Limb Onset Research Articles

Clinical and Pathological Characterization of VPS16 Dystonia (P11-11.005)

<h3>Objective:</h3> To expand the clinical, radiologic and pathologic understanding of VPS16 related dystonia. <h3>Background:</h3> Variants in VPS16 have been associated with isolated dystonia in 35 cases from Chinese and European cohorts, including report of brainstem signal change on MRI. <h3>Design/Methods:</h3> We describe clinical features in 10 additional individuals with isolated dystonia and VPS16 variants, including neuroimaging on a subset and pathology in one, and perform pooled analysis with published cases. <h3>Results:</h3> 80% were men, mean age onset was 14.1 years (range 5–30), and mean age at exam was 35.89 years (range 11–73). Four began with arm, 3 with leg, and 3 with neck dystonia. Only one remained focal (arm); others became generalized (7), multifocal (1) or segmental (1). Brachial involvement was present in 90%, with 80% crural, 70% cranial/bulbar, and 50% cervical involvement. Two individuals underwent deep brain stimulation and one thalamotomy. Four cases were related, and five others had family history. MRI was available in two cases and demonstrated red nucleus and cerebral peduncle T2 hypointensity. Neuropathologic evaluation in one case (post bilateral GPi DBS) demonstrated asymmetric severe gliosis and marked neuronal loss of the left subthalamic nucleus with optically empty vacuoles and much less right-sided involvement. Pooled analysis with 34 additional published cases showed 62.22% male and average onset of 14.53 years (range 3–50). Onset site was 20.45% cranial/bulbar, 54.55% limb, and 36.36% axial (cervical or trunk); 75% of cases exhibited cranial/bulbar symptoms, 90.9% limb and 81.82% axial involvement. <h3>Conclusions:</h3> Expansion of known cases of VPS16 dystonia further support that it is a childhood-or adolescent-onset disorder, typically with limb or cervical onset that often spreads to the arm and leg. Additional histopathologic and metabolomic evaluation is underway to better understand the lysosomal and endolysosomal pathophysiology that may contribute to both vacuolization in the subthalamic nucleus as well as T2 brainstem hypointensities. <b>Disclosure:</b> The institution of Dr. Pullman has received research support from Empire Clinical Research Investigator Program. The institution of Ms. Raymond has received research support from NIH. Dr. Molofsky has nothing to disclose. Dr. Lubarr has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for applied therapeutics. Dr. Leaver has nothing to disclose. Roberto Ortega has nothing to disclose. Ms. Rawal has nothing to disclose. The institution of Dr. Bennett has received research support from Prevail. Mr. Bushnik has nothing to disclose. Dr. Khorsandi has nothing to disclose. Fedor Panov has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for neuropace. Fedor Panov has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for zimmer biomet. Jean Paul Vonsattel has nothing to disclose. The institution of Dr. Ozelius has received research support from NIH. Dr. Ozelius has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Saunders-Pullman has received research support from NIH, Bigglesworth Family Foundation, Empire Clinical Research Investigatory Program. The institution of Dr. Bressman has received research support from Michael J Fox Foundation . The institution of Dr. Bressman has received research support from NIH .

Exploring the causal role of the immune response to varicella-zoster virus on multiple traits: a phenome-wide Mendelian randomization study

