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Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive disease caused by mutations in the TTR gene leading to multisystem organ dysfunction. Pathogenic TTR aggregation, misfolding, and fibrillization lead to deposition of amyloid in multiple body organs and frequently involve the peripheral nerve system and the heart. Common neurologic manifestations include: sensorimotor polyneuropathy (PN), autonomic neuropathy, small-fiber PN, and carpal tunnel syndrome. Many patients have significant progression due to diagnostic delays as hATTR PN is not considered within the differential diagnosis. Recently, two effective novel disease-modifying therapies, inotersen and patisiran, were approved by Health Canada for the treatment of hATTR PN. Early diagnosis is crucial for the timely introduction of these disease-modifying treatments that reduce impairments, improve quality of life, and extend survival. In this guideline, we aim to improve awareness and outcomes of hATTR PN by making recommendations directed to the diagnosis, monitoring, and treatment in Canada.

Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy., Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261., Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups., Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran., Funding: Alnylam Pharmaceuticals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

We report the recruitment activities and outcomes of a multi-disease neuromuscular patient registry in Canada. The Canadian Neuromuscular Disease Registry (CNDR) registers individuals across Canada with a confirmed diagnosis of a neuromuscular disease. Diagnosis and contact information are collected across all diseases and detailed prospective data is collected for 5 specific diseases: Amyotrophic Lateral Sclerosis (ALS), Duchenne Muscular Dystrophy (DMD), Myotonic Dystrophy (DM), Limb Girdle Muscular Dystrophy (LGMD), and Spinal Muscular Atrophy (SMA). Since 2010, the CNDR has registered 4306 patients (1154 pediatric and 3148 adult) with 91 different neuromuscular diagnoses and has facilitated 125 projects (73 academic, 3 not-for-profit, 3 government, and 46 commercial) using registry data. In conclusion, the CNDR is an effective and productive pan-neuromuscular registry that has successfully facilitated a substantial number of studies over the past 10 years.

The COVID-19 pandemic has had a major impact on clinical practice. Safe standards of practice are essential to protect health care workers while still allowing them to provide good care. The Canadian Society of Clinical Neurophysiologists, the Canadian Association of Electroneurophysiology Technologists, the Association of Electromyography Technologists of Canada, the Board of Registration of Electromyography Technologists of Canada, and the Canadian Board of Registration of Electroencephalograph Technologists have combined to review current published literature about safe practices for neurophysiology laboratories. Herein, we present the results of our review and provide our expert opinion regarding the safe practice of neurophysiology during the COVID-19 pandemic in Canada.

Background: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population., Methods: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials., Results: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner., Conclusion: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.

