Search

This is a long-term open follow-up of a prospective double-blind crossover study, where electrodes were bilaterally implanted in both the Subthalamic nucleus (STN) and internal pallidum (GPi) in patients with isolated dystonia.Patients with isolated dystonia were included to undergo surgery with Deep Brain stimulation (DBS) and after randomization, in a double-blind cross-over study, receiving bilateral stimulation of either STN or GPi for 6 months in each target. Preoperative and postoperative assessments with the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the 36-item Short Form Health Survey (SF-36) were performed. In this long-term follow-up (LFU), these ratings were repeated, and patients were evaluated with cognitive tests.21 patients were included in the protocol, 9 patients with generalized dystonia, 12 with a diagnosis of cervical dystonia. The mean duration of disease was 19.3 years, age at time of surgery 50.1 years. Fourteen patients participated in the LFU. At a mean follow-up of 10.2 years (range 4.8-15.4), BFMDRS movement score was improved with a mean of 36% (p 0.05) compared with baseline. At LFU both a statistically significant improvement of stimulation in STN on BFMDRS movement score (p = 0.029) and Gpi (p = 0.008) was demonstrated, no significant difference was found between the two targets (p = 0.076). SF-36 improved for both targets.In this study we performed a long-term follow-up in 14 patients with cervical or generalized dystonia, who received stimulation in GPi, STN or both. The mean follow-up time was more than 10 years. Our data support a long-term effect of both STN-DBS and GPi-DBS in dystonia with equal effect and safety for up to 15 years. STN has been proven a viable safe and effective target and may be used as an alternative to GPi in both adult-onset cervical dystonia and generalized dystonia.

Neuroserpin is a serine protease inhibitor identified in a search for proteins implicated in neuronal axon growth and synapse formation. Since its discovery over 30 years ago, it has been the focus of active research. Many efforts have concentrated in elucidating its neuroprotective role in brain ischemic lesions, the structural bases of neuroserpin conformational change and the effects of neuroserpin polymers that underlie the neurodegenerative disease FENIB (familial encephalopathy with neuroserpin inclusion bodies), but the investigation of the physiological roles of neuroserpin has increased over the last years. In this review, we present an updated and critical revision of the current literature dealing with neuroserpin, covering all aspects of research including the expression and physiological roles of neuroserpin, both inside and outside the nervous system; its inhibitory and non-inhibitory mechanisms of action; the molecular structure of the monomeric and polymeric conformations of neuroserpin, including a detailed description of the polymerisation mechanism; and the involvement of neuroserpin in human disease, with particular emphasis on FENIB. Finally, we briefly discuss the identification by genome-wide screening of novel neuroserpin variants and their possible pathogenicity.

The investigation of genetic forms of juvenile neurodegeneration could shed light on the causative mechanisms of neuronal loss. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome caused by mutations in the SETBP1 gene, inducing the accumulation of its protein product. SGS features multi-organ involvement with severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here we introduce a human SGS model that displays disease-relevant phenotypes. We show that SGS neural progenitors exhibit aberrant proliferation, deregulation of oncogenes and suppressors, unresolved DNA damage, and resistance to apoptosis. Mechanistically, we demonstrate that high SETBP1 levels inhibit P53 function through the stabilization of SET, which in turn hinders P53 acetylation. We find that the inheritance of unresolved DNA damage in SGS neurons triggers the neurodegenerative process that can be alleviated either by PARP-1 inhibition or by NAD + supplementation. These results implicate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis., Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome characterized by severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here the authors introduce a human SGS model that displays disease-relevant phenotypes to demonstrate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.