BackgroundThe immune response to infections could be largely driven by the individual’s genes, especially in the major histocompatibility complex (MHC) region. Varicella-zoster virus (VZV) is a highly communicable pathogen. In addition to infection, the reactivations of VZV can be a potential causal factor for multiple traits. Identification of VZV immune response-related health conditions can therefore help elucidate the aetiology of certain diseases.MethodsA phenome-wide Mendelian randomization (MR) study of anti-VZV immunoglobulin G (IgG) levels with 1370 traits was conducted to explore the potential causal role of VZV-specific immune response on multiple traits using the UK Biobank cohort. For the robustness of the results, we performed MR analyses using five different methods. To investigate the impact of the MHC region on MR results, the analyses were conducted using instrumental variables (IVs) inside (IVmhc) and outside (IVno.mhc) the MHC region or all together (IVfull).ResultsForty-nine single nucleotide polymorphisms (IVfull) were associated with anti-VZV IgG levels, of which five (IVmhc) were located in the MHC region and 44 (IVno.mhc) were not. Statistical evidence (false discovery rate < 0.05 in at least three of the five MR methods) for a causal effect of anti-VZV IgG levels was found on 22 traits using IVmhc, while no evidence was found when using IVno.mhc or IVfull. The reactivations of VZV increased the risk of Dupuytren disease, mononeuropathies of the upper limb, sarcoidosis, coeliac disease, teeth problems and earlier onset of allergic rhinitis, which evidence was concordant with the literature. Suggestive causal evidence (P < 0.05 in at least three of five MR methods) using IVfull, IVmhc and IVno.mhc was detected in 92, 194 and 56 traits, respectively. MR results from IVfull correlated with those from IVmhc or IVno.mhc. However, the results between IVmhc and IVno.mhc were noticeably different, as evidenced by causal associations in opposite directions between anti-VZV IgG and ten traits.ConclusionsIn this exploratory study, anti-VZV IgG was causally associated with multiple traits. IVs in the MHC region might have a substantial impact on MR, and therefore, could be potentially considered in future MR studies.

Analysis of SOD1 variants in Chinese patients with familial amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, and genetic contributors exert a significant role in the complicated pathogenesis. Identification of the genetic causes in ALS families could be valuable for early diagnosis and management. The development of potential drugs for patients with genetic defects will shed new light on ALS therapy. To identify causative variants in three Chinese families with familial ALS (FALS), reveal the pathogenic mechanism and look for the targeted drug for ALS. Whole-exome sequencing and bioinformatics were used to perform genetic analysis of the ALS families. Functional analysis was performed to study the variants' function and search for potential drug targets. Three heterozygous missense variants of the superoxide dismutase 1 gene (SOD1) were identified in families with FALS. The clinical manifestations of these patients include spinal onset, predominant lower motor neurons presentation and absence of cognitive involvement. Functional analysis showed that all three SOD1 variants led to increased reactive oxygen species (ROS) levels, reduced cell viability and formation of cytoplasmic aggregates. Remarkably, the decreased cell viability induced by variants was rescued after treatment with the ROS inhibitor N-acetylcysteine. This study identified three SOD1 variants in three families with FALS. The variant SOD1 toxicity was associated with oxidative damage and aggregation, and N-acetylcysteine could rescue the decreased cell viability induced by these variants. Our findings support a pathogenic role for ROS in SOD1 deficiencies and provide a potential drug N-acetylcysteine for ALS therapy, especially in SOD1 patients with limb onset.

DYT30 due to VPS16 Mutation: An Etiology of Childhood-Onset Generalized Dystonia.

DYT30 due to VPS16 Mutation: An Etiology of Childhood-Onset Generalized Dystonia.

Experience with telemedicine in neuromuscular clinic during COVID-19 pandemic.

The aim of the present study was to evaluate the feasibility and acceptability of telehealth for the care of neuromuscular patients during the COVID-19 pandemic. Neuromuscular patients or their caregivers, as well as health care providers (HCPs), who completed a televisit during the pandemic received an online survey, assessing satisfaction with the visit, quality of care, and experience with the televisit interference. Surveys from 46 neuromuscular patients (including 18 with motor neuron disease [MND])/caregivers and 7 HCPs were completed. Several aspects of televisits including good communication, adequate time to discuss concern, provision of equal care, and telemedicine interference were rated favorably among participants. Telehealth was strongly satisfactory in 30 (65.22%) and satisfactory in 15 (32.61%) neuromuscular patients/caregivers. In 18 MND patients, this was 10 (55.56%) and 7 (38.89%), respectively. Moreover, 24 (52.17%) neuromuscular patients/caregivers would strongly agree and 18 (39.13%) would agree to participate again in televisits. This was 10 (55.56%) and 4 (33.33%) for MND cases, respectively. Various medical issues were addressed during the televisits including medication management, ordering tests/referrals, discussion of goals of care, and research. The predictive stepwise logistic model found younger age as a predicting factor for higher satisfaction from, or participation again in, televisits in neuromuscular patients. Limb onset location was also a predicting factor for strong satisfaction from televisits in MND cases. Telemedicine is feasible and highly effective at achieving personalized care that was rated satisfactory by the majority of neuromuscular patients/caregivers and HCPs during the COVID-19 pandemic.

