Neuromuscular disease genetics in under-represented populations: increasing data diversity

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses ‘solved’ or ‘possibly solved’ ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% ‘solved’ and ∼13% ‘possibly solved’ outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally

Longitudinally extensive transverse myelitis due to toxoplasma: An autopsy study

Toxoplasma is an obligate intracellular parasite that remains asymptomatic in humans but, at times, can cause devastating disease. Here, we describe an autopsy study of a young immunocompetent gentleman with no comorbidities whose presentation was acute transverse myelitis. Magnetic resonance imaging spine showed longitudinally extensive spinal cord lesion (LESCL) that mimicked neuromyelitis optica with normal brain imaging at presentation. Investigations showed albuminocytological dissociation which prompted a course of parenteral steroid. However, the lesion relentlessly progressed to involve the brain stem and cerebrum leading to toxoplasmic encephalitis that terminated fatally. This report highlights that toxoplasma can present as LESCL and needs to be considered in the differential diagnosis of atypical myelitis

Predictors of Prolonged Duration of Mechanical Ventilation and Mortality in Patients with Guillian-Barre Syndrome

Background: Nearly one-third of the patients with Guillian-Barre syndrome (GBS) require ventilatory assistance, the duration of which is variable. There are no studies from India to predict the duration of ventilatory requirement in patients with GBS which might help direct the clinician to perform a tracheostomy. Aim: To study the predictors that determine the duration of mechanical ventilation (MV) and the outcome of GBS patients requiring MV. Materials and Methods: This is a retrospective, observational study from a referral teaching hospital. All consecutive patients diagnosed with GBS and requiring mechanical ventilation between 2009-2018 were included in the study. The demographic, clinical parameters, electrophysiological data, complications and outcome of these patients was noted. Factors predicting prolonged MV (>2 weeks) were statistically assessed. Result: Out of 79 patients requiring MV, 45(57%) patients needed prolonged MV and tracheostomy was performed in 29(37%). On multivariate regression analysis, sepsis (p=0.02; {95%CI 1.3-24.4}), MRC sum score (p=0.01; {95% CI 0.89-0.99}) and lower albumin levels on day 14(p=0.004{95% CI 0.05-0.57}) correlated with prolonged duration of MV. On univariate analysis, axonal variant of GBS(p=0.02), presence of chronic renal disease(p=0.03) and pulmonary disease(p=0.01) were associated with significant mortality. On multivariate regression analysis, age (>60 years) (p=0.001) {95% CI 0.89-0.97}, prolonged duration of MV(p=0.02) {95%CI 0.88-0.99}, MRC sum score(p=0.01) {95% CI 1.01-1.1} correlated with poor outcome. Conclusions: Sepsis and septic shock and not the choice of immunotherapy nor the electrophysiological subtypes of GBS determined the prolonged duration of MV in our cohort, though the axonal variant on electrophysiology predicted the mortality

The sensitivity of electrodiagnostic criteria in subtype identification at the presentation in patients of Guillain-Barre syndrome

Introduction: Electrophysiology plays a pivotal role in identifying various GBS subtypes. Despite having many electrodiagnostic criteria,studies addressing their applicability in patients of GBS at diagnosis are quite a few. Purpose: This study evaluates the sensitivity of 5 known electrophysiological criteria in patients with GBS at the time of presentation. Material & Methods: Clinical and electrophysiological data of GBS patients admitted with us between January 2011 and December 2016 were collected retrospectively from our hospital database, compiled and analyzed. For each patient, 5 different criteria for the electrophysiological diagnosis of GBS were applied, and the sensitivity of these 5 criteria in the diagnosis was evaluated. Results: A total of 288 patients were included. Closer concordance was noted between the criteria in diagnosing axonal subtype (Range- 36.81% to 41.32%).Italian criteria had the highest sensitivity (41.32%). There was a wider variation in the diagnosis of AIDP (Range- 19.79 to 34.72%). Hadden criteria showed the highest sensitivity (34.72%) closely followed by Ho et al (34.02%). Conclusion: As the timing of Nerve Conduction Studies (NCS) and the severity of disease influence the grouping of each patient into a specific electrophysiologic subtype, one should be cautious in interpreting electrodiagnosticdata. Serial nerve conduction studies may be required to subtype each patient as electrophysiology evolves over the first few weeks of illness

