 1-38 years. In most nerve samples tuberculoid type of disease was identified. Bacilli were detected in skin and nerve in 44% of cases., Discussion: Mononeuritis is the most common presentation of leprosy but other clinical manifestations are possible, including skin lesions. Infection with M. leprae injures myelinated and unmyelinated fibres, with replacement of nerve tissue by collagen fibrosis. The diagnosis of leprosy is only achieved by neuropathological study of skin lesions and / or peripheral nerve, supported by the identification of the bacillus., Conclusion: Hansen disease remains a public health problem in tropical areas and, although rare, still described in Western countries reason why should still be considered as a diagnostic possibility in the investigation of peripheral neuropathy.

Objectives: Since liver transplant (LT) was introduced to treat patients with familial amyloid polyneuropathy carrying the V30M mutation (ATTR-V30M), ocular and cardiac complications have developed. Long-term central nervous system (CNS) involvement was not investigated. Our goals were to: (1) identify and characterise focal neurological episodes (FNEs) due to CNS dysfunction in ATTR-V30M patients; (2) characterise neuropathological features and temporal profile of CNS transthyretin amyloidosis., Methods: We monitored the presence and type of FNEs in 87 consecutive ATTR-V30M and 35 non-ATTR LT patients. FNEs were investigated with CT scan, EEG and extensive neurovascular workup. MRI studies were not performed because all patients had cardiac pacemakers as part of the LT protocol. We characterised transthyretin amyloid deposition in the brains of seven ATTR-V30M patients, dead 3-13 years after polyneuropathy onset., Results: FNEs occurred in 31% (27/87) of ATTR-V30M and in 5.7% (2/35) of the non-ATTR transplanted patients (OR=7.0, 95% CI 1.5 to 33.5). FNEs occurred on average 14.6 years after disease onset (95% CI 13.3 to 16.0) in ATTR-V30M patients, which is beyond the life expectancy of non-transplanted ATTR-V30M patients (10.9, 95% CI 10.5 to 11.3). ATTR-V30M patients with FNEs had longer disease duration (OR=1.24; 95% CI 1.07 to 1.43), renal dysfunction (OR=4.65; 95% CI 1.20 to 18.05) and were men (OR=3.57; 95% CI 1.02 to 12.30). CNS transthyretin amyloidosis was already present 3 years after polyneuropathy onset and progressed from the meninges and its vessels towards meningocortical vessels and the superficial brain parenchyma, as disease duration increased., Conclusions: Our findings indicate that CNS clinical involvement occurs in ATTR-V30M patients regardless of LT. Longer disease duration after LT can provide the necessary time for transthyretin amyloidosis to progress until it becomes clinically relevant. Highly sensitive imaging methods are needed to identify and monitor brain ATTR. Disease modifying therapies should consider brain TTR as a target., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Mutations in ryanodine receptor 1 gene (RYR1) are frequent causes of myopathies. They classically present with central core disease; however, clinical variability and histopathologic overlap are being increasingly recognized., Patients: Patient 1 is a 15-year-old girl with mild proximal, four-limb weakness from age 5, presenting with a progressive scoliosis starting at age 10. Patient 2 is an 18-year-old girl with progressively worsening muscle hypotrophy and mild proximal, four-limb weakness. She developed a rapidly progressive scoliosis from age 11 and needed surgical treatment at age 14 years. Patient 3 is an 11-year-old boy with moderate proximal limb weakness and progressive neck flexor weakness, first noticed at age 2. Muscle biopsies revealed type 1 fiber predominance (Patients 1 and 2) or abnormal type 1 fiber uniformity (Patient 3). Different RYR1 variants were identified in all patients. In Patients 1 and 3, these changes were validated as being pathogenic., Conclusions: These patients illustrate early-onset, progressive myopathies with predominant axial involvement. Histopathologic findings were abnormal but not specific for a diagnosis, particularly central core myopathy. Genetic testing helped broaden the range of phenotypes included in the RYR1-related myopathies. Our patients reinforce the need to recognize the broad histopathologic variability of RYR1-related myopathies and sometimes lack of pathognomonic findings that may reduce the diagnostic threshold of this disease. We suggest that the predominance of type 1 fibers and involvement of axial muscles may be an important element to consider the RYR1 gene as candidate., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Glioblastoma is a malignant infiltrative glial tumor occurring most often over 50 years of age, with diverse clinical presentations. We describe a case of temporal lobe glioblastoma with a rare presentation as an acute ischemic stroke, discussing the imaging and histopathological findings, and reviewing the literature. A 77-year-old woman had sudden onset of left hemiparesis and hemihypoesthesia. The neuroradiological studies revealed an acute ischemic lesion in the right lenticulostriate arteries territory and a right anterior temporal lobe tumor, enhancing heterogeneously after contrast with enhancement of the right middle cerebral artery wall. Histopathological analysis of the resected temporal lesion revealed a glioblastoma multiforme with tumoral infiltration of the vascular wall. Glioblastoma should be considered in the etiology of acute ischemic stroke, where neuroimaging plays an important diagnostic role, enabling a more immediate therapeutic approach, with a consequent impact on survival.