Mutation spectrum of chinese amyotrophic lateral sclerosis patients with frontotemporal dementia

BackgroundStudies have reported that a noncoding hexanucleotide repeat in C9ORF72, is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) among Caucasian population, nevertheless it is rare in Chinese population. Therefore, we aimed to investigate the mutation spectrum of Chinese ALS patients with FTD (ALS-FTD).MethodsALS patients with and without cognitive impairments were enrolled. Clinical features were collected including age, sex, disease duration, ALSFRS-r, family history and cognitive evaluation. Thirty-six ALS genes were screened by whole exome sequencing (WES) and repeat-primed polymerase chain reaction (PCR) were used for detection of and abnormal repeat expansions of C9ORF72.ResultsA total of 1208 patients, including 66 familial ALS (FALS) and 1142 sporadic ALS (SALS) patients were included. Twenty-three patients with sporadic ALS and one familial ALS index had concomitant FTD, which accounts for 1.99% (24/1208) of patients with ALS. In sporadic ALS-FTD, one case harboring C9ORF72 expansion variant, two cases harboring ANXA11 variants and one individual carrying CCNF variant were identified. A recurrent UBQLN2 variant was detected in a familial ALS-FTD patient. All of the ALS-FTD patients carrying variants in known causative genes manifested motor symptom onset (two bulbar onset and three limb onset) and developed cognitive impairment thereafter. It is not easy to draw a conclusion of the genotype-phenotype association in ALS-FTD with certain variants, limited by the small number of patients.ConclusionOur findings provide an overview of spectrum of genetic variants in Chinese ALS-FTD patients. Variants of uncertain significance in UBQLN2, ANXA11 and CCNF were identified and further studies are required for causal relations of these variants with ALS-FTD.

Pathogenicity classification of SOD1 variants of uncertain significance by in vitro aggregation propensity

Deposition of insoluble SOD1 aggregates in motor neurons is the hallmark of SOD1-associated ALS. Mutant SOD1 protein promotes structural instability that leads to misfolded SOD1 protein aggregates, which can be recapitulated in vitro. Therefore, aggregation propensity in cell lines can be a reliable indicator for the pathogenicity classification of SOD1 variants. Herein, we performed in vitro experiment to classify the pathogenicity of 34 SOD1 variants of uncertain significance (VUS) from 215 variants reported previously. The clinical features of 234 ALS patients with 31 SOD1 likely pathogenic (LP) variants were summarized. 31 VUS variants formed aggregates spontaneously, indicating LP variants. Missense variants were mainly located in the C-terminal of SOD1. Among patients with 31 SOD1 LP variants, 75% of patients had lower limb onset. The onset of familial ALS patients (45.7±14.0 years) is earlier than sporadic ALS patients (50.6±13.1 years). Our results expand the spectrum of SOD1 mutations and highlight the natural history of SOD1-positive ALS patients for further clinical trials in SOD1-related ALS.

Effectiveness of herbal medicine on patients with amyotrophic lateral sclerosis: Analysis of the PRO-ACT data using propensity score matching

BackgroundPatients with amyotrophic lateral sclerosis (ALS) have restricted pharmacotherapy options and thus resort to herbal medicines (HMs), despite limited and conflicting evidence. Therefore, use of HMs needs to be assessed in patients with ALS. PurposeThis study aimed to evaluate the benefits of HMs in ALS and to describe the characteristics of HM users. Study DesignThe correlation between HMs and prognosis was determined based on data obtained from the largest ALS database with high-quality clinical trials. Propensity score (PS) matching was used to address confounding and selection bias. MethodsIn total, 321 and 231 HM users with at least a 4-week HM prescription were identified and PS-matched with non-HM users at a 1:1 ratio based on predefined confounders. Time-to-event models with censoring at 12 or 18 months were established for survival analyses. For evaluating activity limitation and respiratory function, 320 and 376 HM users were included, respectively, and analyzed using multivariate analysis of variance (MANOVA). ResultsThe profiles of 321 HM users indicated a better condition compared with that of non-HM users before PS-matching, including higher weight (median [IQR], 77.90 [21.8] kg vs. 74.00 [21.2] kg, p < 0.01), higher body mass index (26.00 [5.4] vs. 25.20 [5.8], p < 0.01), more percentage of limb onset (261 [81.3%] vs. 2366 [67.2%], p < 0.01), and slower progression (0.47 [0.5] vs. 0.51 [0.5], p = 0.03). HM did not significantly affect survival at 12 months (adjusted hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.49–1.03; log-rank p = 0.069), but it significantly prolonged survival at 18 months (adjusted HR 0.74, 95% CI 0.56–0.98; log-rank p = 0.038). After imputation of missing data, MANOVA revealed significant effectiveness of HMs in improving activity limitation (Pillai trace, 0.0195; p = 0.03). ConclusionPS-based methods eliminated baseline differences between HM and non-HM users. Overall, the use of HM to treat patients with ALS is favored based on their association with prolonged overall survival within 18 months and improved activity limitation.