Vasculitic neuropathy: A retrospective analysis of nerve biopsies and clinical features from a single tertiary care center

Objective: Vasculitic neuropathy can be either restricted to the peripheral nerves or associated with systemic involvement of other organs. The objective of this study was to analyze the nerve biopsies reported as “vasculitic neuropathy” with clinical features. Materials and Methods: All cases diagnosed with vasculitic neuropathy were retrospectively analyzed and categorized as systemic vasculitis and nonsystemic vasculitic neuropathy based on the clinical features. The histological features were further evaluated and classified according to the Peripheral Nerve Society Guidelines. Results: Of the 126 cases, there were 65 nonsystemic vasculitis, 45 secondary systemic vasculitis, and 16 primary systemic vasculitis. Definite vasculitis was more common in the systemic vasculitis group. The epineurial vessels were predominantly involved with chronic axonal changes. Conclusion: The sensitivity of definite vasculitis on nerve biopsy was 54.76%. The sensitivity increases when the diagnostic criteria of definite and probable vasculitis were applied taking into account perivascular inflammation accompanied by vascular changes and axonopathy

A series of biopsy-proven patients with immunoglobulin G4-related neurological disease

Aim: To study the clinical presentation, radiological findings, and therapy responsiveness of patients with biopsy-proven immunoglobulin G4 (IgG4)-related neurological disease. Methods: The study was conducted between January 2016 and March 2018 from the Department of Neurology and Pathology of Nizam's Institute of Medical Sciences. Patients with neurological symptoms and biopsy suggestive of IgG4-related disease (IgG4-RD) were included. These patients were studied for their demographic pattern and clinical presentation. The presence of serological markers such as vasculitic profile and IgG4 levels was analyzed. Radiological findings were studied in detail. Therapeutic agents used and the response to therapy were assessed. Results: There were six cases with IgG4-related neurological disease which were all hypertrophic pachymeningitis. The age ranged from 35 to 64 (mean = 46) years. The clinical presentation was acute in one, subacute in two, and chronic in three patients. The most common presenting symptom was headache (4), followed by gait and/or urinary disturbances (2), paraparesis (1), and diplopia (1). IgG4 levels were elevated in 50% of them. Pseudotumor-like mass and sinovenous thrombosis, not described previously, were seen in one patient. All the patients were treated with oral or intravenous steroid. Rituximab was given in three patients; azathioprine was the steroid-sparing agent in one patient. Those with acute/subacute onset of presentation had an excellent response to steroids. All the patients with a chronic duration of their symptoms received empirical anti-tuberculous therapy before a definitive diagnosis of Ig G4-RD was made. Conclusions: The characterization of patients with IgG4-related neurological disease based on the understanding of the clinical spectrum increases the confidence in the clinician to resort to early immunosuppression, thereby having prognostic implications

Development of global rating instruments for pediatric patients with ataxia telangiectasia

NTRODUCTION: Ataxia telangiectasia (AT) is a neurodegenerative disorder with cerebellar and extrapyramidal features. Interventional and epidemiological studies in AT should rely on specific scales which encompass the specific neurological features, as well the early progressive course and the subsequent plateau. The aim of this study was to build a scale of the CGI type (Clinical Global Impression) which is disease specific, as well as to check the feasibility of the ICARS scale for ataxia in this population. METHODS: We recruited 63 patients with ataxia, aged 10.76 ± 3.2 years, followed at 6 international AT centers, 49 of them (77.8%) with classical AT. All patients were evaluated for ataxia with ICARS scale. In patients with AT, two CGI scales were scored, unstructured as structured for which separate anchors were provided. RESULTS: Mean ICARS score was 44.7 ± 20.52, and it's severity positively correlated with age (Spearman correlation, r = 0.46, p < 0.01). Mean CGI score was 2 (moderately involved). There was a high correlation between the structured and unstructured CGIs (Spearman correlation, r = 0.87, p < 0.01). Both CGI scales showed positive correlation between severity and increasing age (Spearman correlation r = 0.59, p < 0.01 for structured CGI and r = 0.61, p < 0.01 for unstructured). DISCUSSION: We succeeded to build two CGI scales: structured and unstructured, which are disease specific for AT. The unstructured scale showed better connection to disease course; the sensitivity of the unstructured scale could be improved by adding anchors related to extrapyramidal features. In addition we showed that ataxia can be reliably measured in children with AT by using ICAR