McArdle disease typically presents in childhood or young adults with myalgia, exercise intolerance, cramps and myoglobinuria. Deficiency of myophosphorylase enzyme results in inability to degrade glycogen stores, causing glycogen accumulation in muscle tissue and energy deficit. Evolution with rhabdomiolysis may occur and can be complicated with acute kidney injury but rarely, in about 11% of cases, is the initial disease manifestation. We report a case of McArdle Disease in a 38-year-old male patient. The disease went unrecognized despite previous symptoms (myalgia, exercise intolerance and single myoglobinuria episode) until an episode of rhabdomyolisis complicated with oliguric acute kidney injury requiring hemodialysis. The kidney biopsy showed evidence of acute tubular necrosis. Despite normalization of renal function, muscle lysis markers remained abnormal. Metabolic myopathy was suspected and a muscle biopsy was performed. It showed subsarcolemic glycogen deposition and absence of myophosphorylase activity. This case-report underlines the importance of considering metabolic myopathy in patients with acute kidney injury and severe rhabdomyolisis.

Importance: The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. Recently, Rademakers and colleagues identified mutations in the CSF1R gene as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), offering the possibility for an in-life diagnosis. The detection of mutations in this gene in cases diagnosed with different clinical entities further demonstrated the difficulties in the clinical diagnosis of HDLS., Objective: To better understand the genetic role of mutations in this gene, we sequenced a large cohort of adult-onset leukodystrophy cases., Design: Whole-exome sequencing and follow up-screening by Sanger sequencing., Setting: Collaborative study between the Institute of Neurology, University College London and the Inserm, Paris, France., Participants: A total of 114 probands, mostly European patients, with a diagnosis of adult-onset leukodystrophy or atypical cases that could fit within a picture of leukodystrophy. These included 3 extended families within the spectrum of leukodystrophy phenotype., Interventions: Whole-exome sequencing in a family and Sanger sequencing of CSF1R., Main Outcomes and Measures: Mutations in CSF1R., Results: We identified 12 probands with mutations in CSF1R. The clinical diagnoses given to these patients included dementia with spastic paraplegia, corticobasal degeneration syndrome, and stroke disorders. Our study shows that CSF1R mutations are responsible for a significant proportion of clinically and pathologically proven HDLS., Conclusions and Relevance: These results give an indication of the frequency of CSF1R mutations in a European leukodystrophy series and expand the phenotypic spectrum of disorders that should be screened for this gene.

Complex III of the mitochondrial respiratory chain (CIII) catalyzes transfer of electrons from reduced coenzyme Q to cytochrome c. Low biochemical activity of CIII is not a frequent etiology in disorders of oxidative metabolism and is genetically heterogeneous. Recently, mutations in the human tetratricopeptide 19 gene (TTC19) have been involved in the etiology of CIII deficiency through impaired assembly of the holocomplex. We investigated a consanguineous Portuguese family where four siblings had reduced enzymatic activity of CIII in muscle and harbored a novel homozygous mutation in TTC19. The clinical phenotype in the four sibs was consistent with severe olivo-ponto-cerebellar atrophy, although their age at onset differed slightly. Interestingly, three patients also presented progressive psychosis. The mutation resulted in almost complete absence of TTC19 protein, defective assembly of CIII in muscle, and enhanced production of reactive oxygen species in cultured skin fibroblasts. Our findings add to the array of mutations in TTC19, corroborate the notion of genotype/phenotype variability in mitochondrial encephalomyopathies even within a single family, and indicate that psychiatric manifestations are a further presentation of low CIII.