Objectives: To approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families., Design: Retrospective cohort study., Setting: Clinics across North America., Participants: The study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis., Methods: Phenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed., Results: Among 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members., Discussion: The familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis., Competing Interests: Competing interests: RJB served as a consultant for NuFactor and Momenta Pharmaceutical and receives research support from PTC Therapeutics, Ra Pharma, Orphazyme, Sanofi Genzyme, FDA OOPD, NIH and PCORI. MB reports grant support from Muscular Dystrophy Association, ALS Association, ALS Recovery Fund, Kimmelman Estate, Target ALS, Eli Lilly & Company and the National Institutes of Health (NIH) during the conduct of the study. He also reports grant support from FDA, CDC and DOD; research support from Alexion Pharmaceuticals, UCB, Cytokinetics, Neuraltus, Biogen and Orphazyme A/S; and personal fees from NMD Pharma, Ra Pharmaceuticals, Mitsubishi-Tanabe, Avexis, UCB and Denali outside the submitted work. VC served as a consultant for review and expert testimony for the Department of Health and Human Services and the Department of Justice under the Vaccine Injury and Compensation Program. Dr Chaudhry has received royalty for total neuropathy score (TNS) patented (through Johns Hopkins University) for license of TNS use from AstraZeneca, Genentech, Seattle Genetics, Calithera Biosciences, Merrimack Pharmaceuticals, Levicept, and Acetylon Pharmaceuticals. MMD serves or recently served as a consultant for ArgenX, Catalyst, CSL-Behring, Kezar, Momenta, NuFactor, RMS Medical, Sanofi Genzyme, Shire Takeda, and Spark Therapeutics. Dr Dimachkie received grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, CSL-Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Sanofi Genzyme, Octapharma, Orphazyme, Sarepta Therapeutics, Shire Takeda, Spark, UCB Biopharma, Viromed & TMA. AE was a member of the advisory board for Alexion, a scientific award jury member for Grifols and safety data monitor for UCB. MF has received honoraria for serving on advisory boards for ARGNX pharma, Alexion. MF also has research support from Catalyst, Ra pharma, Amicus, Orphazyme, Alexion, Momenta and Alnylam. JFH reports research support and grants from Alexion Pharmaceuticals, argenx BVBA, Centers for Disease Control and Prevention, Muscular Dystrophy Association, NIH (including the National Institute of Neurologic Disorders and Stroke and the National Institute of Arthritis and Musculoskeletal and Skin Disease), PCORI (Patient-Centered Outcomes Research Institute) and Ra Pharmaceuticals; and nonfinancial support from Alexion Pharmaceuticals, argenx BVBA, Ra Pharmaceuticals and Toleranzia. HJK is funded by the Muscular Dystrophy Association (508240) and by NIH grant U54NS115054; is a consultant for Alnylam Pharmaceuticals, Ra Pharmaceuticals, and UCB Pharmaceuticals; and is CEO of ARC Biotechnology, LLC, which receives support from the NIH (R41NS110331). He serves on the Editorial Board of Experimental Neurology. MMe has received honoraria as a speaker and/or moderator from Alnylam, Akcea, Pfizer and CSL Behring. She has served on Advisory Boards for Pfizer, Alnylam and Akcea. She serves as an investigator for clinical trials with Alnylam and Biogen. SM has served on advisory board meetings for Alexion and argenx. MP served on advisory board for CSL Behring, Alexion pharmaceuticals, Argenx Pharmaceuticals and has been consultant for Momenta Pharmaceuticals. DPR receives research funding from a Sponsored Research Agreement from Cabaletta Bioscience. BJT holds an American and European Union patent on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72, and has received research grants from The Myasthenia Gravis Foundation, the Robert Packard Center for ALS Research, the ALS Association (ALSA), the Italian Football Federation (FIGC), the Center for Disease Control and Prevention (CDC), the Muscular Dystrophy Association (MDA), Merck and Microsoft Research. BJT receives funding through the Intramural Research Program at the National Institutes of Health., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Animal studies suggest that decreased vascular mitochondrial DNA copy number can promote hypertension. We conducted a chart review of blood pressure and hemodynamics in patients with either mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS, n = 36) or individuals with variants in the mitochondrial DNA polymerase gamma (POLG, n = 26). The latter included both pathogenic variants and variants of unknown significance (VUS). Hypertension rates (MELAS 50%, POLG 50%) were elevated relative to Canadian norms in 20-39 (MELAS) and 40-59 (MELAS and POLG) years of age groups. Peripheral resistance was high in the hypertensive versus normotensive patients, potentially indicative of microvascular disease. Despite antihypertensive treatment, systolic blood pressure remained elevated in the POLG versus MELAS group. The risk of hypertension was not associated with MELAS heteroplasmy. Hypertension rates were not different between individuals with known pathogenic POLG variants and those with VUS, including common variants. Hypertension (HT) also did not differ between patients with POLG variants with (n = 17) and without chronic progressive external opthalmoplegia (n = 9) (CPEO). HT was associated with variants in all three functional domains of POLG. These findings suggest that both pathogenic variants and several VUS in the POLG gene may promote human hypertension and extend our past reports that increased risk of HT is associated with MELAS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Background: A 56-year-old female, diagnosed as a carrier of the mitochondrial DNA mutation (MTTK c.8344A > G) associated with the MERRF (myoclonic epilepsy with ragged red fibers) syndrome, presented with a relatively uncommon but well-known phenotypic manifestation: severe multiple symmetric lipomatosis (MSL). After surgical resection of three kilograms of upper mid-back lipomatous tissue, the patient experienced a significant decline in her functional capacity and quality of life, which ultimately resulted in her placement on long-term disability., Methods: Dissatisfied with the available treatment options centered on additional resection surgeries, given the high probability of lipoma regrowth, the patient independently researched and applied alternative therapies that centred on a carbohydrate-restricted diet and a supervised exercise program., Results: The cumulative effect of her lifestyle interventions resulted in the reversal of her MSL and her previously low quality of life. She met all her personal goals by the one-year mark, including reduced size of the residual post-surgical lipomas, markedly enhanced exercise tolerance, and return to work. She continues to maintain her interventions and to experience positive outcomes at the two-year mark., Interpretation: This case report documents the timing and nature of lifestyle interventions in relation to the reversal in growth pattern of her previously expanding and debilitating lipomas. The profound nature of the apparent benefit on lipoma growth demonstrates the intervention's potential as a new feasible non-surgical therapy for mitochondrial-disease-associated MSL, and justifies its systematic study. We also describe how this case has inspired the care team to re-examine its approach to involved patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Background: Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin., Methods: In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]×albumin level in grams per liter; lower values indicated worse nutritional status)., Results: A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (±SD) mNIS+7 at baseline was 80.9±41.5 in the patisiran group and 74.6±37.0 in the placebo group; the least-squares mean (±SE) change from baseline was -6.0±1.7 versus 28.0±2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (±SD) baseline Norfolk QOL-DN score was 59.6±28.2 in the patisiran group and 55.5±24.3 in the placebo group; the least-squares mean (±SE) change from baseline was -6.7±1.8 versus 14.4±2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08±0.02 m per second with patisiran versus -0.24±0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7±9.6 versus -119.4±14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups., Conclusions: In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).

