Characteristics Of Motoneurons Research Articles

Single Center Experience of RETREG1-related Hereditary Sensory Autonomic Neuropathy in Turkey (P11-8.009)

<h3>Objective:</h3> To describe the clinical characteristics of patients with <i>RETREG1</i> mutations. <h3>Background:</h3> Homozygous loss-of-function mutations in <i>RETREG1</i> result in Hereditary Sensory Autonomic Neuropathy (HSAN) Type 2. Clinical features include variable autonomic disturbances and upper motor neuron features such as brisk tendon reflexes, spasticity, and Babinski sign. <h3>Design/Methods:</h3> Herein, we evaluated the clinical and genetic features of 6 patients from 3 unrelated families with <i>RETREG1</i> mutation at the Neuromuscular Unit of the Istanbul Faculty of Medicine, Istanbul University. <h3>Results:</h3> Four patients were male. The median age of onset was 7.0 ± 2.5 (between 2 and 9 years). Foot ulcerations were the presenting symptom in four patients and walking difficulties in two. All patients were born to consanguineous marriages. In a median disease duration of 23.0 ± 14.4 years, four patients had osteomyelitis, and two had toe amputations. Five patients had a history of painless fractures in different lower extremity bones. Four patients had autonomic nervous system symptoms such as excessive sweating, constipation and orthostatism. Neurological examination of all patients showed spasticity, and brisk tendon reflexes. Muscle weakness in the lower extremities was noted in five patients. Sensory examination showed stocking type hypoesthesia and diminished vibration sensation in all patients. Five patients had pes planus deformity. Nerve conduction studies showed axonal sensory neuropathy in four patients and sensory-motor in two. Two families had homozygous c.433C&gt;T (p.Gln145*), and one had c.826delA (p.S276VfsX8) pathogenic variants in the <i>RETREG1</i> gene. <h3>Conclusions:</h3> In our study, all patients showed signs and symptoms consistent with pain insensitivity. Although shadowed by marked sensory symptoms, motor signs, such as spasticity, and muscle weakness, were also noted in our patients. Considering the autosomal recessive inheritance, new cases with <i>RETREG1</i> mutation are likely to be reported from Turkey, a country with a high rate of consanguineous marriages. <b>Disclosure:</b> Arman Cakar has nothing to disclose. Ms. BAGIROVA has nothing to disclose. Dr. Durmus has nothing to disclose. Prof. UYGUNER has nothing to disclose. Dr. Parman has nothing to disclose.

Paraneoplastic pure motor neuropathy in a 48-year-old male with recently diagnosed DLBCL (P3-8.014)

<h3>Objective:</h3> To report a case of paraneoplastic pure motor neuropathy associated with DLBCL <h3>Background:</h3> Paraneoplastic lower motor neuron disease is a rare clinical entity. Patient’s present with a slow progressive painless asymmetric weakness in the limbs and without upper motor neuron features. Neoplasms that are associated with this syndrome include: lymphoma, ovarian, breast, renal, and lung cancers. Usually, no paraneoplastic antibodies are identified. We report a case of a 48-year-old male with newly diagnosed DLBCL, a non-Hodgkin lymphoma (NHL), who presented with subacute painless asymmetric upper extremity weakness without clear sensory loss prior to initiation of any chemo or radiation therapy. Imaging of the bilateral plexus and cervical spine did not reveal enhancement or infiltration and cerebrospinal fluid studies were unrevealing. Electromyography provided evidence of a primarily demyelinating greater than axonal purely motor polyradiculoneuropathy limited to the arms. Neurological improvement was seen with intravenous immunoglobulin and treatment of malignancy. <h3>Design/Methods:</h3> N/A <h3>Results:</h3> N/A <h3>Conclusions:</h3> Upon literature review, a case of paraneoplastic purely motor neuron syndrome associated with an NHL such as DLBCL has not been described before. There have been reports of paraneoplastic neurological syndromes associated with NHL none of which were purely motor neuron disease. <i>Flanagan et al</i> reported a similar case of paraneoplastic motor neuron disease associated with a type of Hodgkin’s Lymphoma. Similarly, to their findings, we observed neurological improvement with concurrent IVIG and treatment of the underlying malignancy. This case highlights the continued role for documentation of peripheral neuropathies secondary paraneoplastic etiologies with goals to further characterize novel onconeural antibodies. <b>Disclosure:</b> Dr. Kolli has nothing to disclose. Dr. Ata has nothing to disclose. Dr. Hurst has nothing to disclose.