Background: Huntington Disease-Like 2 (HDL2) is a rare autosomal dominant disorder caused by an abnormal CAG/CTG triplet repeat expansion on chromosome 16q24. The symptoms of progressive decline in motor, cognitive and psychiatric functioning are similar to those of Huntington’s disease (HD). The psychiatric features of the HDL2 have been poorly characterized. Objective: To describe the neuropsychiatric features of HDL2 and compare them with those of HD. Methods: A blinded cross-sectional design was used to compare the behavioural component of the Unified Huntington’s Disease Rating Scale (UHDRS) in participants with HDL2 (n = 15) and HD (n = 13) with African ancestry. Results: HDL2 patients presented with psychiatric symptoms involving mood disturbances and behavioural changes that were not significantly different from those in the HD group. Duration of disease and motor performance correlated (p

Spastic paraplegia 35 (SPG35) (OMIM: 612319) or fatty acid hydroxylase-associated neurodegeneration (FAHN) is caused by deficiency of fatty acid 2-hydroxylase (FA2H). This enzyme synthesizes sphingolipids containing 2-hydroxylated fatty acids, which are particularly abundant in myelin. Fa2h-deficient (Fa2h−/−) mice develop symptoms reminiscent of the human disease and therefore serve as animal model of SPG35. In order to understand further the pathogenesis of SPG35, we compared the proteome of purified CNS myelin isolated from wild type and Fa2h−/− mice at different time points of disease progression using tandem mass tag labeling. Data analysis with a focus on myelin membrane proteins revealed a significant increase of the oligodendrocytic myelin paranodal and inner loop protein (Opalin) in Fa2h−/− mice, whereas the concentration of other major myelin proteins was not significantly changed. Western blot analysis revealed an almost 6-fold increase of Opalin in myelin of Fa2h−/− mice aged 21–23 months. A concurrent unaltered Opalin gene expression suggested a decreased turnover of the Opalin protein in Fa2h−/− mice. Supporting this hypothesis, Opalin protein half-life was reduced significantly when expressed in CHO cells synthesizing 2-hydroxylated sulfatide, compared to cells synthesizing only non-hydroxylated sulfatide. Degradation of Opalin was inhibited by inhibitors of lysosomal degradation but unaffected by proteasome inhibitors. Taken together, these results reveal a new function of 2-hydroxylated sphingolipids namely affecting the turnover of a myelin membrane protein. This may play a role in the pathogenesis of SPG35.

Background: The diagnostic workup for choreiform movement disorders including Huntington’s disease (HD) and those mimicking HD like phenotype is complex. Objective: The aim of the present study was to genetically define HD and HD-like presentations in an Indian cohort. We also describe HTT-CAG expansion manifesting as neuroferritinopathy-like disorder in four families from Punjab in India. Materials and methods: 159 patients clinically diagnosed as HD and HD-like presentations from various tertiary neurology clinics were referred to our centre (CSIR-IGIB) for genetic investigations. As a first tier test, CAG-TNR for HTT was performed and subsequently HD-negative samples were screened for JPH3 (HDL2), TBP (SCA17), ATN1 (DRPLA), PPP2R2B (SCA12) and GGGGCC expansion in C9orf72 gene. Four families presenting as neuroferritinopathy-like disorder were also investigated for HTT-CAG expansion. Results: 94 of 159 (59%) patients were found to have expanded HTT-CAG repeats. Pathogenic repeat expansion in JPH3, TBP, ATN1 and C9orf72 were not found in HD negative cases. Two patients were positive for SCA12-CAG expansion in pathogenic length, whereas 5 cases harboured TBP-CAG repeats falling in reduced penetrance range of 41– 48 repeats for SCA17. Four unrelated families, presented with atypical chorea and brain MRI findings suggestive of basal ganglia abnormalities mimicking neuroferritinopathy were found to harbour HTT-CAG expansion. Conclusion: We present SCA12 as a new reported phenocopy of HD which should be considered for diagnostic workout along with SCA17 for HD-like syndromes. This study also illustrates the necessity, to consider evolving HD like phenotype, as a clinical diagnosis for cases with initial manifestations depicting neuroferritinopathy.