Reassessing the Diagnostic Utility of the Split Hand Index in Amyotrophic Lateral Sclerosis Patients-The Divide by Zero Problem.

We set out to assess the diagnostic utility of the split hand index (SHI) for amyotrophic lateral sclerosis (ALS) and also to see if and how it can be applied to severely atrophied muscles, a frequent finding in this setting. We enrolled 38 patients from our clinic, 19 diagnosed with ALS and 19 controls, matched for age and sex. The SHI was calculated, on both sides, for all the patients. We calculated a SHI of 0 when the abductor pollicis brevis muscle (ABD) or first dorsal interosseous muscle (FDI) compound muscle action potentials (CMAPs) were unobtainable, and we allotted a value of 0.1 mV to abductor digiti minimi muscle (ADM) CMAP, for mathematical purposes, when the value would have been 0. The means differences were large between groups, with a significant variance heterogeneity. We performed a ROC analysis and obtained an accuracy of 0.83 for a SHI of 7.2, p-value < 0.0001. In conclusion, we reaffirm the utility of the SHI in the diagnosis of ALS, especially in limb onset cases, and we think that it can be safely extended to severely atrophied muscles with absent or very low CMAP values, without endangering the sensitivity or specificity.

Daily Hemodialysis Helps Critical Nephritic Lupus Patient: A Case Report

Background: Nephritic lupus is the most common and serious complication of systemic lupus erythematosus (SLE) and is associated with a worse prognosis. Hemodialysis is effective in alleviating symptoms and renal involvement in a nephritic lupus patient.&#x0D; Method: A 33-year-old female was diagnosed with SLE in September 2017. She was also diagnosed with diffuse membranous proliferative glomerulonephritis, as confirmed with a kidney biopsy. She complained of gradual onset limb weakness and peripheral edema 3 months before admission. She was treated with 6 cycles of cyclophosphamide and continued with methylprednisolone 16 mg once daily, hydroxychloroquine 200 mg once daily, and myfortic 360 mg twice daily. A day before ICU admission, her creatinine level was increased to 4.6 mg/dl with an estimated GFR of 12 ml/min and her symptoms then worsened into seizures and lung edema. Daily hemodialysis with heparin-free SLEDD was performed. About 2L was extracted for the first 6 hours with Qb 150 ml and Qd 300 ml and was continued until the day after. For the next 4 days, 3L was extracted per day with Qb 200ml and Qd 500 ml. The patients’ hemodynamic status was within normal limits during dialysis period. The condition improved and the patient was transferred to the ward.&#x0D; Discussions: Hemodialysis is a way to solve kidney problems in in nephritic lupus and SLE patients in general. It should not only be employed for mainly kidney problems but could be beneficial in autoimmune patients with conditions such as nephritic lupus. Slowly extracted dialysis type would be a good and inexpensive option to resolve nephritic lupus in compromising lupus patients. Filtration is ensured and solute removal is achieved relatively equivalent to CRRT.&#x0D; Conclusion: Daily hemodialysis could increase renal salvation by providing less creatinine serum and removing accumulated fluids. The SLEDD type could be used for critical nephritic lupus patients with reduced hemodynamic perturbations, minimal anticoagulant, and lower cost.