Novel Homozygous Variant in COQ7 in Siblings With Hereditary Motor Neuropathy.

Coenzyme Q10 (CoQ10) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ10), the second-to-last step in the CoQ10 biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A > G p.? variant of COQ7 with abnormal CoQ10 biosynthesis. Affected family members underwent clinical assessments that included nerve conduction testing, histologic analysis, and MRI. Pathogenicity of the COQ7 variant was assessed in cultured fibroblasts and skeletal muscle using a combination of immunoblots, respirometry, and quinone analysis. Three affected siblings, ranging from 12 to 24 years of age, presented with a severe length-dependent motor neuropathy with marked symmetric distal weakness and atrophy with normal sensation. Muscle biopsy of the quadriceps revealed chronic denervation pattern. An MRI examination identified moderate to severe fat infiltration in distal muscles. Exome sequencing demonstrated the homozygous COQ7 c.1A > G p.? variant that is expected to bypass the first 38 amino acid residues at the n-terminus, initiating instead with methionine at position 39. This is predicted to cause the loss of the cleavable mitochondrial targeting sequence and 2 additional amino acids, thereby preventing the incorporation and subsequent folding of COQ7 into the inner mitochondrial membrane. Pathogenicity of the COQ7 variant was demonstrated by diminished COQ7 and CoQ10 levels in muscle and fibroblast samples of affected siblings but not in the father, unaffected sibling, or unrelated controls. In addition, fibroblasts from affected siblings had substantial accumulation of DMQ10, and maximal mitochondrial respiration was impaired in both fibroblasts and muscle. This report describes a new neurologic phenotype of COQ7-related primary CoQ10 deficiency. Novel aspects of the phenotype presented by this family include pure distal motor neuropathy involvement, as well as the lack of upper motor neuron features, cognitive delay, or sensory involvement in comparison with cases of COQ7-related CoQ10 deficiency previously reported in the literature.

Novel neuron-Schwann cell co-culture models to study peripheral nerve degeneration and regeneration.

Novel neuron-Schwann cell co-culture models to study peripheral nerve degeneration and regeneration.

Pathological features of glial cells and motor neurons in the anterior horn of the spinal cord in sporadic ALS using ADAR2 conditional knockout mice

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective degeneration of motor neurons (MNs). In the MNs of patients with ALS, adenosine deaminase acting on RNA 2 (ADAR2)-mediated RNA editing of GluA2 mRNA at the Q/R site is profoundly deficient. In genetically modified mice (ADAR2flox/flox/VAChT-Cre.Fast; AR2), the selective knockout of ADAR2 in cholinergic neurons induced progressive loss of lower MNs. MNs exhibiting an age-related increase in abnormal TDP-43 localization and reduced ADAR2 immunoreactivity are localized in the lateral areas of the anterior horns (AHs) in aged wild-type mice. However, the patterns in the AHs of AR2 mice remain unknown. In this study, we investigated whether similar degeneration is observed in AR2 mice. We compared the number of astrocytes and MNs in the lateral and medial AHs of the lumbar spinal cord of 12-month-old AR2 mice with age-matched wild-type mice. The number of MNs significantly decreased in both the lateral and medial areas in AR2 mice AHs, particularly in the former. The number of reactive astrocytes increased significantly in the lateral areas of the AHs of AR2 mice. In conclusion, stronger activation of astrocytes with reduction of MNs in the ADAR2 deficiency-related lateral area increases in AR2 mice AHs. Fast fatigable MNs are expected to be present in the lateral area of the AHs. We found that MN death is more common in the lateral area of AHs associated with FF MNs due to differences in vulnerability to MN under ADAR2 deficiency.