Choline acetyltransferase catalyzes the synthesis of acetylcholine at cholinergic nerves. Mutations in human CHAT cause a congenital myasthenic syndrome due to impaired synthesis of ACh; this severe variant of the disease is frequently associated with unexpected episodes of potentially fatal apnea. The severity of this condition varies remarkably, and the molecular factors determining this variability are poorly understood. Furthermore, genotype-phenotype correlations have been difficult to establish in patients with biallelic mutations. We analyzed the protein expression of phosphorylated ChAT of seven CHAT mutations, p.Val136Met, p.Arg207His, p.Arg186Trp, p.Val194Leu, p.Pro211Ala, p.Arg566Cys, and p.Ser694Cys, in HEK-293 cells to phosphorylated ChAT, determined their enzyme kinetics and thermal stability, and examined their structural changes. Three mutations, p.Arg207His, p.Arg186Trp, and p.Arg566Cys, are novel, and p.Val136Met and p.Arg207His are homozygous in three families and associated with severe disease. The characterization of mutants showed a decrease in the overall catalytic efficiency of ChAT; in particular, those located near the active-site tunnel produced the most seriously disruptive phenotypic effects. On the other hand, p.Val136Met, which is located far from both active and substrate-binding sites, produced the most drastic reduction of ChAT expression. Overall, CHAT mutations producing low enzyme expression and severe kinetic effects are associated with the most severe phenotypes., (© 2015 WILEY PERIODICALS, INC.)

Importance: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood., Objective: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study., Design, Setting, and Participants: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication., Main Outcomes and Measures: We calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0×10(-8) was set for genome-wide significance after Bonferroni correction for multiple testing., Results: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98×10(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08×10(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60×10(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32×10(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02×10(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52×10(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases., Conclusions and Relevance: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.

Introduction: Myasthenia gravis (MG) is an autoimmune disorder characterized by autoantibodies against the postsynaptic nicotinic acetylcholine receptors, muscle-specific tyrosine kinase, low-density lipoprotein receptor-related protein 4, and agrin. The incidence of thymoma in MG is reported as ∼10%-15%. The incidence of extrathoracic metastatic thymoma is exceedingly rare and may present years after resection. Associations between thymoma and immunodeficiency have also been described, including Good syndrome., Methods and Results: We describe the clinical course, investigations, and treatments performed in a patient presenting with a myasthenic crisis in the setting of acetylcholine receptor antibody-positive generalized MG 10 years postthymectomy. Computed tomography imaging revealed 2 pancreatic lesions, but no residual thoracic thymoma. Biopsy confirmed metastatic pancreatic thymoma, which was successfully resected. His course was further complicated by cytomegalovirus retinitis with a depressed CD4 count and perniosis., Discussion: This presentation was felt to be consistent with Good immunodeficiency syndrome.