A systematic review of disease prevalence, health-related quality of life, and economic outcomes associated with Friedreich’s Ataxia

Introduction Friedreich ataxia (FA) is a rare, inherited neuromuscular disease characterized by an early onset and progressive limb and gait ataxia. Currently, there are no approved treatments for FA. It is important to understand the burden of FA, including its extent and the most salient elements. The objective of this study is therefore to systematically review the literature regarding the aspects of prevalence, health-related quality of life (HRQoL), and economic outcomes that are associated with FA, and to subsequently identify relevant knowledge gaps. Methods Three systematic literature reviews were conducted to assess publications regarding FA prevalence, HRQoL, and economic outcomes. Search strategies were implemented in MEDLINE (Ovid) and EMBASE databases; study selection and quality assessment were conducted using current best practices. For each review, study characteristics and findings were summarized. Results A total of 36 studies were included. Review of prevalence studies (n = 22) indicated variation in the number of cases by region, and many regions were not represented at all. Regarding HRQoL (n = 12 studies), physical domains were consistently impacted, although findings regarding other domains and overall HRQoL were less clear. Cost studies (n = 2) encompassed 4 regions and revealed that costs related to the provision of care, including non-medical direct costs and indirect costs, accounted for the majority of FA-related costs. Discussion Findings from this systematic review revealed several knowledge gaps that would preclude the conduct of a robust assessment of the benefits and outcomes associated with a disease-modifying FA therapy. Additional understanding regarding patient and caregiver HRQoL and costs is required.

First Two-Year Observational Exploratory Real Life Clinical Phenotyping, and Societal Impact Study of Parkinson's Disease in Emiratis and Expatriate Population of United Arab Emirates 2019-2021: The EmPark Study.

Background: Phenotypic differences in Parkinson’s Disease (PD) among locals (Emiratis) and Expatriates (Expats) living in United Arab Emirates have not been described and could be important to unravel local aspects of clinical heterogenicity of PD pointing towards genetic and epigenetic variations. Objective: To investigate the range and nature of motor and nonmotor clinical presentations of PD and its impact on time to diagnosis, local service provisions, and quality of life in Emiratis and Expats in UAE, as well as address the presence of current unmet needs on relation to care and etiopathogenesis of PD related to possible genetic and epigenetic factors. Methods: a cross-sectional one point in time prospective, observational real-life study of 171 patients recruited from PD and Neurology clinics across United Arab Emirates from 2019–2021. Primary outcomes were sociodemographic data, motor and nonmotor symptoms (NMS), including cognition and sleep, and quality of life (QOL) assessments, Results: A total of 171 PD patients (52 Emiratis 119 Expats) were included with mean age (Emiratis 48.5 (13.1) Expats 64.15 (13.1)) and mean disease duration (Emiratis 4.8 (3.2) Expats 6.1 (2.9)). In the Emiratis, there was a significant mean delay in initiating treatment after diagnosis (Emiratis 1.2 (0.9) Expats 1.6 (1.1)), while from a clinical phenotyping aspect, there is a high percentage of akinesia 25 (48.1) or tremor dominant (22 (42.3)) phenotypes as opposed to mixed subtype 67 (56.3) in Expat cohorts; double tremor dominant, especially Emirati females (25%), had a predominant lower limb onset PD. Both Emirati (27.9 (24.0)) and Expat 29.4 (15.6) showed moderate NMS burden and the NMS profile is dominated by Sleep, Fatigue, Mood, Emotional well-being 3.0 (1.1) and Social Stigma 3.5 (0.9) aspects of PDQ8 SI measurements are predicted worse QOL in Emiratis, while lack of social support 2.3 (1.3) impaired QOL in Expat population. Awareness for advanced therapies was low and only 25% of Emiratis were aware of deep brain surgery (DBS), compared to 69% Expats. Only 2% of Emiratis, compared to 32% of Expats, heard of Apomorphine infusion (CSAI), and no (0%) Emiratis were aware of intrajejunal levodopa infusion (IJLI), compared to 13% of expats. Conclusion: Our pilot data suggest clinical phenotypic differences in presentation of PD in Emiratis population of UAE compared to expats. Worryingly, the data also show delayed treatment initiation, as well as widespread lack of knowledge of advanced therapies in the Emirati population.