Anti-Neurofascin Antibodies Associated with White Matter Diseases of the Central Nervous System: A Red Flag or a Red Herring?

Autoantibodies against nodal and paranodal proteins, specifically anti-neurofascin antibodies (ANFAs), have been recently described in central and peripheral nervous system demyelinating disorders. We retrospectively reviewed the charts of six individuals evaluated at our Multiple Sclerosis Program who tested positive for serum ANFAs on Western blot. We describe these patients’ clinical and diagnostic findings and attempt to identify features that might guide clinicians in checking for ANFAs. In our series, the women-to-men ratio was 2:1. At presentation, the median age was 60 years (range 30–70). The clinical presentation was pleiotropic and included incomplete transverse myelitis (n = 3), progressive myelopathy (n = 1), recurrent symmetric polyneuropathy (n = 1), and nonspecific neurological symptoms (n = 1). Atypical features prompting further workup included coexisting upper and lower motor neuron features, older age at presentation with active disease, atypical spinal cord MRI features, and unusual cerebrospinal fluid findings. The serum ANFAs panel was positive for the NF-155 isoform in five patients (IgM n = 2; IgG n = 2; both n = 1) and the NF-140 isoform in two (IgG n = 2). Larger studies are needed to assess the relevance of ANFAs in demyelinating nervous system diseases, their impact on long-term clinical outcomes, and associated therapeutic implications.

Rehabilitation of a young girl with acute transverse myelitis and prolonged lower motor neuron features: a longitudinal case report over 12 months

BackgroundThis report describes an effective rehabilitation programme for a 13-year-old girl, diagnosed with acute transverse myelitis, as an example of best clinical practice.Case descriptionMiss A was admitted to the National Institute of Neurosciences and Hospital in Dhaka, where she was diagnosed with acute transverse myelitis, in September 2018. She was discharged and referred for intensive rehabilitation over 3 months as an outpatient at the Centre for the Rehabilitation of the Paralysed in Bangladesh. The therapy team conducted a baseline assessment before starting treatment, which included the following outcome measures: the International Standards for Neurological Classification of Spinal Cord Injury Scale; Spinal Cord Independence Measure; and the Spinal Cord Injury Functional Ambulation Inventory. After 3 months, Miss A was discharged home to continue with a home exercise programme supported by her parents. Outcome measurements were repeated at 3-, 6- and 12-month time points.ResultsMiss A regained muscle power in her legs and normal sensation in S4/5 dermatomes, in addition to regaining voluntary anal muscle contraction. Her mobility and transfers improved so that she was able to transfer in and out of her wheelchair independently and use two elbow crutches to walk short distances outdoors.ConclusionsThis report shows that it is possible for a child who had been severely disabled by acute transverse myelitis to make substantial physical improvements up to 12 months after diagnosis when provided with effective rehabilitation. It also identifies that rehabilitation can provide multiple benefits and value for the individual patient, family, community and society.

Dual pathogenic mutations in SQSTM1 and C9orf72 as a cause of frontotemporal dementia

