Cytokines and chemokines in patients with chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy: A systematic review.

Advances in the understanding of cytokines have revolutionized mechanistic treatments for chronic inflammatory and autoimmune diseases, as exemplified by rheumatoid arthritis. We conducted a systematic literature review on the role of cytokines and chemokines in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN). Ovid Medline, EMBASE and Web of Science were searched until August 31, 2022 for human studies investigating cytokines levels in CIDP or MMN. Fifty-five articles on 1061 CIDP patients and 86 MMN patients were included, with a median of 18 patients per study (range 3-71). Studies differed in the inclusion criteria, type of assay, manufacturer, control subjects, and tested biological material. Only a minority of studies reported data on disease activity. Interleukin (IL)-6, IL-17, CXCL10, and tumor necrosis factor alpha (TNF-α), were elevated in CIDP compared to controls in most of the studies. IL-6 and TNF-α levels are also correlated with disability. In MMN patients, IL-1Ra was elevated in the majority of the reports. While acknowledging the challenges in comparing studies and the various limitations of the studies, including small patient numbers, particularly in MMN, our review suggests that IL-6, IL-17, CXCL10, and TNF-α might play a role in CIDP pathogenesis. Larger studies are needed in MMN.

A 21-bp deletion in the complement regulator CD55 promotor region is associated with multifocal motor neuropathy and its disease course.

BACKGROUND AND AIMS: To further substantiate the role of antibody-mediated complement activation in multifocal motor neuropathy (MMN) immunopathology, we investigated the distribution of promotor polymorphisms of genes encoding the membrane-bound complement regulators CD46, CD55, and CD59 in patients with MMN and controls, and evaluated their association with disease course. METHODS: We used Sanger sequencing to genotype five common polymorphisms in the promotor regions of CD46, CD55, and CD59 in 133 patients with MMN and 380 controls. We correlated each polymorphism to clinical parameters. RESULTS: The genotype frequencies of rs28371582, a 21-bp deletion in the CD55 promotor region, were altered in patients with MMN as compared to controls (p .009; Del/Del genotype 16.8% vs. 7.7%, p .005, odds ratio: 2.43 [1.27-4.58]), and patients carrying this deletion had a more favorable disease course (mean difference 0.26 Medical Research Council [MRC] points/year; 95% confidence interval [CI]: 0.040-0.490, p .019). The presence of CD59 rs141385724 was associated with less severe pre-diagnostic disease course (mean difference 0.940 MRC point/year; 95% CI: 0.083-1.80, p .032). INTERPRETATION: MMN susceptibility is associated with a 21-bp deletion in the CD55 promotor region (rs2871582), which is associated with lower CD55 expression. Patients carrying this deletion may have a more favorable long-term disease outcome. Taken together, these results point out the relevance of the pre-C5 level of the complement cascade in the inflammatory processes underlying MMN.

[Diagnostic workup for polyneuropathy]. / Diagnostische Abklärung bei Polyneuropathie.

Polyneuropathy is a disease of the peripheral nervous system that usually results in distally emphasized, often symmetrical sensory and motor stimulation and deficits. These are often extremely painful. They can be divided into hereditary and acquired causes; inflammatory and infectious causes should be further differentiated among the acquired causes. A careful diagnostic workup is essential. Clinical signs and distribution patterns of symptoms can often already provide clues to the underlying aetiology. This review describes this workup, which in addition to the medical history and clinical examination always includes thorough laboratory diagnostics, electrophysiological examination and cerebrospinal fluid diagnostics. In individual cases, further diagnostic steps may be necessary in order to make the correct diagnosis.

Utility of single fibre electromyography (SFEMG)and motor unit number estimation technique (MUNE) in the diagnosis and differentiation of polyneuropathies of different aetiology.