Identification of TARDBP Gly298Ser as a founder mutation for amyotrophic lateral sclerosis in Southern China

BackgroundAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by predominant impairment of upper and lower motor neurons. Over 50 TARDBP mutations have been reported in both familial (FALS) and sporadic ALS (SALS). Some mutations in TARDBP, e.g. A382T and G294V, have genetic founder effects in certain geographic regions. However, such prevalence and founder effect have not been reported in Chinese.MethodsWhole-exome sequencing (WES) was performed in 16 Chinese FALS patients, followed by Sanger sequencing for the TARDBP p.Gly298Ser mutation (G298S) in 798 SALS patients and 1,325 controls. Haplotype analysis using microsatellites flanking TARDBP was conducted in the G298S-carrying patients and noncarriers. The geographic distribution and phenotypic correlation of the TARDBP mutations reported worldwide were reviewed.ResultsWES detected the TARDBP G298S mutation in 8 FALS patients, and Sanger sequencing found additional 8 SALS cases, but no controls, carrying this mutation. All the 16 cases came from Southern China, and 7 of these patients shared the 117-286-257-145-246-270 allele for the D1S2736-D1S1151-D1S2667-D1S489-D1S434-D1S2697 markers, which was not found in the 92 non-carrier patients (0/92) (p < 0.0001) and 65 age-matched and neurologically normal individuals (0/65) (p < 0.0001). The A382T and G298S mutations were prevalent in Europeans and Eastern Asians, respectively. Additionally, carriers for the M337V mutation are dominated by bulbar onset with a long survival, whereas those for G298S are dominated by limb onset with a short survival.ConclusionsSome prevalent TARDBP mutations are distributed in a geographic pattern and related to clinical profiles. TARDBP G298S mutation is a founder mutation in the Southern Chinese ALS population.

Patients with lower limb‐onset ALS who have a longer duration from onset to diagnosis have a better prognosis

Background Useful and plain prognostic markers for amyotrophic lateral sclerosis (ALS) progression are desired to propose a suitable living setting for patients and their caregivers and to archive appropriate clinical trials. Aim To archive an additional prognostic marker for ALS progression, we evaluated the usefulness of duration from onset to diagnosis (DOD) as a prognostic factor by stratifying patients with onset sites. Methods We retrospectively enrolled 200 patients. The cutoff period for DOD was set to 12 months, which was derived from ROC curve. The patients were divided into two groups by DOD. We analyzed the differences in the time from onset to the endpoint in the two groups. The endpoint was defined as their death due to ALS progression or the application of invasive positive pressure ventilation. Results We found that patients in short DOD group had significantly shorter survival rate than patients in the long DOD group. When divided by onset sites, the time from onset to the endpoint was significantly different among each group. Particularly, the prognosis of patients in the long DOD group with lower limb onset was extremely better than other groups. A significant positive correlation was detected between DOD and the time from onset to the endpoint. Moreover, DOD was negatively correlated with changes in body mass index and ALS functional rating scale-revised, both of which were reported as the prognostic markers of ALS. Conclusion DOD might become a simple and useful indicator for the prognosis of ALS.

Progressive medial temporal degeneration with TDP-43 pathology is associated with upper limb and bulbar onset types of amyotrophic lateral sclerosis

This study aimed to clarify the relationship between progressive medial temporal atrophy and onset subtype in patients with amyotrophic lateral sclerosis (ALS). Medial temporal atrophy, ALS functional rating scale (ALSFRS), and cognitive function were assessed in 119 patients who were grouped into three ALS subtypes: bulbar, upper limb, and lower limb onset. Medial temporal atrophy, represented by a Z-score, was determined using an analysis software of magnetic resonance images known as the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD). Among 119 patients, 60 underwent follow-up VSRAD, ALSFRS, and cognitive testing. The sequential data were compared among onset subtypes. Furthermore, TDP-43 pathology was assessed in 20 autopsied patients (including seven who underwent VSRAD before death) to examine the relationships among medial temporal atrophy, onset subtypes, and severity of the hippocampal TDP-43 pathology. Multiple regression analysis revealed that the Z-score at baseline was associated with the age of onset and duration of illness. A high Z-score at baseline and the bulbar/upper limb subtypes affected the progression rate of Z-score. Pathological examination revealed increased hippocampal TDP-43 pathology score associated with bulbar and upper limb subtypes. Moreover, the Z-score before death correlated with the hippocampal TDP-43 pathology score. Medial temporal atrophy in ALS is associated with bulbar and upper limb onset subtypes. This progression may be related to the extent of TDP-43 pathology.