Myotubular myopathy (MIM#310400), the X-linked form of Centronuclear myopathy (CNM) is mainly characterized by neonatal hypotonia and inability to maintain unassisted respiration. The MTM1 gene, responsible for this disease, encodes myotubularin - a lipidic phosphatase involved in vesicle trafficking regulation and maturation. Recently, it was shown that myotubularin interacts with desmin, being a major regulator of intermediate filaments. We report the development of a locus-specific database for MTM1 using the Leiden Open Variation database software (http://www.lovd.nl/MTM1), with data collated for 474 mutations identified in 472 patients (by June 2012). Among the entries are a total of 25 new mutations, including a large deletion encompassing introns 2-15. During database implementation it was noticed that no large duplications had been reported. We tested a group of eight uncharacterized CNM patients for this specific type of mutation, by multiple ligation-dependent probe amplification (MLPA) analysis. A large duplication spanning exons 1-5 was identified in a boy with a mild phenotype, with results pointing toward possible somatic mosaicism. Further characterization revealed that this duplication causes an in-frame deletion at the mRNA level (r.343&#95;444del). Results obtained with a next generation sequencing approach suggested that the duplication extends into the neighboring MAMLD1 gene and subsequent cDNA analysis detected the presence of a MTM1/MAMLD1 fusion transcript. A complex rearrangement involving the duplication of exon 10 has since been reported, with detection also enabled by MLPA analysis. It is thus conceivable that large duplications in MTM1 may account for a number of CNM cases that have remained genetically unresolved.

Intravascular large B-cell lymphoma (IVLBCL) is a rare lymphoproliferative disorder characterized by massive intravascular growth of lymphoma cells with a predilection for the central nervous system (CNS). Diagnosis is generally delayed by variable clinical presentation and nonspecific laboratory findings. Brain biopsy is the gold standard diagnostic test. Prognosis is poor with a high mortality rate. We report a case of "in vivo" diagnosis of IVLBCL presenting with rapidly progressive encephalopathy secondary to multiple cerebral infarcts. This case highlights IVLBCL as a possible cause of unexplained multifocal and recurrent strokes. Earlier diagnosis and consequent earlier treatment may be associated with better prognosis., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Hereditary neuropathy with liability to pressure palsy is characterized by acute, painless, recurrent mononeuropathies secondary to minor trauma or compression. A 16-year-old boy had the first episode of right foot drop after minor motorcycle accident. Electromyography revealed conduction block and slowing velocity conduction of the right deep peroneal nerve at the fibular head. After motor rehabilitation, he fully recovered. Six months later he had the second episode of foot drop in the opposite site after prolonged squatting position. Electromyography revealed sensorimotor polyneuropathy of left peroneal, sural, posterior tibial, and deep peroneal nerves and also of ulnar, radial, and median nerves of both upper limbs. Histological examination revealed sensory nerve demyelination and focal thickenings of myelin fibers. The diagnosis of hereditary neuropathy with liability to pressure palsy was confirmed by PMP22 deletion of chromosome 17p11.2. He started motor rehabilitation and avoidance of stressing factors with progressive recovery. After one-year followup, he was completely asymptomatic. Recurrent bilateral foot drop history, "sausage-like" swellings of myelin in histological examination, and the results of electromyography led the authors to consider the diagnosis despite negative family history. The authors highlight this rare disease in pediatric population and the importance of high index of clinical suspicion for its diagnosis.

Gastrointestinal symptoms are frequent in familial amyloid polyneuropathy, mainly resulting from autonomic nervous system involvement. Dysphagia is one of the possible symptoms, although rarely severe or sudden. We describe a case of a sudden onset and severe dysphagia, a rare form of presentation, in a patient whose polyneuropathy was still beeing investigated and turned out to be ATTRVal30Met-polyneuropathy.

We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5-intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.

Neurodegenerative dementias are a group of neurological disorders characterized by deterioration in several cognitive domains in which there is selective and progressive loss of specific populations of neurons. The precise neurobiological basis for the different neurodegenerative dementias remains unknown. It is expected that different pathologies reflect different mechanisms, at least early in the neurodegeneration process. The next decades promise treatments directed to causes and mechanisms, bringing an outstanding challenge to clinicians due to heterogeneous clinical presentations with the same molecular pathology. The purpose of this brief review is to describe the key neuropathological features of the most common neurodegenerative dementias (Alzheimer disease, dementia with Lewy bodies and Parkinson's disease dementia, and frontotemporal lobar degeneration) and the relationship with the clinical syndromes described in clinico-pathological studies. We expect this overview contributes for the understanding of this broad topic integrating the two ends of the spectrum: clinical and pathological.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) can be present with negative family history and, especially in younger patients, with normal brain magnetic resonance. For this reason, those CADASIL patients that present only with migraine may be misdiagnosed. In the case of migraine with motor aura, sporadic hemiplegic migraine (SHM) is one of the possible misdiagnoses., Case Results: We present a case of a patient who, in the first years of her disease, met the clinical criteria for SHM. A diagnosis of CADASIL was considered only when her sister presented with headache and an unknown leukoencephalopathy., Conclusions: This case illustrates the need for a careful review of the clinical and family history during the follow-up of primary headaches.