Background: The pathophysiology of hypertension in patients with mitochondrial diseases is different from that of the general population. Growing evidence exists linking mtDNA, its mutations, and mitochondrial dysfunction to the pathogenesis of hypertension. No reports on the prevalence of hypertension in late-onset mtDNA diseases have been described., Methods: We performed a retrospective chart review of adult patients with late-onset mtDNA diseases between January 1999 and January 2012 at our center. We grouped them into age categories to allow comparison with previously reported Canadian Health Measures Survey (CHMS) prevalence data., Results: Twenty-three subjects with hypertension were identified for a crude prevalence of 39.7 % (95 % CI 27-53 %) as compared to the CHMS age-predicted prevalence of 30.5 %. When analyzed by individual age group, there were no significant differences between the observed and the CHMS predicted prevalence rates in the 40 years and older cohorts (age category 40-59, p = 0.63; age category 60-79, p = 0.85). However, hypertension rates were significantly higher than predicted in the under 40 years cohort (55.6 vs. 2.8 %, p < 0.001, CI 21-86 %), in which hypertensive patients with the MELAS m.3243A>G mutation were significantly clustered (p < 0.01). This younger MELAS cohort (n = 4, mean age = 24 years) with hypertension had heteroplasmy levels (mean = 68 %) that were significantly higher than the levels found in the older non-hypertensive MELAS cohort (n = 8, mean age = 52 years, mean = 33 %) (p = 0.04)., Conclusion: Relative to age, gender, and mtDNA disease subtype, young adults with high heteroplasmy levels of the MELAS m.3243A>G mutation demonstrate an increased prevalence of hypertension. Further prospective data are needed to confirm this initial finding, which has potentially important treatment implications.

Introduction: Patients with mitochondrial myopathies may develop cardiac complications such as cardiomyopathy and/or cardiac conduction defects. To identify these potentially life-threatening and treatable conditions, it is common practice to screen patients intermittently with electrocardiography and echocardiography. The optimal time interval for such screening investigations is unknown. We developed this study to review our screening results in adult-onset patients with progressive external ophthalmoplegia (PEO)., Methods: This study was a retrospective review of PEO patients with 5 years or more of cardiac screening investigations who did not have any cardiac symptoms., Results: Fifteen patients were included, and cardiomyopathy was identified on screening echocardiogram in 1 patient. Four patients had other abnormalities identified, which were unrelated to their mitochondrial myopathy., Conclusions: Only 1 patient in 15 developed cardiac complications related to mitochondrial disease during 5 years of follow-up. We suggest that a screening interval of 3-5 years is probably appropriate for adult-onset PEO patients who do not have cardiac symptoms., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Progressive external ophthalmoplegia (PEO) is a mitochondrial myopathy of ocular muscles. Diagnostic investigation usually involves limb skeletal muscle biopsy and molecular genetic studies, although diagnostic yield tends to be low. The purpose of this study was to evaluate the diagnostic yield obtained by analysis of levator palpebrae (LP) muscle tissue., Methods: This is a clinicopathologic study of 8 patients with a diagnosis of PEO, who had LP muscle biopsies as part of oculoplastic procedures. Six of these patients also had limb muscle biopsies. Histopathology, electron microscopy and genetic studies were performed., Results: Diagnostic histopathologic findings were present in 4/6 quadriceps biopsies, and 7/8 LP biopsies. Genetic testing on DNA extracted from LP muscle revealed abnormalities in 4 patients., Conclusion: In patients whose LP. muscle demonstrate both genetic defects and histopathological abnormalities, the diagnosis of PEO can be confirmed without limb muscle biopsy. Patients having LP resection during oculoplastics procedures for treatment of ptosis may therefore be able to avoid a separate procedure for limb muscle biopsy. Further study is required to determine the specificity of these findings.

Diagnosis of mitochondrial disease is often a challenge because of the extreme heterogeneity of the clinical phenotype and the variety of underlying gene defects. Insight into the range of clinical phenotypes associated with a particular mitochondrial DNA mutation will facilitate better recognition of patients at risk by focused gene testing. We present a family affected by the mitochondrial m.13513G>A (p.D393N, ND5) mutation, illustrating a previously unreported degree of clinical heterogeneity, varying from mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) in a 10-year-old female, to a fatal neonatal course with metabolic acidosis and hypotonia in a younger sister, to absence of medical problems in the mother. The mutation loads ranging from 66% in the deceased neonate to 30% in the female with MELAS and 7% in the asymptomatic mother, correlated with severity of the clinical phenotype. The importance of proactive collection and storage of appropriate samples during the diagnostic work-up of an acutely ill or deceased neonate, allowing subsequent mitochondrial investigations, is hereby illustrated., (© The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.)