The polyglutamine (polyQ) diseases are a group of inherited neurodegenerative diseases that include Huntington’s disease, various spinocerebellar ataxias, spinal and bulbar muscular atrophy, and dentatorubral pallidoluysian atrophy. They are caused by the abnormal expansion of a CAG repeat coding for the polyQ stretch in the causative gene of each disease. The expanded polyQ stretches trigger abnormal β-sheet conformational transition and oligomerization followed by aggregation of the polyQ proteins in the affected neurons, leading to neuronal toxicity and neurodegeneration. Disease-modifying therapies that attenuate both symptoms and molecular pathogenesis of polyQ diseases remain an unmet clinical need. Here we identified arginine, a chemical chaperone that facilitates proper protein folding, as a novel compound that targets the upstream processes of polyQ protein aggregation by stabilizing the polyQ protein conformation. We first screened representative chemical chaperones using an in vitro polyQ aggregation assay, and identified arginine as a potent polyQ aggregation inhibitor. Our in vitro and cellular assays revealed that arginine exerts its anti-aggregation property by inhibiting the toxic β-sheet conformational transition and oligomerization of polyQ proteins before the formation of insoluble aggregates. Arginine exhibited therapeutic effects on neurological symptoms and protein aggregation pathology in Caenorhabditis elegans, Drosophila, and two different mouse models of polyQ diseases. Arginine was also effective in a polyQ mouse model when administered after symptom onset. As arginine has been safely used for urea cycle defects and for mitochondrial myopathy, encephalopathy, lactic acid and stroke syndrome patients, and efficiently crosses the blood–brain barrier, a drug-repositioning approach for arginine would enable prompt clinical application as a promising disease-modifier drug for the polyQ diseases.

We aimed to clarify the correlations between motor symptoms and obsessive–compulsive symptoms and between the volumes of basal ganglia components and obsessive–compulsive symptoms. We retrospectively included 14 patients with medically intractable, moderate and severe generalized dystonia. The Burke–Fahn–Marsden Dystonia Rating Scale and Maudsley Obsessional Compulsive Inventory were used to evaluate the severity of dystonia and obsessive–compulsive symptoms, respectively. Patients with generalized dystonia were divided into two groups; patients whose Maudsley Obsessional Compulsive Inventory score was lower than 13 (Group 1) and 13 or more (Group 2). Additionally, the total Maudsley Obsessional Compulsive Inventory scores in patients with dystonia were significantly higher than normal volunteers’ scores (p = 0.025). Unexpectedly, Group 2 (high Maudsley Obsessional Compulsive Inventory scores) showed milder motor symptoms than Group 1 (low Maudsley Obsessional Compulsive Inventory scores) (p = 0.016). “Checking” rituals had a strong and significant negative correlation with the Burke–Fahn–Marsden Dystonia Rating Scale (ρ = − 0.71, p = 0.024) and a strong positive correlation with the volumes of both sides of the nucleus accumbens (right: ρ = 0.72, p = 0.023; left: ρ = 0.70, p = 0.034). Our results may provide insights into the pathogenesis of obsessive–compulsive disorder and dystonia.

Mitochondrial DNA depletion syndromes (MDS) are clinically heterogenous and often severe diseases, characterized by a reduction of the number of copies of mitochondrial DNA (mtDNA) in affected tissues. In the context of MDS, yeast has proved to be both an excellent model for the study of the mechanisms underlying mitochondrial pathologies and for the discovery of new therapies via high-throughput assays. Among the several genes involved in MDS, it has been shown that recessive mutations in MPV17 cause a hepatocerebral form of MDS and Navajo neurohepatopathy. MPV17 encodes a non selective channel in the inner mitochondrial membrane, but its physiological role and the nature of its cargo remains elusive. In this study we identify ten drugs active against MPV17 disorder, modelled in yeast using the homologous gene SYM1. All ten of the identified molecules cause a concomitant increase of both the mitochondrial deoxyribonucleoside triphosphate (mtdNTP) pool and mtDNA stability, which suggests that the reduced availability of DNA synthesis precursors is the cause for the mtDNA deletion and depletion associated with Sym1 deficiency. We finally evaluated the effect of these molecules on mtDNA stability in two other MDS yeast models, extending the potential use of these drugs to a wider range of MDS patients.