P.022 Prognosis in arm and leg tremor onset Parkinson Disease

Background: There is no biological marker of progression in early Parkinson Disease (PD). Upper limb (UL) tremor is the most common motor symptom at onset. The significance of lower limb (LL) tremor remains unknown. We report on longitudinally followed autopsy-verified PD tremor onset cases. Methods: A chart review of longitudinally followed autopsy-verified PD cases was performed. Age and mode of onset were recorded at initial evaluation. Prognosis was measured by change in Hoehn and Yahr scale while on levodopa (LD). Results: Forty-nine patients were included. Thirty-eight cases had upper limb (UL), four lower limb (LL), and seven upper and lower limb (ULL) onset tremor. UL had 86.8% response to LD, LL 50% and ULL 85.7%. Sub-analysis of UL responders found 20% mild improvement, 53.3% moderate and 26.7% marked. ULL had moderate response in 83.3% and marked in 16.7%. LL responders only had mild improvement with LD. Conclusions: Tremor onset is most common in UL, followed by ULL and then LL. LL onset tremor cases have an inferior response to LD when compared to UL and ULL cases. We plan for further pathophysiologic studies to investigate LL onset in PD.

100 All that glitters is not GARS

BackgroundA 22-year-old woman was initially assessed in the context of a family history of distal wasting and weakness, typically with upper limb onset, then lower limb involvement. When assessed as a child her phenotype was recognised to be atypical compared to her sister, but she was thought to be affected. Ultimately the family was diagnosed with distal hereditary motor neuropathy due to a GARS mutation. However, this patient did not carry the mutation, prompting further evaluation.CaseAt age 11 the left foot was smaller with some toe clawing and cavus deformity. Left sided wasting of tibialis anterior and the posterior compartment was seen, ankle dorsiflexors were grade 3.ResultsNerve conduction studies and EMG were normal in the right leg and arms. Chronic denervation was identified in L4, L5 and S1. MRI of lumbar spine was normal. However, 2 areas of marked thickening and enhancement were seen in the left sciatic nerve in the upper thigh and a further lesion in the mid- thigh. Fascicular preservation of the nerve was felt to be strongly suggestive of a perineurioma.DiscussionThis case highlights the importance of careful phenotyping when validating novel variants in potentially causative genes.c.doherty@ucl.ac.uk

Creatine kinase and prognosis in amyotrophic lateral sclerosis: a literature review and multi-centre cohort analysis

BackgroundAmyotrophic lateral sclerosis (ALS) is a prognostically heterogeneous neurodegenerative disease. Blood creatine kinase (CK) level has been inconsistently reported as a prognostic biomarker and raised levels in some ALS patients have been presumed to reflect muscle wasting, which is also variable.MethodsMEDLINE was systematically searched for papers related to CK in ALS and the relevant studies were reviewed. Using data from 222 ALS patients in a multi-centre, prospective, longitudinal cohort, survival analyses using Kaplan–Meier and Cox proportional hazards models were undertaken in relation to CK and other prognostic factors.ResultsTwenty-five studies investigating CK in ALS were identified, of which 10 specifically studied the link between CK and survival. Five studies observed no association, four found that higher CK levels were associated with longer survival and one, the opposite. In our cohort (n = 222), 39% of patients had a CK level above the laboratory reference range. Levels were higher in males compared to females (p < 0.001), in patients with limb versus bulbar onset of symptoms (p < 0.001) and in patients with higher lower motor neuron burden (p < 0.001). There was no significant trend in longitudinal CK values. Although a higher standardised log (CK) at first visit was associated with longer survival in univariate analysis (hazard ratio 0.75, p = 0.003), there was no significant association after adjusting for other prognostic covariates.ConclusionWhile raised CK levels in ALS do reflect lower motor neuron denervation to a large extent, they are not independently associated with survival when measured in the symptomatic phase of the disease.