AbstractBackgroundHexanucleotide repeat expansions in the C9orf72 gene have been found to be the leading genetic cause of both familial frontotemporal dementia (FTD) and motor neuron disease (MND). However there are a number of other genetic causes of both FTD and MND including, less commonly, mutations in sequestosome 1 (SQSTM1) which codes for the cargo protein p62. Occasionally, people with FTD or MND have been described with dual pathogenic mutations, although this is rare.MethodWe describe the clinical and imaging features of a woman who presented with FTD and motor neurone involvement who was found to carry both a pathogenic C9orf72 expansion and a deleterious c.1185dup, p.Glu396* heterozygous SQSTM1 mutation.ResultSymptoms started at the age of 60 with change in personality and impaired behaviour followed at the age of 63 by prosopagnosia and semantic impairment. Brain magnetic resonance imaging showed right‐sided predominant temporal more than frontal lobe atrophy, and she was initially diagnosed with behavioural variant FTD. However at the age of 66 she developed asymmetrical limb weakness and stiffness, with upper motor neurone features only on examination, suggestive of primary lateral sclerosis (PLS). She deteriorated rapidly over the next couple of years, although never developed lower motor neurone features when subsequently examined. She died at the age of 69.ConclusionThe co‐presence of both a SQSTM1 mutation and C9orf72 expansion is rare. It remains unclear which mutation accounts for which of the features seen. Focal right temporal lobe atrophy is more common with SQSTM1 mutations, but PLS is uncommon with both mutations. It may be therefore that it is the dual mutations together that explain the altered phenotype. It is paramount to better understand the roles which SQSTM1 and C9orf72 mutations have on cellular pathways and how their combination results in rare phenotypes.

Pediatric Idiopathic Intracranial Hypertension Post-measles Vaccine: A Case Report

Idiopathic intracranial hypertension is characterized by an increase in intracranial pressure with no significant structural cause. The diagnostic criteria include general signs and symptoms of generalized increased intracranial pressure or papilledema, increased Cerebrospinal Fluid (CSF) pressure (&gt;250 mm H2 O), and normal brain imaging. It usually occurs in adults but rarely can be seen in children. We report a 7-year-old child with a manifestation of increased intracranial tension after the measles vaccine, associated with bilateral sixth nerve palsy and bilateral facial palsy with lower motor neuron features. Normal magnetic resonance imaging and CSF results were normal, except for an increase in CSF pressure. The symptoms began to be resolved after lumbar puncture with the complete resolution of symptoms after one and half months. We add also acetazolamide at the proper dose to reduce intracranial pressure from the first day of diagnosis.

Isolated Infarctions of the Conus Medullaris: Clinical Features and Outcomes

ObjectiveThis study aims to describe the clinical features and outcomes of patients with isolated infarctions of the conus medullaris, and to identify factors associated with poor functional outcomes. Materials and methodsWe performed a systematic review and retrospective analysis on the clinical characteristics and outcomes of patients with isolated conus medullaris infarctions reported in literature over the past 30 years. ResultsWe analyzed a total of 19 cases; 18 identified in literature from January 1991 to June 2021, together with our patient. Their median age was 56 years (range 28–79), with twice as many females as males. Pain was prominent at onset (15/19, 79%), only a third had vascular risk factors (7/19, 37%), and half had no significant preceding activities or events (9/19, 47%). Almost all experienced paraplegia or paraparesis (16/19, 84%), in which upper motor neuron features were rare (3/19, 16%). The underlying cause was unknown in half (10/19, 53%). Functional outcomes appeared fair, with nearly half being capable of unassisted ambulation (9/11, 82%). Patients with vascular risk factors (67% vs 13%, p = 0.024) or with identified underlying causes (78% vs 13%, p = 0.007) were less likely to walk unassisted. ConclusionIsolated conus medullaris but should be considered in patients with acute cauda equina syndrome, especially in females. Patients with vascular risk factors, or with known causes of infarction, are less likely to walk unassisted. DWI sequences should be included in conventional MRI sequences when evaluating patients with acute cauda equina syndrome.

Splicing factor proline and glutamine rich intron retention, reduced expression and aggregate formation are pathological features of amyotrophic lateral sclerosis.