International audience; Background and aims: The identification of underlying genes of genetic conditions has expanded greatly in the past decades, which has broadened the field of genes responsible for inherited neuromuscular diseases. We aimed to investigate mutations associated with neuromuscular disorders phenotypes in 2 Moroccan families.Material and methods: Next-generation sequencing combined with Sanger sequencing could assist with under-standing the hereditary variety and underlying disease mechanisms in these disorders. Results: Two novel homozygous mutations were described in this study. The SIL1 mutation is the first identified in the Moroccan population, the mutation was identified as the main cause of Marinesco-Sjogren syndrome in one patient. While the second mutation identified in the fatty acid 2-hydroxylase gene (FA2H) was associated with the Spastic paraplegia 35 in another patient, both transmitted in an autosomal recessive pattern.Discussion and conclusions: These conditions are extremely rare in the North African population and may be underdiagnosed due to overlapping clinical characteristics and heterogeneity of these diseases. We have reported in this study mutations associated with the diseases found in the patients. In addition, we have narrowed the phenotypic spectrum, as well as the diagnostic orientation of patients with neuromuscular disorders, who might have very similar symptoms to other disease groups.

A possible role for calcium signalling in the autosomal dominant form of dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB), has been proposed, which may point towards a mechanism by which cells could sense and respond to the accumulation of mutant serpin polymers in the endoplasmic reticulum (ER). We therefore explored possible defects in Ca2+-signalling, which may contribute to the pathology associated with another serpinopathy, α1-antitrypsin (AAT) deficiency. Using CHO K1 cell lines stably expressing a wild type human AAT (MAAT) and a disease-causing polymer-forming variant (ZAAT) and the truncated variant (NHK AAT), we measured basal intracellular free Ca2+, its responses to thapsigargin (TG), an ER Ca2+-ATPase blocker, and store-operated Ca2+-entry (SOCE). Our fura2 based Ca2+ measurements detected no differences between these 3 parameters in cell lines expressing MAAT and cell lines expressing ZAAT and NHK AAT mutants. Thus, in our cell-based models of α1-antitrypsin (AAT) deficiency, unlike the case for FENIB, we were unable to detect defects in calcium signalling.

The mitochondrion is an essential organelle important for the generation of ATP for cellular function. This is especially critical for cells with high energy demands, such as neurons for signal transmission and cardiomyocytes for the continuous mechanical work of the heart. However, deleterious reactive oxygen species are generated as a result of mitochondrial electron transport, requiring a rigorous activation of antioxidative defense in order to maintain homeostatic mitochondrial function. Indeed, recent studies have demonstrated that the dysregulation of antioxidant response leads to mitochondrial dysfunction in human degenerative diseases affecting the nervous system and the heart. In this review, we outline and discuss the mitochondrial and oxidative stress factors causing degenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and Friedreich’s ataxia. In particular, the pathological involvement of mitochondrial dysfunction in relation to oxidative stress, energy metabolism, mitochondrial dynamics, and cell death will be explored. Understanding the pathology and the development of these diseases has highlighted novel regulators in the homeostatic maintenance of mitochondria. Importantly, this offers potential therapeutic targets in the development of future treatments for these degenerative diseases.