OBJECTIVE: To determine whether single fibre electromyography and motor unit number index can distinguish between axonal and myelin lesions in polyneuropathies. METHODS: This case-control study was conducted at the Department of Medical Physiology, School of Medicine, University of Duhok, Iraq, and the Neurophysiology Department, Hawler Teaching Hospital, Erbil, Iraq, from January 2021 to March 2022. Group A had patients diagnosed with polyneuropathy regardless of the aetiology, while group B had age-matched healthy controls. Both groups were subjected to single fibre electromyography and motor unit number index as well as conventional nerve conduction study and concentric needle electromyography. Data was analysed using SPSS 26. RESULTS: Of the 140 subjects, 60(43%) were patients in group A; 40(67%) males and 20(33%) females with mean age 55.3±7.2 years. There were 80(57%) controls in group B; 43(54%) females and 37(46%) males with mean age 53.81±7.15. Group A had significantly higher single fibre electromyography jitter, and mean consecutive difference (MCD) values than group B (p<0.05). Group A patients with axonal polyneuropathy had a higher mean jitter (MCD) value (36.476.7ms) than those with demyelinating polyneuropathy (23.262.31 ms) (P <0.05). Patients in group A had a motor unit number index value with a significantly lower mean value (p<0.05) when compared to the controls. Axonal polyneuropathy patients had a lower MUNIX value (99.612.8) than demyelinating polyneuropathy patients (149.845.7) (P< 0.05). CONCLUSIONS: Single fibre electromyography and motor unit number index could help differentiate between the pathophysiology of axonal and demyelinating polyneuropathy.

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill.

Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca(2+) dysregulation is present through altered Ca(2+) homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

Anticipation and compensation for somatosensory deficits in object handling: evidence from a patient with large fiber sensory neuropathy.

The purpose of this study was to determine the contributions of feedforward and feedback processes on grip force regulation and object orientation during functional manipulation tasks. One patient with massive somatosensory loss resulting from large fiber sensory neuropathy and 10 control participants were recruited. Three experiments were conducted: 1) perturbation to static holding; 2) discrete vertical movement; and 3) functional grasp and place. The availability of visual feedback was also manipulated to assess the nature of compensatory mechanisms. Results from experiment 1 indicated that both the deafferented patient and controls used anticipatory grip force adjustments before self-induced perturbation to static holding. The patient exhibited increased grip response time, but the magnitude of grip force adjustments remained correlated with perturbation forces in the self-induced and external perturbation conditions. In experiment 2, the patient applied peak grip force substantially in advance of maximum load force. Unlike controls, the patient's ability to regulate object orientation was impaired without visual feedback. In experiment 3, the duration of unloading, transport, and release phases were longer for the patient, with increased deviation of object orientation at phase transitions. These findings show that the deafferented patient uses distinct modes of anticipatory control according to task constraints and that responses to perturbations are mediated by alternative afferent information. The loss of somatosensory feedback thus appears to impair control of object orientation, whereas variation in the temporal organization of functional tasks may reflect strategies to mitigate object instability associated with changes in movement dynamics.NEW & NOTEWORTHY This study evaluates the effects of sensory neuropathy on the scaling and timing of grip force adjustments across different object handling tasks (i.e., holding, vertical movement, grasping, and placement). In particular, these results illustrate how novel anticipatory and online control processes emerge to compensate for the loss of somatosensory feedback. In addition, we provide new evidence on the role of somatosensory feedback for regulating object orientation during functional prehensile movement.

Psychometric longitudinal evaluation of the Chronic Acquired Polyneuropathy Patient-Reported Index (CAPPRI) in patients with chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: We studied the performance of a 15-item, health-related quality-of-life polyneuropathy scale in a longitudinal study of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Sixty-one patients with CIDP completed the Chronic Acquired Polyneuropathy Patient-Reported Index (CAPPRI) scale and Patient Impression of Change (PIC) at baseline and follow-up visits. Clinicians completed Inflammatory Neuropathy Cause and Treatment (INCAT) disability scores at baseline and follow-up visits. Conventional and modern psychometric analyses were performed on the completed forms. RESULTS: CAPPRI was psychometrically stable between visits without significant difference in response pattern between visits 1 and 2 (paired t-test P = .72). There was strong correlation between changes in INCAT and changes in CAPPRI scores between two visits (rho = 0.6, P < .001). In addition, we showed robust CAPPRI effect sizes between PIC categories. CONCLUSIONS: We demonstrated psychometric stability and construct longitudinal validity of CAPPRI.

Motor axonal neuropathy associated with GNE mutations.