Iron-sensitive MR imaging of the primary motor cortex to differentiate hereditary spastic paraplegia from other motor neuron diseases.

Hereditary spastic paraplegia (HSP) is a group of genetic neurodegenerative diseases characterised by upper motor neuron (UMN) impairment of the lower limbs. The differential diagnosis with primary lateral sclerosis (PLS) and amyotrophic lateral sclerosis (ALS) can be challenging. As microglial iron accumulation was reported in the primary motor cortex (PMC) of ALS cases, here we assessed the radiological appearance of the PMC in a cohort of HSP patients using iron-sensitive MR imaging and compared the PMC findings among HSP, PLS, and ALS patients. We included 3-T MRI scans of 23 HSP patients, 7 PLS patients with lower limb onset, 8 ALS patients with lower limb and prevalent UMN onset (UMN-ALS), and 84 ALS patients with any other clinical picture. The PMC was visually rated on 3D T2*-weighted images as having normal signal intensity, mild hypointensity, or marked hypointensity, and differences in the frequency distribution of signal intensity among the diseases were investigated. The marked hypointensity in the PMC was visible in 3/22 HSP patients (14%), 7/7 PLS patients (100%), 6/8 UMN-ALS patients (75%), and 35/84 ALS patients (42%). The frequency distribution of normal signal intensity, mild hypointensity, and marked hypointensity in HSP patients was different than that in PLS, UMN-ALS, and ALS patients (p < 0.01 in all cases). Iron-sensitive imaging of the PMC could provide useful information in the diagnostic work - up of adult patients with a lower limb onset UMN syndrome, as the cortical hypointensity often seen in PLS and ALS cases is apparently rare in HSP patients. • The T2* signal intensity of the primary motor cortex was investigated in patients with HSP, PLS with lower limb onset, and ALS with lower limb and prevalent UMN onset (UMN-ALS) using a clinical 3-T MRI sequence. • Most HSP patients had normal signal intensity in the primary motor cortex (86%); on the contrary, all the PLS and the majority of UMN-ALS patients (75%) had marked cortical hypointensity. • The T2*-weighted imaging of the primary motor cortex could provide useful information in the differential diagnosis of sporadic adult-onset UMN syndromes.

Differentiating Slowly Progressive Subtype of Lower Limb Onset ALS From Typical ALS Depends on the Time of Disease Progression and Phenotype.

BackgroundFlail leg syndrome (FLS) is a regional variant of amyotrophic lateral sclerosis (ALS) with the characteristics of slow progression and the symptoms confined to the lumbosacral region for extended periods. However, FLS may not be easily differentiated from typical ALS.ObjectiveThe objective of the study was to determine a cutoff time of disease progression that could differentiate FLS from the typical lower limb onset ALS.MethodsA cutoff point analysis was performed with maximally selected log–rank statistics in patients with lower limb onset ALS registered from 2009 to 2013. Based on the cutoff duration from the lower limb onset to second region significantly involved (SRSI), all patients were divided into the slowly progressive subtype of lower limb onset ALS group and the typical lower limb-onset ALS group. Patients with the slowly progressive subtype of the lower limb onset ALS, who had the flail leg phenotype, were classified as patients with FLS. Differences between groups were analyzed.ResultsAmong the 196 patients recruited, 157 patients with a duration <14 months from lower limb onset to SRSI were classified as having typical lower limb onset ALS. Twenty-nine patients with a duration more than or equal to 14 months and the flail leg phenotype were classified as having FLS. Patients with FLS exhibited a median diagnostic delay of 25 months, a median duration of 24 months from lower limb onset to SRSI, a forced vital capacity abnormity rate of 12.5% at the first visit to our department, and a median survival time of 80 months, which were significantly different from those of patients with typical lower limb onset ALS (p < 0.001, p < 0.001, p = 0.024, p < 0.001). The 5-year survival rate of the FLS group (79.3%) was much higher than that of the other group (1.9%).ConclusionsA crucial feature in differentiating FLS from typical lower limb onset ALS in Chinese patients may be symptoms confined to the lumbosacral region for at least 14 months, which may be better than 12 or 24 months used in the previous studies. The FLS was characterized by slower progression, less and later respiratory dysfunction, and a more benign prognosis than the typical lower limb onset ALS.