Merrilee Needham

Introduction: Clinico-pathologically overlapping inherited dis- orders indicate that genetic factors might be involved in sporadic inclusion body myositis (IBM) pathogenesis. Objectives: To identify genetic risk factors associated with IBM. Methods: Whole-exome sequencing was performed in 205 IBM patients. Muscle tissue was pathologically evaluated and whole- transcriptome expression profiles generated. Results: We identified eight rare missense mutations in the SQSTM1 and VCP genes in 10 IBM patients (5%). Five of the mutations had been previously reported in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) with Paget’s disease of bone (PDB); p62 staining was increased and MHC-I was up-regulated in the muscle tissue of these patients, Conclusions: Variants in SQSTM1 and VCP may constitute genetic susceptibility factors for IBM. The occurrence of mutations in SQSTM1 and VCP in IBM, ALS, FTD and PDB rein- forces the link between these disorders, pinpointing converging pathogenic pathways resulting in impaired autophagy-lysosome processing, causing dysregulation of protein homeostasis.

Introduction: Our knowledge of incidence and outcomes of MS relapses with specific symptomatology is limited. For example, optic neuritis is more common in early MS and the ability to recover deteriorates with longer disease duration. However, a comprehensive evaluation of multiple sclerosis relapse phenotypes, comprising clinical presentations, severity, impact and recovery, and capturing full spectrum of MS courses, duration and patient demography, has not yet been done. Aim: To identify patterns of clinical MS relapses, their impact on specific neuroanatomical locations and their associations with demographic and clinical parameters. Methods: Information about relapse symptomatology was collected prospectively in 17,555 eligible patients and 104,333 patient-years recorded in MSBase, an international observational MS registry. In a proportion of the relapses, information about relapse severity, impact on activities of daily living and recovery was available. Associations between relapse phenotype and patient characteristics were tested with a series of multivariable logistic regression models. Principal component analysis was conducted to assess the tendency of the specific relapse locations to be involved sequentially in individual patients. Results: Of 63,343 relapses, the majority affected pyramidal and sensory functions. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were recorded mostly in earlier disease and less commonly in relapsing-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women more commonly presented with sensory or visual symptoms, while men were more prone to pyramidal, brainstem and cerebellar relapses. Relapses were likely to recur within the previously affected locations (odd ratios 1.8 – 5, p = 10^-13), with pyramidal, sphincter and sensory relapses often converging within the same individuals (eigenvalue = 2.1, loadings 0.59-0.68). Sensory relapses had a lower impact on daily activities and together with visual and brainstem relapses showed better recovery than the other relapse presentations. Finally, relapse severity increased and the ability to recover decreased with age or more advanced disease. Conclusions: Patterns of clinical relapse symptomatology vary with respect to demographic and clinical factors, including age, sex, MS duration, course and stage.

Introduction: Only one large retrospective cohort study and several smaller analyses examined predictors of relapse incidence in MS. Sex, age and MS duration were suggested as determinants of relapse activity. While in relapsing-remitting MS women are overrepresented in the ratio of 3:1 to men, in primary progressive disease both sexes are represented equally. A lower probability of relapse in men could be the reason for this change, with primary progressive (PP) MS representing the “extreme” of low relapse activity. Aims: To evaluate effect of sex on the incidence of MS relapses. To assess the hypothesis that the female-to-male ratio increases gradually with relapse activity and that PPMS represents a non-relapsing extreme along this continuum. To directly compare effects of age and MS duration on relapse incidence. Methods: Annualised relapse rates were calculated using the MSBase registry. Patients with incomplete data or less than one year of follow-up were excluded. Patients with PPMS were only included in the sex ratio analysis. Relapse incidences over 40 years of MS duration or up to 70 years of age were compared between females and males using Andersen-Gill and Poisson models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and PPMS. All models were adjusted for therapy and pregnancy. Results: Among 11,570 eligible patients with relapse-onset MS (82,552 patient-years), 48,362 relapses were recorded. Relapse frequency was 17.7% higher in females compared to males. Within the initial five years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 to >=4 relapses per year, respectively. The magnitude of this sex effect increased at longer MS duration and older age. However, the female-to-male ratio in patients with relapse-onset MS and zero relapses in any given year was double that of the patients with PPMS. Patient age was a more important determinant of decline in relapse incidence than disease duration. Conclusions: Females are predisposed to higher relapse activity than males. However, this sex-related effect does not explain the markedly lower female-to-male ratio in PPMS. Decline in relapse activity over time is more closely related to patient age than MS duration. This information helps us better understand the effects of sex and time on relapse incidence and define PPMS as an entity distinct from the relapse-onset MS.

Background: While much has been written in recent years about mirror movements, where voluntary movements of the fingers on one side invoke involuntary movements of a similar character in contralateral fingers, the related phenomenon of homolateral imitative synkinesis (HIS) has been largely ignored. Here, voluntary movements of the hand invoke similar movements in the ipsilateral leg or vice versa. Both phenomena are seen in normal children but persistence into adulthood implies a pathological process. Method and Results: We describe four patients with HIS. The first was a 71 year-old man with mild right hemiparesis associated with a small $48 Monday, November 7, 2005 Oral Platform Abstracts single melanoma metastasis in the hand area of the left primary motor cortex. Each time he raised his right arm, the right leg elevated. This amused him. It did not happen on the other side. The other patients with similar findings had, respectively: vascular dementia, right parietal meningioma and dystonia (with signal intensity changes in the basal ganglia). Mirror movements were present in some patients. Previous studies also reported a wide variety of lesion location for this sign: parietal cortex, thalamus, internal capsule, cerebellum and dorsal columns. The hallmark of HIS is loss of specificity of voluntary movements in a limb with respect to the other ipsilateral limb. Possible mechanisms include changes in cortical functional localization in response to focal lesions, loss of surround inhibition, and 'cross-talk" between adjacent fibres (as occurs in facial nerve synkinesis). Conclusion: HIS is an interesting but neglected sign which may provide insights into plasticity and the brain's response to focal lesions.