Background: Gliomatosis cerebri is a specific entity defined as a diffuse neoplastic glial cell infiltration of the brain, preserving the architecture of the normal surrounding tissues, involving more than 2 cerebral lobes. Clinical symptoms or radiologic features are nonspecific, and patients are often misdiagnosed with other neurologic diseases., Review Summary: Here, we report the diagnostic workup of 2 patients with gliomatosis cerebri, discussing the clinical, radiologic, and pathologic findings. Case 1: a 64-year-old woman who presented with an intracranial hypertension syndrome and had symmetrical white matter T2-weighted and fluid-attenuated inversion recovery hyperintensities pattern on magnetic resonance imaging; and case 2: a 54-year-old man with the diagnosis of multiple sclerosis for 8 years who presented with de novo cognitive impairment and focal deficits., Conclusions: This report highlights the difficulty of this differential diagnosis and the need of considering it also in the presence of a symmetrical pattern of white matter involvement. Cerebral biopsy remains crucial for the correct diagnosis and treatment approach.

Acute hemorrhagic leukoencephalitis (AHLE) is a rare and fulminant demyelinating disease considered to be the most severe form of acute disseminated encephalomyelitis (ADEM). A 70-year-old man was admitted to our emergency department (ED) after 1 week of unspecific abdominal symptoms and moderate fever in the first 3 days. Within the ED he developed a rapid onset coma and flaccid tetraparesis. Cerebrospinal fluid (CSF) analysis showed mild polymorphonuclear pleocytosis and magnetic resonance imaging (MRI) revealed supratentorial focal white matter lesions and diffuse involvement of the medulla and spinal cord. A presumptive diagnosis of ADEM was made and the patient was treated with corticosteroids followed by intravenous immunoglobulin. His neurological state did not improve and the MRI on day 8 after admission showed an increased number of lesions, mainly in the brainstem, with hemorrhagic foci. The patient died the following day and pathological features confirmed the diagnosis of AHLE. This is a unique presentation of a rare disease with detailed MRI characteristics and pathological confirmation. Although this condition is usually fatal, early recognition and aggressive therapeutic management can facilitate survival., (Copyright © 2011 Wiley-Liss, Inc.)

Acquisition of new perceptual-motor skills depends on multiple brain areas, including the striatum. However, the specific contribution of each structure to this type of learning is still poorly understood. Focusing on the striatum, we proposed (a) to replicate the finding of impaired rotary pursuit (RP) and preserved mirror tracing (MT) in Huntington's disease (HD); and (b) to further explore this putative learning dissociation with other human models of striatal dysfunction (i.e., Parkinson's disease and focal vascular damage) and two new paradigms (i.e., Geometric Figures, GF, and Control Stick, CS) of skill learning. Regardless of the etiology, participants with damage to the striatum showed impaired learning of visuomotor tracking skills (i.e., RP and GF), whereas the ability to learn skills that require motor adaptation (i.e., MT and CS) was not affected. These results suggest a task-specific involvement of the striatum in the early stages of skill learning.

Cerebrovascular and cardiovascular diseases are the leading causes of death and disability worldwide. They are complex disorders resulting from the interplay of genetic and environmental factors, and may share several susceptibility genes. Several recent studies have implicated variants of the Kalirin (KALRN) gene with susceptibility to cardiovascular and metabolic phenotypes, but no studies have yet been performed in stroke patients. KALRN is involved, among others, in the inhibition of inducible nitric oxide synthase, in the regulation of ischemic signal transduction, and in neuronal morphogenesis, plasticity, and stability. The goal of the present study was to determine whether SNPs in the KALRN region on 3q13, which includes the Ropporin gene (ROPN1), predispose to ischemic stroke (IS) in a cohort of Portuguese patients and controls. We genotyped 34 tagging SNPs in the KALRN and ROPN1 chromosomal region on 565 IS patients and 517 unrelated controls, and performed genotype imputation for 405 markers on chromosome 3. We tested the single-marker association of these SNPs with IS. One SNP (rs4499545) in the ROPN1-KALRN intergenic region and two SNPs in KALRN (rs17286604 and rs11712619) showed significant (P < 0.05) allelic and genotypic (unadjusted and adjusted for hypertension, diabetes, and ever smoking) association with IS risk. Thirty-two imputed SNPs also showed an association at P < 0.05, and actual genotyping of three of these polymorphisms (rs7620580, rs6438833, and rs11712039) validated their association. Furthermore, rs11712039 was associated with IS (0.001 < P < 0.01) in a recent well-powered genomewide association study (Ikram et al. 2009). These studies suggest that variants in the KALRN gene region constitute risk factors for stroke and that KALRN may represent a common risk factor for vascular diseases.