Splicing factor proline and glutamine rich (SFPQ) is an RNA-DNA binding protein that is dysregulated in Alzheimer's disease and frontotemporal dementia. Dysregulation of SFPQ, specifically increased intron retention and nuclear depletion, has been linked to several genetic subtypes of amyotrophic lateral sclerosis (ALS), suggesting that SFPQ pathology may be a common feature of this heterogeneous disease. Our study aimed to investigate this hypothesis by providing the first comprehensive assessment of SFPQ pathology in large ALS case-control cohorts. We examined SFPQ at the RNA, protein and DNA levels. SFPQ RNA expression and intron retention were examined using RNA-sequencing and quantitative PCR. SFPQ protein expression was assessed by immunoblotting and immunofluorescent staining. At the DNA level, SFPQ was examined for genetic variation novel to ALS patients. At the RNA level, retention of SFPQ intron nine was significantly increased in ALS patients' motor cortex. In addition, SFPQ RNA expression was significantly reduced in the central nervous system, but not blood, of patients. At the protein level, neither nuclear depletion nor reduced expression of SFPQ was found to be a consistent feature of spinal motor neurons. However, SFPQ-positive ubiquitinated protein aggregates were observed in patients' spinal motor neurons. At the DNA level, our genetic screen identified two novel and two rare SFPQ sequence variants not previously reported in the literature. Our findings confirm dysregulation of SFPQ as a pathological feature of the central nervous system of ALS patients and indicate that investigation of the functional consequences of this pathology will provide insight into ALS biology.

Long-Term Suppression of c-Jun and nNOS Preserves Ultrastructural Features of Lower Motor Neurons and Forelimb Function after Brachial Plexus Roots Avulsion.

Brachial plexus root avulsions cause debilitating upper limb paralysis. Short-term neuroprotective treatments have reported preservation of motor neurons and function in model animals while reports of long-term benefits of such treatments are scarce, especially the morphological sequelae. This morphological study investigated the long-term suppression of c-Jun- and neuronal nitric oxide synthase (nNOS) (neuroprotective treatments for one month) on the motor neuron survival, ultrastructural features of lower motor neurons, and forelimb function at six months after brachial plexus roots avulsion. Neuroprotective treatments reduced oxidative stress and preserved ventral horn motor neurons at the end of the 28-day treatment period relative to vehicle treated ones. Motor neuron sparing was associated with suppression of c-Jun, nNOS, and pro-apoptotic proteins Bim and caspases at this time point. Following 6 months of survival, neutral red staining revealed a significant loss of most of the motor neurons and ventral horn atrophy in the avulsed C6, 7, and 8 cervical segments among the vehicle-treated rats (n = 4). However, rats that received neuroprotective treatments c-Jun JNK inhibitor, SP600125 (n = 4) and a selective inhibitor of nNOS, 7-nitroindazole (n = 4), retained over half of their motor neurons in the ipsilateral avulsed side compared. Myelinated axons in the avulsed ventral horns of vehicle-treated rats were smaller but numerous compared to the intact contralateral ventral horns or neuroprotective-treated groups. In the neuroprotective treatment groups, there was the preservation of myelin thickness around large-caliber axons. Ultrastructural evaluation also confirmed the preservation of organelles including mitochondria and synapses in the two groups that received neuroprotective treatments compared with vehicle controls. Also, forelimb functional evaluation demonstrated that neuroprotective treatments improved functional abilities in the rats. In conclusion, neuroprotective treatments aimed at suppressing degenerative c-Jun and nNOS attenuated apoptosis, provided long-term preservation of motor neurons, their organelles, ventral horn size, and forelimb function.

Zebrafish Minichromosome Maintenance Protein 5 Gene Regulates the Development and Migration of Facial Motor Neurons via Fibroblast Growth Factor Signaling

Minichromosome maintenance protein 5 (MCM5), a member of the microchromosomal maintenance protein family, plays an important role in the initiation and extension of DNA replication. However, its role in neural development in zebrafish remains unclear. Here, we used morpholino (MO) and CRISPR/Cas9 to knock down mcm5 and investigated the developmental features of facial motor neurons (FMNs) in the hindbrain of zebrafish. We found that knockdown of mcm5 using mcm5 MO resulted in a small head, small eyes, and a blurred midbrain-hindbrain boundary, while MO injection of mcm5 led to decrease in FMNs and their migration disorder. However, the mutant of mcm5 only resulted in the migration defect of FMNs rather than quantity change. We further investigated the underlying mechanism of mcm5 in the development of hindbrain using in situ hybridization (ISH) and fgfr1a mRNA co-injected with mcm5 MO. Results from ISH showed that the fibroblast growth factor (FGF) signaling pathway was changed when the MCM5 function was lost, with the decrease in fgfr1a and the increase in fgf8, while that of pea3 had opposite trend. FMN development defects were rescued by fgfr1a mRNA co-injected with mcm5 MO. Our results demonstrated that FGF signaling pathway is required for FMN development in zebrafish. Specifically, mcm5 regulates FMN development during zebrafish growing.