BACKGROUND: Mutations in the GNE gene have been so far described as predominantly associated with distal lower-limb myopathies. Recent reports describe mutations in this gene in patients with peripheral neuropathy and motor neuron disease. METHODS: We describe three patients displaying motor neuropathy in association with GNE mutations. Clinical, electrophysiological, imaging, pathological, and genetic data are presented in a retrospective manner. RESULTS: The three patients had different phenotypes, ranging from mildly progressive lower limb weakness to a rapidly progressive 4-limb weakness. Genetic testing revealed GNE gene mutations in all patients; of those mutations, p.(His186Arg) has not been previously reported. All patients showed evidence of axonal motor nerve involvement on electrodiagnostic examination and/or muscle biopsy. CONCLUSIONS: Nerve involvement associated with GNE gene mutations may be an underdiagnosed pathology and may influence clinical presentation and disease progression.

Pattern of muscle strength improvement after intravenous immunoglobulin therapy in multifocal motor neuropathy.

INTRODUCTION: In multifocal motor neuropathy (MMN), knowledge about the pattern of treatment response in a wide spectrum of muscle groups, distal as well as proximal, after intravenous immunoglobulin (IVIg) initiation is lacking. METHODS: Hand-held dynamometry data of 11 upper and lower limb muscles, from 47 patients with MMN was reviewed. Linear mixed models were used to determine the treatment response after IVIg initiation and its relationship with initial muscle weakness. RESULTS: All muscle groups showed a positive treatment response after IVIg initiation. Changes in SD scores ranged from +0.1 to +0.95. A strong association between weakness at baseline and the magnitude of the treatment response was found. DISCUSSION: Improved muscle strength in response to IVIg appears not only in distal, but to a similar degree also in proximal muscle groups in MMN, with the largest response in muscle groups that show the greatest initial weakness.

The complex association between pain and neuropathy.

BACKGROUND: Several studies of patients with polyneuropathy failed to show differences between patients with and without pain. In the current study, we aimed to explore the association between neuropathic symptoms, mainly pain, and polyneuropathy characteristics. METHODS: A prospective cross-sectional study recruiting 151 patients with non-diabetic polyneuropathy was performed between November 2016 and May 2017. A total of 38 patients with chronic inflammatory demyelinating neuropathy were excluded. Patients underwent clinical, electrophysiological and functional assessments of their polyneuropathy. Polyneuropathy characteristics were compared depending on the presence and severity of neuropathic symptoms. RESULTS: The presence and the severity of weakness were associated with a more severe neuropathy as measured by clinical, electrophysiological and functional assessments, while the presence of pain was associated with higher sural amplitudes, and the severity of pain showed a curvilinear association with neuropathy severity. CONCLUSIONS: Our study shows a novel finding of a curvilinear association between pain and polyneuropathy severity.

Sensitivity and specificity of single and combined clouds analyses compared with quantitative motor unit potential analysis.

INTRODUCTION: Turns-amplitude, number of small segments (NSS)-activity, and envelope-activity clouds are three methods of electromyography (EMG) interference pattern analysis. Our objective was to evaluate the sensitivity and specificity of each individual cloud analysis and combined clouds analysis to compare with that of quantitative motor unit potential (QMUP) analysis. METHODS: A total of 379 muscles from 100 patients were analyzed by both QMUP and clouds analyses. Calculation of sensitivity and specificity was based on the clinical diagnosis as the "gold standard." RESULTS: For discrimination of abnormal vs normal and neuropathic vs non-neuropathic, combined clouds analysis had greater sensitivity than QMUP analysis and any single cloud analysis, but there were no differences in specificity. For discrimination of myopathic vs non-myopathic, combined clouds analysis and single cloud analysis had greater sensitivity than QMUP analysis, but there were no differences in specificity. DISCUSSION: Combined clouds analysis was superior to QMUP and each single cloud analysis for distinguishing normal, myopathic, and neuropathic muscles.

Clinical features with anti fibroblast growth factor receptor 3 (FGFR3) antibody-related polyneuropathy: a retrospective study.