Introduction: Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial syndrome on a disease spectrum with Kearns-Sayre syndrome (KSS). Clinical presentation is variable and our experience suggested that phenotypic differences exist in CPEO with onset after age 20., Methods: This descriptive study is a retrospective chart review of 40 patients with late-onset CPEO. Clinical features, laboratory and neurophysiology results were reviewed., Results: Multisystem dysfunction was very common in this series. Gastrointestinal dysfunction was more common than expected (60%) as was migraine headache (40%). Clinical characteristics on the KSS disease spectrum were uncommon in this series with only 2.5% having pigmentary retinopathy, 5% with cardiac conduction abnormality, and 22.5% having endocrinopathy (most often thyroid dysfunction rather than diabetes). Neurophysiology abnormalities included length-dependent axonal polyneuropathy in 44% (sometimes subclinical) and myopathic EMG changes in 26%. Exposure to sources of acquired mitochondrial toxicity including cigarette use and hepatitis C infection were more common than expected in this series., Discussion: Phenotype was different in this late-onset series compared with previous reports in CPEO patients. In this series of late-onset patients, multi-organ dysfunction was more common than previously reported in CPEO, and some classical mitochondrial manifestations, such as pigmentary retinopathy were rare. We suggest that acquired mitochondrial toxicity may have a role in the pathogenesis of adult-onset CPEO.

Two hundred and fifty-four ALS patients from British Columbia, Canada were screened for mutations in the gene encoding the enzyme superoxide dismutase type 1 (SOD1). Thirteen patients (5.1%) carried one of six missense mutations (A4V, G72C, D76Y, D90A, C111Y, I113T). Mutations were found both in sporadic and familial ALS cases. Atypical clinical features delayed diagnosis in some cases. The demographic and clinical features of the mutation carrying index cases are summarized, and compared with those of screened patients without mutations. The phenotypic variability between SOD1 mutation carrying patients in this study is dramatic, even among patients with the same mutation This underlines the hypothesis that ALS is a biologically heterogeneous disorder in which genetics, environment and ageing all interrelate to form the final clinical phenotype.

Prior studies describing the relationship between CAG size and the age at onset of Huntington disease (HD) have focused on affected persons. To further define the relationship between CAG repeat size and age at onset of HD, we now have analyzed a large cohort of affected and asymptomatic at-risk persons with CAG expansion. This cohort numbered 1,049 persons, including 321 at-risk and 728 affected individuals with a CAG size of 29-121 repeats. Kaplan-Meier analysis has provided curves for determining the likelihood of onset at a given age, for each CAG repeat length in the 39-50 range. The curves were significantly different (P < .0005), with relatively narrow 95% confidence intervals (95% CI) (+/-10%). Penetrance of the mutation for HD also was examined. Although complete penetrance of HD was observed for CAG sizes of > or = 42, only a proportion of those with a CAG repeat length of 36-41 showed signs or symptoms of HD within a normal life span. These data provide information concerning the likelihood of being affected, by a specific age, with a particular CAG size, and they may be useful in predictive-testing programs and for the design of clinical trials for persons at increased risk for HD.

Background: The eosinophilic ulcer is a rare lesion of the oral mucosa that has been infrequently described in the literature., Objective: We attempted to characterize the history, demographics, clinical features, histologic features, pathogenesis, and treatment of the eosinophilic ulcer., Methods: We observed three new cases of eosinophilic ulcer and reviewed the English-language literature., Results: Eosinophilic ulcer occurs in any age group, without sex preference. The most common site in the oral cavity is the tongue, and the average size at diagnosis is 1.6 cm2. These lesions are often ulcerated, may be tender, and are sometimes multiple. The histologic features are characteristic but likely represent a spectrum of related disorders. Most eosinophilic ulcers will resolve spontaneously within a month. Recurrences are uncommon (< 15%)., Conclusion: The eosinophilic ulcer is a benign, self-limited, reactive process of the oral mucosa of unknown origin. Its histologic features are characteristic but may be confused with atypical histiocytic granuloma and angiolymphoid hyperplasia with eosinophilia or, more importantly, lymphoma. This condition most likely represents a spectrum of related disorders with overlapping clinical and histologic features. After the diagnosis has been histologically confirmed, conservative management is suggested.