The national protocol of genetic counselling and pre-symptomatic testing for late-onset neurological diseases began in Portugal in 1995. Initially, it was accessible only to adults at-risk for Machado-Joseph disease, but was later extended to other hereditary ataxias, to Huntington's disease and to familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene. The aim of this study was to describe the profile of the population seeking pre-symptomatic testing, while also reflecting on the experience of conducting the protocol of multidisciplinary sessions since 1996.We conducted a retrospective study and collected data from clinical records of consultands who requested pre-symptomatic testing at our centre in Porto (Portugal) during the first twenty years of practice (1996 - 2015).A total of 1446 records were reviewed. The most common reason for testing was to reduce uncertainty (41.7%). The rate of withdrawals before results disclosure was lower (16%) than reported in other international experiences with pre-symptomatic testing, while 45% of the consultands dropped out the protocol after learning the test results (73.5% of them were non-carriers). As far as the mutation carriers were concerned, 29.6% adhered to the protocol a year after test disclosure. Consultands that had learned about presymptomatic testing through healthcare professionals tended to adhere more to pre-symptomatic testing consultations.The profile of Portuguese consultands at risk for late-onset neurological diseases is similar to those reported in other international programs. The largest group in this data set was the one comprising the subjects at risk for familial amyloid polyneuropathy caused by Val30Met mutation at the transthyretin gene, and it is likely that therapeutic options for this condition may have influenced this result. Adherence to pre-symptomatic testing may change in the future since effective therapies are available (or given the fact that people think effective treatments are imminent).This study reflects the first comprehensive description of a Portuguese experience with pre-symptomatic testing for late onset neurological diseases. The development of innovative approaches to improve the consultands' experience with pre-symptomatic testing and their engagement in genetic departments is still a challenge in Portuguese genetics healthcare departments. A better coordination among primary care and genetics healthcare services is needed.Introdução: Em 1995 foi iniciado em Portugal um protocolo nacional para o aconselhamento genético e teste pré-sintomático de doenças neurológicas de início tardio. Inicialmente, foi disponibilizado para indivíduos adultos em risco para a doença de Machado-Joseph e posteriormente estendido a outras ataxias hereditárias, doença de Huntington e polineuropatia amiloidótica familiar ATTR Val30Met. O objetivo deste estudo é descrever o perfil dos consultandos envolvidos no teste pré-sintomático desde 1996, e refletir no protocolo de sessões multidisciplinares. Material e Métodos: Realizámos um estudo retrospetivo com recolha de dados dos processos clínicos dos utentes que solicitaram teste pré-sintomático ao longo dos primeiros 20 anos do Centro de Genética Preditiva e Preventiva (1996 - 2015), localizado no Porto, Portugal. Resultados: Analisámos um total de 1446 processos clínicos; a principal motivação para a realização do teste pré-sintomático foi o alívio da incerteza (41,7%). A taxa de abandono do protocolo antes da comunicação dos resultados do pré-sintomático (16% dos casos) foi mais baixa do que em outras experiências internacionais; 45% dos consultandos abandonaram o protocolo depois de saberem o resultado do teste pré-sintomático (73,5% dos quais eram não-portadores). 29,6% de consultandos portadores continuaram envolvidos no protocolo um ano após saberem o resultado do teste pré-sintomático. Os consultandos encaminhados para o protocolo através de outros profissionais de saúde revelaram maior adesão ao protocolo. Discussão: O perfil sociodemográfico dos consultandos no Centro de Genética Preditiva e Preventiva é similar ao reportado noutras experiências internacionais. Os consultandos em risco para polineuropatia amiloidótica familiar ATTR Val30Met representaram o maior grupo nos nossos dados, sendo provável que as opções terapêuticas disponíveis para esta doença tenham influenciado este resultado. A adesão ao teste pré-sintomático poderá alterar-se no futuro quando terapias eficazes estiverem disponíveis (ou as pessoas as percepcionem como estando iminentes). Conclusão: Este trabalho constitui a descrição mais completa até ao momento publicada acerca da realização de teste pré-sintomático em Portugal. O desenvolvimento de abordagens com vista à melhoria da experiência dos consultandos com os testes pré-sintomáticos e ao seu envolvimento nos serviços de genética é um desafio atual, assim como a melhor articulação dos mesmos com os cuidados de saúde primários.

Facial-onset sensory and motor neuronopathy (FOSMN) syndrome represents a rare, slowly progressive, lower motor neuron disease with sensory compromise, involving mainly the face, bulbar region and upper limbs. However, non-motor symptoms and neurogenetic studies have rarely been evaluated in large case series. In the present study, 10 unrelated Brazilian patients with FOSMN syndrome underwent extensive clinical, laboratory, neurophysiological and neurogenetic assessment. Median age at symptom onset was 52.1 years, and men and women were equally affected. Patients presented with hemifacial or bilateral facial paresthesia and weakness, which evolved with dysphagia, dysphonia, and facial and tongue atrophy and, finally, a dropped-head, upper limb weakness and syringomyelia-like sensory disturbances in the upper limbs. All 10 patients showed chronic diffuse neurogenic compromise of bulbar, cervical and thoracic myotomes, and abnormal blink reflex tests. A positive family history of neurodegeneration was identified in six cases, and revealed pathogenic gene variants in three families (involving VCP, TARDBP and CHCHD10). Thus, our case series has revealed new findings regarding FOSMN syndrome: (i) its clinical course is not always benign, with poorer prognoses associated with dropped-head syndrome and early bulbar compromise; (ii) FOSMN syndrome may be part of a complex familial neurodegenerative spectrum; and (iii) a definite genetic basis may be observed in some cases.