BACKGROUND: Despite its initial association with sensory neuropathies, anti-fibroblast growth factor receptor 3 (FGFR3) antibodies have been since reported with a broad range of neuropathies and clinical features. The aim of the study is to report the clinical and electro diagnostic findings in a cohort of patients with sensory or sensorimotor polyneuropathy and anti-FGFR3 antibodies. METHODS: We performed a retrospective chart review to assess the clinical characteristics of patients with sensory or sensorimotor neuropathy related to FGFR3 antibodies. Descriptive statistics were reported using frequencies and percentages for categorical variables and median and interquartile range (IQR) for continuous variables. RESULTS: This study included 14 patients (9 women) with a median age of 51.9 years (IQR 48-57). The most common presenting symptoms were painful paresthesia (100%), gait instability (42.9%), constitutional symptoms (42.9%), and autonomic symptoms (28.6%). Onset of symptoms was chronic (≥12 weeks) in eight patients (57.1%). Examination showed a distal loss of sensation to pin prick (100%), as well as impaired vibration sensation (78.6%) and proprioception (35.7%), in the distal extremities. We also observed mild weakness in the distal lower-extremities (42.9%). Three patients (21.4%) had trigeminal neuralgia, three patients (21.4%) had co-existing autoimmune disease, and one patient (7.1%) had a history of renal cell carcinoma. The mean titer of FGFR3 antibody was 14,285.71 (IQR 5000-16,750). All 14 patients produced normal results in the neuropathy workup. Nerve conduction study and electromyography showed sensory axonal neuropathy in four patients (28.6%), sensorimotor axonal neuropathy in seven patients (50%), and a normal result in three patients (21.4%). For those with a normal NCS/EMG, a skin biopsy showed a non-length-dependent small fiber neuropathy. CONCLUSIONS: Neuropathy related to FGFR3 antibodies can potentially involve small and large fibers, sensory and motor fibers, and even the trigeminal nerve, which contributes to a highly variable clinical presentation.

Electrodiagnostic findings in patients with non-COVID-19- and COVID-19-related acute respiratory distress syndrome.

BACKGROUND: Critical illness polyneuropathy and myopathy (CIPNM) is a frequent neurological manifestation in patients with acute respiratory distress syndrome (ARDS) from coronavirus disease 2019 (COVID-19) infection. CIPNM diagnosis is usually limited to clinical evaluation. We compared patients with ARDS from COVID-19 and other aetiologies, in whom a neurophysiological evaluation for the detection of CIPNM was performed. The aim was to determine if there were any differences between these two groups in frequency of CINPM and outcome at discharge from the intensive care unit (ICU). MATERIALS AND METHODS: This was a single-centre retrospective study performed on mechanically ventilated patients consecutively admitted (January 2016-June 2020) to the ICU of Careggi Hospital, Florence, Italy, with ARDS of different aetiologies. Neurophysiological evaluation was performed on patients with stable ventilation parameters, but marked widespread hyposthenia (Medical Research Council score <48). Creatine phosphokinase (CPK), lactic dehydrogenase (LDH) and mean morning glycaemic values were collected. RESULTS: From a total of 148 patients, 23 with COVID-19 infection and 21 with ARDS due to other aetiologies, underwent electroneurography/electromyography (ENG/EMG) recording. Incidence of CIPNM was similar in the two groups, 65% (15 of 23) in COVID-19 patients and 71% (15 of 21) in patients affected by ARDS of other aetiologies. At ICU discharge, subjects with CIPNM more frequently required ventilatory support, regardless the aetiology of ARDS. CONCLUSION: ENG/EMG represents a useful tool in the identification of the neuromuscular causes underlying ventilator wean failure and patient stratification. A high incidence of CIPNM, with a similar percentage, has been observed in ARDS patients of all aetiologies.

Neurological and Neuropsychiatric Impacts of COVID-19 Pandemic.