Global transcriptome profile of the developmental principles of in vitro iPSC-to-motor neuron differentiation

BackgroundHuman induced pluripotent stem cells (iPSC) have opened new avenues for regenerative medicine. Consequently, iPSC-derived motor neurons have emerged as potentially viable therapies for spinal cord injuries and neurodegenerative disorders including Amyotrophic Lateral Sclerosis. However, direct clinical application of iPSC bears in itself the risk of tumorigenesis and other unforeseeable genetic or epigenetic abnormalities.ResultsEmploying RNA-seq technology, we identified and characterized gene regulatory networks triggered by in vitro chemical reprogramming of iPSC into cells with the molecular features of motor neurons (MNs) whose function in vivo is to innervate effector organs. We present meta-transcriptome signatures of 5 cell types: iPSCs, neural stem cells, motor neuron progenitors, early motor neurons, and mature motor neurons. In strict response to the chemical stimuli, along the MN differentiation axis we observed temporal downregulation of tumor growth factor-β signaling pathway and consistent activation of sonic hedgehog, Wnt/β-catenin, and Notch signaling. Together with gene networks defining neuronal differentiation (neurogenin 2, microtubule-associated protein 2, Pax6, and neuropilin-1), we observed steady accumulation of motor neuron-specific regulatory genes, including Islet-1 and homeobox protein HB9. Interestingly, transcriptome profiling of the differentiation process showed that Ca2+ signaling through cAMP and LPC was downregulated during the conversion of the iPSC to neural stem cells and key regulatory gene activity of the pathway remained inhibited until later stages of motor neuron formation. Pathways shaping the neuronal development and function were well-represented in the early motor neuron cells including, neuroactive ligand-receptor interactions, axon guidance, and the cholinergic synapse formation. A notable hallmark of our in vitro motor neuron maturation in monoculture was the activation of genes encoding G-coupled muscarinic acetylcholine receptors and downregulation of the ionotropic nicotinic acetylcholine receptors expression. We observed the formation of functional neuronal networks as spontaneous oscillations in the extracellular action potentials recorded on multi-electrode array chip after 20 days of differentiation.ConclusionsDetailed transcriptome profile of each developmental step from iPSC to motor neuron driven by chemical induction provides the guidelines to novel therapeutic approaches in the re-construction efforts of muscle innervation.

Czy cechy skurczu mięśni szkieletowych są zależne od płci?

Artykuł przedstawia bieżący stan wiedzy o różnicach międzypłciowych cech skurczu jednostek ruchowych, unerwienia ruchowego i czuciowego mięśni szkieletowych, cech neuronów motorycznych, proporcji białek kurczliwych i włókien mięśniowych różnych typów oraz cech morfometrycznych mięśni i włókien mięśniowych. Badania te prowadzone na zwierzętach na poziomie komórkowym, pozwalają wyjaśniać podstawy istotnych różnic uwarunkowań motorycznych kobiet i mężczyzn.

Clinicoradiological dissociation in sarcoid myelopathy

More than half of patients with neurosarcoidosis present primarily with neurological symptoms, often with delayed diagnosis given the heterogeneous presentation of this granulomatous multisystem inflammatory disorder.1 We report two cases...