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a rare childhood onset neurodegenerative disease caused by mutations in the FA2H gene. Patients display abnormal myelination, cerebellar atrophy and some have iron deposition in the central nervous system. Here we describe the generation of AKOSi010-A, a human induced pluripotent stem cell (hiPSC) line derived from fibroblasts of a female patient carrying the compound heterozygous p.Gly45Arg/p.His319Arg, using non-integrating Sendai virus. The generated iPSCs express pluripotency markers, can differentiate into cell types of the three germ layers and show a normal karyotype. This cell line displays a unique source to study the pathophysiology of FAHN.

The cavus foot deformity is an often less understood deformity within the spectrum of foot and ankle conditions. The hallmark concern is the possibility of an underlying neurologic or neuromuscular disorder. Although a proportion of these deformities are idiopathic, a significant majority do correlate with an underlying disorder. The appropriate evaluation of this deformity, in coordination within the multidisciplinary scope of health care, allows for a timely diagnosis and understanding of the patient's condition. We provide an abbreviated survey of possible underlying etiologies for the patient with the cavus foot deformity as a reference to the foot and ankle surgeon.

Funder: Pasteur Institute – Cenci Bolognetti Foundation, Funder: Sapienza University of Rome, Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a progressive neurodegenerative disease caused by point mutations in the gene for neuroserpin, a serine protease inhibitor of the nervous system. Different mutations are known that are responsible for mutant neuroserpin polymerization and accumulation as inclusion bodies in many cortical and subcortical neurons, thereby leading to cell death, dementia and epilepsy. Many efforts have been undertaken to elucidate the molecular pathways responsible for neuronal death. Most investigations have concentrated on analysis of intracellular mechanisms such as endoplasmic reticulum (ER) stress, ER-associated protein degradation (ERAD) and oxidative stress. We have generated a HEK-293 cell model of FENIB by overexpressing G392E-mutant neuroserpin and in this study we examine trafficking and toxicity of this polymerogenic variant. We observed that a small fraction of mutant neuroserpin is secreted via the ER-to-Golgi pathway, and that this release can be pharmacologically regulated. Overexpression of the mutant form of neuroserpin did not stimulate cell death in the HEK-293 cell model. Finally, when treating primary hippocampal neurons with G392E neuroserpin polymers, we did not detect cytotoxicity or synaptotoxicity. Altogether, we report here that a polymerogenic mutant form of neuroserpin is secreted from cells but is not toxic in the extracellular milieu.

Gangliosides are expressed on plasma membranes throughout the body and enriched in the nervous system. A critical role for complex a- and b-series gangliosides in central and peripheral nervous system ageing has been established through transgenic manipulation of enzymes in ganglioside biosynthesis. Disrupting GalNAc-transferase (GalNAc-T), thus eliminating all a- and b-series complex gangliosides (with consequent over-expression of GM3 and GD3) leads to an age-dependent neurodegeneration. Mice that express only GM3 ganglioside (double knockout produced by crossing GalNAc-T-/- and GD3 synthase-/- mice, Dbl KO) display markedly accelerated neurodegeneration with reduced survival. Degenerating axons and disrupted to the node of Ranvier architecture are key features of complex ganglioside-deficient mice. Previously, we have shown that reintroduction of both a- and b-series gangliosides into neurons on a global GalNAcT -/- background is sufficient to rescue this age-dependent neurodegenerative phenotype. To determine the relative roles of a- and b-series gangliosides in this rescue paradigm, we herein reintroduced GalNAc-T into neurons of Dbl KO mice, thereby reconstituting a-series but not b-series complex gangliosides. We assessed survival, axon degeneration, axo-glial integrity, inflammatory markers, and lipid-raft formation in these Rescue mice compared to wild type and Dbl KO mice. We found that this neuronal reconstitution of a-series complex gangliosides abrogated the adult lethal phenotype in Dbl KO mice, and partially attenuated the neurodegenerative features. This suggests that whilst neuronal expression of a-series gangliosides is critical for survival during ageing, it is not entirely sufficient to restore complete nervous system integrity in the absence of either b-series or glial a-series gangliosides.

Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.