BACKGROUND: Albeit primarily a disease of respiratory tract, the 2019 coronavirus infectious disease (COVID-19) has been found to have causal association with a plethora of neurological, neuropsychiatric and psychological effects. This review aims to analyze them with a discussion of evolving therapeutic recommendations. METHODS: PubMed and Google Scholar were searched from 1 January 2020 to 30 May 2020 with the following key terms: "COVID-19", "SARS-CoV-2", "pandemic", "neuro-COVID", "stroke-COVID", "epilepsy-COVID", "COVID-encephalopathy", "SARS-CoV-2-encephalitis", "SARS-CoV-2-rhabdomyolysis", "COVID-demyelinating disease", "neurological manifestations", "psychosocial manifestations", "treatment recommendations", "COVID-19 and therapeutic changes", "psychiatry", "marginalised", "telemedicine", "mental health", "quarantine", "infodemic" and "social media". A few newspaper reports related to COVID-19 and psychosocial impacts have also been added as per context. RESULTS: Neurological and neuropsychiatric manifestations of COVID-19 are abundant. Clinical features of both central and peripheral nervous system involvement are evident. These have been categorically analyzed briefly with literature support. Most of the psychological effects are secondary to pandemic-associated regulatory, socioeconomic and psychosocial changes. CONCLUSION: Neurological and neuropsychiatric manifestations of this disease are only beginning to unravel. This demands a wide index of suspicion for prompt diagnosis of SARS-CoV-2 to prevent further complications and mortality.

Les impacts neurologiques et neuropsychiatriques d'une infection à la COVID-19. CONTEXTE: Bien qu'il s'agisse principalement d'une maladie des voies respiratoires, la maladie infectieuse à coronavirus apparue en 2019 (COVID-19) s'est avérée avoir un lien de causalité avec une pléthore d'impacts d'ordre neurologique, neuropsychiatrique et psychologique. Cette étude entend donc analyser ces impacts tout en discutant l'évolution des recommandations thérapeutiques se rapportant à cette maladie. MÉTHODES: Les bases de données PubMed et Google Scholar ont été interrogées entre les 1er janvier et 30 mai 2020. Les termes clés suivants ont été utilisés : « COVID-19 ¼, « SRAS ­ CoV-2 ¼, « Pandémie ¼, « Neuro ­ COVID ¼, « AVC ­ COVID ¼, « Épilepsie ­ COVID ¼, « COVID ­ encéphalopathie ¼, « SRAS ­ CoV-2 ­ encéphalite ¼, « SRAS ­ CoV-2 ­ rhabdomyolyse ¼, « COVID ­ maladie démyélinisante ¼, « Manifestations neurologiques ¼, « Manifestations psychosociales ¼, « Recommandations thérapeutiques ¼, « COVID-19 et changement thérapeutiques ¼, « Psychiatrie ¼, « Marginalisés ¼, « Télémédecine ¼, « Santé mentale ¼, « Quarantaine ¼, « Infodémique ¼ et « Médias sociaux ¼. De plus, quelques articles de journaux relatifs à la pandémie de COVID-19 et à ses impacts psychosociaux ont également été ajoutés en fonction du contexte. RÉSULTATS: Il appert que les manifestations neurologiques et neuropsychiatriques des infections à la COVID-19 sont nombreuses. Les caractéristiques cliniques d'une implication des systèmes nerveux central et périphérique sautent désormais aux yeux. Ces caractéristiques ont fait l'objet d'une brève analyse systématique à l'aide de publications scientifiques. En outre, la plupart des impacts d'ordre psychologique de cette pandémie se sont révélés moins apparents que les changements réglementaires, socioéconomiques et psychosociaux. CONCLUSION: Les manifestations neurologiques et neuropsychiatriques de cette maladie ne font que commencer à être élucidées. Cela exige donc une capacité accrue de vigilance en vue d'un diagnostic rapide, et ce, afin de prévenir des complications additionnelles et une mortalité accrue.

Association Between Severe Chronic Obstructive Pulmonary Disease and Polyneuropathy.