Background: The genetic contribution to stroke is well established but it has proven difficult to identify the genes and the disease-associated alleles mediating this effect, possibly because only nuclear genes have been intensely investigated so far. Mitochondrial DNA (mtDNA) has been implicated in several disorders having stroke as one of its clinical manifestations. The aim of this case-control study was to assess the contribution of mtDNA polymorphisms and haplogroups to ischemic stroke risk., Methods: We genotyped 19 mtDNA single nucleotide polymorphisms (SNPs) defining the major European haplogroups in 534 ischemic stroke patients and 499 controls collected in Portugal, and tested their allelic and haplogroup association with ischemic stroke risk., Results: Haplogroup H1 was found to be significantly less frequent in stroke patients than in controls (OR = 0.61, 95% CI = 0.45-0.83, p = 0.001), when comparing each clade against all other haplogroups pooled together. Conversely, the pre-HV/HV and U mtDNA lineages emerge as potential genetic factors conferring risk for stroke (OR = 3.14, 95% CI = 1.41-7.01, p = 0.003, and OR = 2.87, 95% CI = 1.13-7.28, p = 0.021, respectively). SNPs m.3010G>A, m.7028C>T and m.11719G>A strongly influence ischemic stroke risk, their allelic state in haplogroup H1 corroborating its protective effect., Conclusion: Our data suggests that mitochondrial haplogroup H1 has an impact on ischemic stroke risk in a Portuguese sample.

We previously demonstrated that hypercorticalism induces pronounced volumetric reductions in the rat medial prefrontal cortex (mPFC) and that these structural changes correlate with deficits in executive function. By applying 3-dimensional analysis of Golgi-Cox-stained material, we now demonstrate that corticosteroids can exert differential effects on dendritic arborizations of pyramidal neurons in lamina II/III of the mPFC. Treatment with the glucocorticoid receptor-selective agonist dexamethasone and with the natural adrenosteroid, corticosterone (CORT), results in significant reductions in the total length of apical dendrites in the pyramidal neurons in lamina II/III of the anterior cingulate/prelimbic and infralimbic cortices. Interestingly, although these treatments do not affect the number of dendritic branches, they are associated with impoverished arborizations in their distal portions and, in CORT-treated animals, with increased branching in the middle portions of the apical dendritic tree. Deprivation of corticosteroids by adrenalectomy leads to decreases in total apical dendritic length and spine number, but in this case, dendritic impoverishment was restricted to the middle/proximal segments of the dendritic trees. None of the treatments influenced the architecture of the basal dendrites. These results add to our knowledge of the morphological substrates through which corticosteroids may disrupt mPFC-dependent behaviors.

Imbalances in the corticosteroid milieu have been implicated in several neuropsychiatric disorders, including depression and schizophrenia. Prefrontal cortex (PFC) dysfunction is also a hallmark of these conditions, causing impairments in executive functions such as behavioral flexibility and working memory. Recent studies have suggested that the PFC might be influenced by corticosteroids released during stress. To test this possibility, we assessed spatial working memory and behavioral flexibility in rats submitted to chronic adrenalectomy or treatment with corticosterone (25 mg/kg) or the synthetic glucocorticoid dexamethasone (300 microg/kg); the behavioral analysis was complemented by stereological evaluation of the PFC (prelimbic, infralimbic, and anterior cingulate regions), the adjacent retrosplenial and motor cortices, and the hippocampal formation. Dexamethasone treatment resulted in a pronounced impairment in working memory and behavioral flexibility, effects that correlated with neuronal loss and atrophy of layer II of the infralimbic, prelimbic, and cingulate cortices. Exposure to corticosterone produced milder impairments in behavioral flexibility, but not in working memory, and reduced the volume of layer II of all prefrontal areas. Interestingly, adrenalectomy-induced deleterious effects only became apparent on the reverse learning task and were not associated with structural alterations in the PFC. None of the experimental procedures influenced the morphology of retrosplenial or motor cortices, but stereological measurements confirmed previously observed effects of corticosteroids on hippocampal structure. Our results describe, for the first time, that imbalances in the corticosteroid environment can induce degeneration of specific layers of the PFC; these changes appear to be the morphological correlate of corticosteroid-induced impairment of PFC-dependent behavior(s).