Ataxia and Male Sterility (AMS) is a mutant mouse strain that contains a missense mutation in the coding region of Nna1, a gene that encodes a deglutamylase. AMS mice exhibit early cerebellar Purkinje cell degeneration and an ataxic phenotype in an autosomal recessive manner. To understand the underlying mechanism, we generated neuronal stem cell (NSC) lines from wild-type (NMW7), Nna1 mutation heterozygous (NME), and Nna1 mutation homozygous (NMO1) mouse brains. The NNA1 levels were decreased, and the glutamylated tubulin levels were increased in NMO1 cultures as well as in the cerebellum of AMS mice at both 15 and 30 days of age. However, total &beta, tubulin protein levels were not altered in the AMS cerebellum. In NMO1 neurosphere cultures, &beta, tubulin protein levels were increased without changes at the transcriptional level. NMO1 grew faster than other NSC lines, and some of the neurospheres were attached to the plate after 3 days. Immunostaining revealed that SOX2 and nestin levels were decreased in NMO1 neurospheres and that the neuronal differentiation potentials were reduced in NMO1 cells compared to NME or NMW7 cells. These results demonstrate that the AMS mutation decreased the NNA1 levels and increased glutamylation in the cerebellum of AMS mice. The observed changes in glutamylation might alter NSC properties and the neuron maturation process, leading to Purkinje cell death in AMS mice.

This article provides an overview of Charcot-Marie-Tooth disease (CMT) and other inherited neuropathies. These disorders encompass a broad spectrum with variable motor, sensory, autonomic, and other organ system involvement. Considerable overlap exists, both phenotypically and genetically, among these separate categories, all eventually exhibiting axonal injury and neurologic impairment. Depending on the specific neural and non-neural localizations, patients experience varying morbidity and mortality. Neurologic evaluations, including neurophysiologic testing, can help diagnose and predict patient disabilities. Diagnosis is often complex, especially when genetic and acquired components overlap.Next-generation sequencing has greatly improved genetic diagnosis, with many third-party reimbursement parties now embracing phenotype-based panel evaluations. Through the advent of comprehensive gene panels, symptoms previously labeled as idiopathic or atypical now have a better chance to receive a specific diagnosis. A definitive molecular diagnosis affords patients improved care and counsel. The new classification scheme for inherited neuropathies emphasizes the causal gene names. A specific genetic diagnosis is important as considerable advances are being made in gene-specific therapeutics. Emerging therapeutic approaches include small molecule chaperones, antisense oligonucleotides, RNA interference, and viral gene delivery therapies. New therapies for hereditary transthyretin amyloidosis and Fabry disease are discussed.Comprehensive genetic testing through a next-generation sequencing approach is simplifying diagnostic algorithms and affords significantly improved decision-making processes in neuropathy care. Genetic diagnosis is essential for pathogenic understanding and for gene therapy development. Gene-targeted therapies have begun entering the clinic. Currently, for most inherited neuropathy categories, specific symptomatic management and family counseling remain the mainstays of therapy.

Huntington Disease Like-2 (HDL2) is a rare autosomal dominant genetic disease caused by a mutation in the JPH3 gene. HDL2 is the Huntington Disease (HD) phenocopy that has the greatest clinical resemblance to HD. Both are characterized by movement, psychiatric and cognitive dysfunction, which progress to dementia. The present study compared the neuropsychological profile of HDL2 with that of HD. Using a Single Case-Control Methodology in Neuropsychology, three HDL2 and seven matched HD patients were assessed with a comprehensive neuropsychological battery and compared to matched control samples, considering age, years of education, type of school (public/government) and language (all bi/multilingual). Potential double dissociations were explored by using Crawford, Garthwaite, and Wood's Inferential Methods for Comparing the Scores of Two Single-Cases in Case-Control Designs. Double dissociation between HDL2 and HD were identified in three tests, namely Letter Number Sequencing, Rey Auditory Learning Test Delayed and Recognition Trials. These dissociations possible are due to methodological limitations.

Gene therapy has become promising in many fields of medicine, as a single treatment could allow long-lasting and curative benefits. New medicines based on cell gene correction are expected to occur in upcoming years and will be hopefully part of the therapeutic armamentarium for inherited and acquired diseases. Issues related to the costs of these new therapies and access to care for all patients, and procedures and expertise needed to facilitate their application worldwide require to be addressed, together with long-term safety and efficacy monitoring.