BACKGROUND Chronic obstructive pulmonary disease (COPD) is a life-threatening and devastating disease associated with low-grade systemic inflammation. In adults, the most common disease of the peripheral nervous system is peripheral neuropathy. While most polyneuropathy has a mixed presentation, some cases are motor dominant and others are sensory dominant. We investigated polyneuropathy in patients with COPD and hypothesized that low-grade systemic inflammation and other pathologies in patients with COPD cause peripheral axonal polyneuropathy. MATERIAL AND METHODS We included 62 patients with COPD without any neurological signs or symptoms, and 30 healthy volunteers with no known neurological or pulmonary diseases as controls. There were 38 men in the COPD group and 17 men in the control group; the mean ages of the 2 groups were 64.88 and 62.7 years, respectively. According to the Global Initiative for Chronic Obstructive Lung Disease COPD report, all COPD patients were group D. After collecting demographic and clinical characteristics of the participants, we performed an electrophysiological examination to investigate polyneuropathy and pulmonary function test results. C-reactive protein, hemoglobin, creatinine, partial carbon dioxide pressure (pCO2) levels were recorded. Electrophysiological examination was performed with a Medelec Synergy device using standard neurographic procedures, and the results were assessed. RESULTS Significant differences were found for forced expiratory volume in 1 sec (FEV1), %FEV1, forced vital capacity (FVC), %FVC, pCO2, and hemoglobin and creatinine levels, but all participants had a creatinine level within the normal range. There was no difference in sensory neuropathy between the groups, but a significant difference was found in terms of motor neuropathy. CONCLUSIONS As noted in previous studies, systemic inflammation, increased oxidative stress, decreased oxygen pressure, and multiple comorbidities in patients with COPD may all contribute to the development of neuropathy.

Mapping the Neuroanatomy of ABHD16A, ABHD12, and Lysophosphatidylserines Provides New Insights into the Pathophysiology of the Human Neurological Disorder PHARC.

Lysophosphatidylserine (lyso-PS), a lysophospholipid derived from phosphatidylserine (PS), has emerged as a potent signaling lipid in mammalian physiology. In vivo, the metabolic serine hydrolases ABHD16A and ABHD12 are major lipases that biosynthesize and degrade lyso-PS, respectively. Of biomedical relevance, deleterious mutations to ABHD12 cause accumulation of lyso-PS in the brain, and this deregulated lyso-PS metabolism leads to the human genetic neurological disorder PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract). While the roles of ABHD16A and ABHD12 in lyso-PS metabolism in the mammalian brain are well established, the anatomical and (sub)cellular localizations of both lipases and the functional cross-talk between them with respect to regulating lyso-PS lipids remain under investigated. Here, using subcellular organelle fractionation, biochemical assays, and immunofluorescence-based high-resolution microscopy, we show that the PS lipase ABHD16A is an endoplasmic reticulum-localized enzyme, an organelle intricately regulating cellular PS levels. In addition, leveraging immunohistochemical analysis using genetic ABHD16A and ABHD12 knockout mice as important controls, we map the anatomical distribution of both of these lipases in tandem in the murine brain and show for the first time the distinct localization of these lipases to different regions and cells of the cerebellum. We complement the aforementioned immunohistochemical studies by quantitatively measuring lyso-PS concentrations in various brain regions using mass spectrometry and find that the cerebellar lyso-PS levels are most affected by deletion of ABHD16A (decreased) or ABHD12 (increased). Taken together, our studies provide new insights into lyso-PS signaling in the cerebellum, the most atrophic brain region in human PHARC subjects.

Defective kinesin binding of TUBB2A causes progressive spastic ataxia syndrome resembling sacsinopathy.

Microtubules participate in fundamental cellular processes, including chromosomal segregation and cell division, migration and intracellular trafficking. Their proper function is required for correct central nervous system development and operative preservation, and mutations in genes coding tubulins, the constituting units of microtubules, underlie a family of neurodevelopmental and neurodegenerative diseases, collectively known as 'tubulinopathies', characterized by a wide range of neuronal defects resulting from defective proliferation, migration and function. Here, we causally link a previously unreported missense mutation in TUBB2A (c.1249G>A, p.D417N), encoding one of the neuron-specific ß-tubulin isotype II, to a disorder characterized by progressive spastic paraplegia, peripheral sensory-motor polyneuropathy and ataxia. Asp417 is a highly conserved solvent-exposed residue at the site mediating binding of kinesin superfamily motors. Impaired binding to KIF1A, a neuron-specific kinesin required for transport of synaptic vesicle precursors of the disease-associated TUBB2A mutant, was predicted by structural analyses and confirmed experimentally in vitro. We show that overexpression of TUBB2AD417N disrupts the mitotic spindle bipolarity and morphology and affects the M phase entry and length. Differently from the TUBB2AN247K and TUBB2AA248V, two mutants previously identified to affect neurodevelopment, TUBB2AD417N retains the ability to assemble into microtubules. Consistent with the differential clinical and structural impact, TUBB2AA248V does not drastically affect TUBB2A binding to KIF1A, nor mitotic spindle bipolarity. Overall, our data demonstrate a pathogenic role of the p.D417N substitution that is different from previously reported TUBB2A mutations and expand the phenotypic spectrum associated with mutations in this gene.