P36. 4-hydroxy(phenyl) retinamide (4HPR) worsens the pathological features of ALS-related TBK1-mutant motor neurons by further disrupting the autophagic flux at the elongation phase

TANK-binding kinase 1 (TBK1) is a protein playing a critical role in the activation of pro-survival pathways, by phosphorylating Akt, and in autophagy, as its phosphorylation and activation of the autophagic receptors p62 and optineurin is fundamental for the correct cargo recruitment at the forming autophagosome. Moreover, mutations in TBK1 gene have been recently linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In our study we aimed to uncover the molecular pathological mechanisms characterizing ALS patients carrying mutations in TBK1 gene. For this scope, we used as a model human induced Pluripotent Stem Cells (hiPSCs), and differentiated them into spinal motor neurons (MNs). TBK1-mutant MNs display reduced TBK1 protein levels up to 50%, supporting the theory that haploinsufficiency might be the pathogenic mechanism leading to ALS in these specific cases. Interestingly, as observed in post-mortem tissues, TBK1 MNs are characterized by decreased viability during long-term culture, and accumulate aberrant cytosolic aggresomes. In order to elucidate the impairment affecting the degrative pathway leading to aggresomes accumulation, and eventually circumvent the pathological phenotype, we performed a small molecule screening, which identified 4-hydroxy(phenyl) retinamide (4HPR) as a potent autophagy modifier. This synthetic retinoid failed in reverting the pathological phenotype in mutant motor neurons:in fact, TBK1-mutant cells accumulated immature phagophores when treated with 4HPR. This highlighted an impaired elongation phase in autophagy, further confirmed by the down regulation of several genes involved in this specific step of the degradative pathway. Notably, over expression of Atg10, a protein directly involved in the autophagic elongation phase, rescued the detrimental effect exerted by the retinoid. Finally, we demonstrated that 4HPR leads to a strong and faster accumulation of disease markers also in human C9ORF72-mutant motor neurons and pre-synthomatic SOD1G93A mice. Our results bring novel mechanistic insights into the autophagy impairment occurring in ALS, confirming that induction of the degratative pathway worsens the disease progression if the levels of the autophagy interplayers are not properly re-established.

ERLIN1 mutations cause teenage-onset slowly progressive ALS in a large Turkish pedigree.

Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with mostly dominant inheritance and a life expectancy of 2-5 years; however, a quite common occurrence of atypical forms of the disease, due to recessive inheritance, has become evident with the use of NGS technologies. In this paper, we describe a family with close consanguinity for at least four generations, suffering from a slowly progressive form of ALS. Spastic walking is observed since teenage years, while bulbar symptoms start much later, at the fifth or sixth decade of life. Patients usually die because of respiratory failure. Using whole-exome sequencing, we identified a novel homozygous p.(Val94Ala) (c.281T>C) (NG_052910.1) (NM_006459) variation in the endoplasmic reticulum lipid raft associated protein 1 (ERLIN1) gene, which segregates with the disease in the family. Here we suggest that ERLIN1 variants, previously shown in juvenile hereditary spastic paraplegia cases, may also be the cause of a slowly progressive early-onset ALS, starting with upper motor neuron features and developing into classical ALS with the addition of lower motor neuron dysfunction. We also demonstrate that ATP-binding cassette subfamily C member 2 (ABCC2) gene, responsible for hyperbilirubinemia, is linked to ERLIN1.

A Rare Case Report on Distal Spinal Muscular Atrophy (SMA)

Spinal muscular atrophies (SMA) are heterogeneous group of motor system disorders of alpha motor neuron clinically characterized by progressive lower motor neuron features. The distal form of SMA is an extremely rare disorder, which usually presents in the young adults and has a relatively slow progression with almost normal life-span. Differential diagnosis of this syndrome includes hereditary motor sensory neuropathy- Charcot-Marie-Tooth disease (CMT) and distal myopathies, which should be excluded before confirming this rare entity. As distal form of SMA is a very extremely rare condition so we would like to present a young male with this disorder and a short discussion of the theoretical aspects.&#x0D; Bangladesh Journal of Neuroscience 2016; Vol. 32 (2): 106-110

SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.

Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal, including premature death due to respiratory dysfunction. With a relative frequency of ∼5%, SYNE1 is one of the more common recessive ataxias worldwide.