No abstract

210Mitochondrial encephalopathy, lactic acidosis, and stroke like episodes (MelaS), first described in 1984, is one of the most common mitochondrial disorders with a prevalence of 0.06 % in the general population 1 . Mitochondrial disorders affect multiple organ systems and tissues which consequently causes a number of "overlaps" or multisystem presentations resulting in varied phenotypes. the triad of stroke-like episodes, seizures and lactic acidosis clinically distinguishes MelaS from other mitochondrial disorders 1 . however, as seen in this family, not all individuals with the MTTL1 A3243G mutation present clinically with MelaS.this disorder is most frequently associated with an a to g transition at position 3243 in the mitochondrial genome 2 . this mutation occurs in the trna leucine gene, which is the site of many ABSTRACT: Background: the maternally inherited MTTL1 A3243G mutation in the mitochondrial genome causes MelaS (Mitochondrial encephalopathy lactic acidosis with Stroke-like episodes), a condition that is multisystemic but affects primarily the nervous system. Significant intra-familial variation in phenotype and severity of disease is well recognized. Methods: retrospective and ongoing study of an extended family carrying the MTTL1 A3243G mutation with multiple symptomatic individuals. tissue heteroplasmy is reviewed based on the clinical presentations, imaging studies, laboratory findings in affected individuals and pathological material obtained at autopsy in two of the family members. Results: there were seven affected individuals out of thirteen members in this three generation family who each carried the MTTL1 A3243G mutation. the clinical presentations were varied with symptoms ranging from hearing loss, migraines, dementia, seizures, diabetes, visual manifestations, and stroke like episodes. three of the family members are deceased from MelaS or to complications related to MelaS. Conclusions: the results of the clinical, pathological and radiological findings in this family provide strong support to the current concepts of maternal inheritance, tissue heteroplasmy and molecular pathogenesis in MelaS. neurologists (both adult and paediatric) are the most likely to encounter patients with MelaS in their practice. genetic counselling is complex in view of maternal inheritance and heteroplasmy. newer therapeutic options such as arginine are being used for acute and preventative management of stroke like episodes.RÉSUMÉ: MELAS : Impact multigénérationnel de la mutation MTTL1 A3243G. Contexte : la mutation Mttl1 a3243g, transmise par la mère dans le génome mitochondrial, cause MelaS (acidose lactique liée à une encéphalopathie mitochondriale, avec des épisodes ressemblant à des accidents vasculaires cérébraux), une maladie multisystémique qui atteint principalement le système nerveux. il existe des variations intrafamiliales du phénotype et de la sévérité de la maladie. Méthode : nous rapportons une étude rétrospective et prospective d'une famille étendue porteuse de la mutation Mttl1 a3243g et...

Understanding developmental milestones and quality of life are important parameters when judging a child's overall health. For CDM patients delineating developmental milestones and QOL have important clinical care and research implications.

Inborn errors of metabolism (IEM) are a heterogenous group of rare, inherited disorders that impair the biochemical processes involved in metabolism. Many are treated with various restrictive diets in early infancy, prior to the appearance of symptoms to improve the overall outcomes of the affected individuals. Identification of individuals at a risk of developing metabolic disorders through newborn screening (NBS) programs and the subsequent early diagnosis and treatment are an invaluable aspect of healthcare in Canada. Incorporation of Canada’s expanding population of refugees and new immigrants presents with potential challenges and changes. Without the availability of NBS programs in many countries contributing to the refugee influx in Canada, it may be difficult to identify patients who are affected with these rare conditions. This article discusses: 1) the utility of newborn screening and diagnosis of metabolic diseases in immigrant and refugee populations, with complex medical presentations, and 2) a recent diagnosis of succinic semialdehyde dehydrogenase deficiency (an IEM) in a refugee child past the age limit of NBS. An increasingly complicated and diverse refugee population requires a need for revision of existing healthcare practices pertaining to the diagnosis of rare diseases.

Background: Congenital Myotonic Dystrophy (CDM1) is a rare neuromuscular condition caused by a triplet repeat expansion in the DMPK gene. Despite there being a well-recognized clinical syndrome, there has not been an effort to use a standardized ontology system to describe the disease characteristics in existing literature. Thus, comparing or contrasting different cohorts from the literature can be challenging, and coding disease features for clinical research or for registry data items is not uniform. PhenoStacks is a visualization analytics tool which helps graphically illustrate phenotypes of patients with genetic disorders using Human Phenotype Ontology (HPO) terms and can sort phenotypes by different disease characteristics. Objective: To demonstrate the efficacy of PhenoStacks and the HPO system as clinical research tools when describing CDM1 cohorts. Methods: Health Endpoints and Longitudinal progression in congenital myotonic dystrophy (HELP-CDM) is an ongoing study which longitudinally follows patients with CDM1. Items from the HELP-CDM data sheet were matched to corresponding HPO terms and analyzed using PhenoStacks. Results: In total 40 subjects' phenotypes were visualized through PhenoStacks and 73 HPO terms were used for the analysis. Frequent phenotypic features included "high narrow palate", "facial palsy", "ptosis", "hyporeflexia", and "weak voice". Contractures were associated with higher repeat sizes. Hypoplastic muscles and infantile axial hypotonia were more frequently observed in infants. Conclusions: PhenoStacks is a valuable clinical and scientific tool as it identifies variability within cohorts and highlights significant phenotypic features.