Presence of val30Met and val122ile mutations in a patient with hereditary amyloidosis.

Amyloidosis, caused by a mutation in the transthyretin (TTR) gene, is the most common hereditary type disease. More than 120 mutations have been described, with extensive phenotypic heterogeneity. Val30Met (p.Val50Met) is the most frequent mutation, and patients exhibit polyneuropathy, possibly including cardiac, renal, gastrointestinal, and/or ocular involvement. Val122Ile (p.Val142Ile) is the mutation associated with cardiomyopathy, and few cases have been reported in Brazil. Most individuals are heterozygous for one pathogenic mutation. Herein, we report a compound heterozygote with two pathogenic mutations (Val30Met/ Val122Ile), and a family history of a deceased brother with amyloidosis, who also carried the same TTR gene mutations. The patient presented with neuropathic, cardiac, and renal impairment and a faster disease progression. Cases of the double mutation have been linked to changes in disease presentation. The concomitance of two pathogenic mutations may have contributed to more exuberant manifestations and faster disease progression.

The impact of COPD on polyneuropathy: results from the German COPD cohort COSYCONET.

BACKGROUND: Peripheral neuropathy is a common comorbidity in COPD. We aimed to investigate associations between alterations commonly found in COPD and peripheral neuropathy, with particular emphasize on the distinction between direct and indirect effects. METHODS: We used visit 4 data of the COPD cohort COSYCONET, which included indicators of polyneuropathy (repeated tuning fork and monofilament testing), excluding patients with diabetes a/o increased HbA1c. These indicators were analysed for the association with COPD characteristics, including lung function, blood gases, 6-min walk distance (6-MWD), timed-up-and-go-test (TUG), exacerbation risk according to GOLD, C-reactive protein (CRP), and ankle-brachial index (ABI). Based on the results of conventional regression analyses adjusted for age, BMI, packyears and gender, we utilized structural equation modelling (SEM) to quantify the network of direct and indirect relationships between parameters. RESULTS: 606 patients were eligible for analysis. The indices of polyneuropathy were highly correlated with each other and related to base excess (BE), ABI and TUG. ABI was linked to neuropathy and 6-MWD, exacerbations depended on FEV1, 6-MWD and CRP. The associations could be summarized into a SEM comprising polyneuropathy as a latent variable (PNP) with three measured indicator variables. Importantly, PNP was directly dependent on ABI and particularly on BE. When also including patients with diabetes and/or elevated values of HbA1c (n = 742) the SEM remained virtually the same. CONCLUSION: We identified BE and ABI as major determinants of peripheral neuropathy in patients with COPD. All other associations, particularly those with lung function and physical capacity, were indirect. These findings underline the importance of alterations of the micromilieu in COPD, in particular the degree of metabolic compensation and vascular status.

Multifocal motor neuropathy: controversies and priorities.

Despite 30 years of research there are still significant unknowns and controversies associated with multifocal motor neuropathy (MMN) including disease pathophysiology, diagnostic criteria and treatment. Foremost relates to the underlying pathophysiology, specifically whether MMN represents an axonal or demyelinating neuropathy and whether the underlying pathophysiology is focused at the node of Ranvier. In turn, this discussion promotes consideration of therapeutic approaches, an issue that becomes more directed in this evolving era of precision medicine. It is generally accepted that MMN represents a chronic progressive immune-mediated motor neuropathy clinically characterised by progressive asymmetric weakness and electrophysiologically by partial motor conduction block. Anti-GM1 IgM antibodies are identified in at least 40% of patients. There have been recent developments in the use of neuromuscular ultrasound and MRI to aid in diagnosing MMN and in further elucidation of its pathophysiological mechanisms. The present Review will critically analyse the knowledge accumulated about MMN over the past 30 years, culminating in a state-of-the-art approach to therapy.