Polyglutamine diseases are a set of progressive neurodegenerative disorders caused by misfolding and aggregation of mutant CAG RNA and polyglutamin protein. To date, there is a lack of effective therapeutics that can counteract the polyglutamine neurotoxicity. Two peptidylic inhibitors, QBP1 and P3, targeting the protein and RNA toxicities, respectively, have been previously demonstrated by us with combinational therapeutic effects on the Drosophila polyglutamine disease model. However, their therapeutic efficacy has never been investigated in vivo in mammals. The current study aims to (a) develop a brain-targeting delivery system for both QBP1 and L1P3V8 (a lipidated variant of P3 with improved stability) and (b) evaluate their therapeutic effects on the R6/2 transgenic mouse model of polyglutamine disease. Compared with intravenous administration, intranasal administration of QBP1 significantly increased its brain-to-plasma ratio. In addition, employment of a chitosan-containing in situ gel for the intranasal administration of QBP1 notably improved its brain concentration for up to 10-fold. Further study on intranasal cotreatment with the optimized formulation of QBP1 and L1P3V8 in mice found no interference on the brain uptake of each other. Subsequent efficacy evaluation of 4-week daily QBP1 (16 μmol/kg) and L1P3V8 (6 μmol/kg) intranasal cotreatment in the R6/2 mice demonstrated a significant improvement on the motor coordination and explorative behavior of the disease mice, together with a full suppression on the RNA- and protein-toxicity markers in their brains. In summary, the current study developed an efficient intranasal cotreatment of the two peptidylic inhibitors, QBP1 and L1P3V8, for their brain-targeting, and such a novel therapeutic strategy was found to be effective on a transgenic polyglutamine disease mouse model.

MPV17 encodes a putative channel-forming protein of the inner mitochondrial membrane and is involved in mitochondrial deoxynucleotide homeostasis. MPV17 mutations were first reported in patients with Navajo neurohepatopathy, an autosomal recessive mitochondrial DNA depletion syndrome, characterized by early-onset liver failure, failure to thrive as well as central and peripheral neurological involvement. Recently, two patients with juvenile-onset peripheral sensorimotor neuropathy associated with an MVP17 c.122G>A (p.Arg41Gln) variant have been reported. Here, we describe five additional patients from two unrelated families with sensorimotor axonal neuropathy without hepatocerebral affection caused by homozygous MPV17 variants. Patients of the first family carried the known c.122G>A variant and affected individuals of the second family had a novel c.376-9T>G near-splice variant, which was shown to result in an in-frame deletion of 11 amino acids. This report provides further evidence that MPV17 mutations should be considered in patients with pure, non-syndromic axonal neuropathy.

Background: Intestinal degenerative neuropathy without extra-intestinal involvement occurs as familial forms (FIDN) but the genetics behind is unknown. We studied a Swedish family with autosomal do...

Huntington disease (HD) is a progressive neurodegenerative disease, characterised by a triad of movement disorder, emotional and behavioural disturbances and cognitive impairment. The underlying cause is an expanded CAG repeat in the huntingtin gene. For a small proportion of patients presenting with HD-like symptoms, the mutation in this gene is not identified and they are said to have a HD “phenocopy”. South Africa has the highest number of recorded cases of an African-specific phenocopy, Huntington disease-like 2 (HDL2), caused by a repeat expansion in the junctophilin-3 gene. However, a significant proportion of black patients with clinical symptoms suggestive of HD still test negative for HD and HDL2. This study thus aimed to investigate five other loci associated with HD phenocopy syndromes - ATN1, ATXN2, ATXN7, TBP and C9orf72. In a sample of patients in whom HD and HDL2 had been excluded, a single expansion was identified in the ATXN2 gene, confirming a diagnosis of Spinocerebellar ataxia 2. The results indicate that common repeat expansion disorders do not contribute significantly to the HD-like phenotype in black South African patients. Importantly, allele sizing reveals unique distributions of normal repeat lengths across the associated loci in the African population studied.