MITO-FIND: A study in 390 patients to determine a diagnostic strategy for mitochondrial disease.

Mitochondrial diseases, due to nuclear or mitochondrial genome mutations causing mitochondrial dysfunction, have a wide range of clinical features involving neurologic, muscular, cardiac, hepatic, visual, and auditory symptoms. Making a diagnosis of a mitochondrial disease is often challenging since there is no gold standard and traditional testing methods have required tissue biopsy which presents technical challenges and most patients prefer a non-invasive approach. Since a diagnosis invariably involves finding a disease-causing DNA variant, new approaches such as next generation sequencing (NGS) have the potential to make it easier to make a diagnosis. We evaluated the ability of our traditional diagnostic pathway (metabolite analysis, tissue neuropathology and respiratory chain enzyme activity) in 390 patients. The traditional diagnostic pathway provided a diagnosis of mitochondrial disease in 115 patients (29.50%). Analysis of mtDNA, tissue neuropathology, skin electron microscopy, respiratory chain enzyme analysis using inhibitor assays, blue native polyacrylamide gel electrophoresis were all statistically significant in distinguishing patients between a mitochondrial and non-mitochondrial diagnosis. From these 390 patients who underwent traditional analysis, we recruited 116 patients for the NGS part of the study (36 patients who had a mitochondrial diagnosis (MITO) and 80 patients who had no diagnosis (No-Dx)). In the group of 36 MITO patients, nuclear whole exome sequencing (nWES) provided a second diagnosis in 2 cases who already had a pathogenic variant in mtDNA, and a revised diagnosis (GLUL) in one case that had abnormal pathology but no pathogenic mtDNA variant. In the 80 NO-Dx patients, nWES found non-mitochondrial diagnosis in 26 patients and a mitochondrial diagnosis in 1 patient. A genetic diagnosis was obtained in 53/116 (45.70%) cases that were recruited for NGS, but not in 11/116 (9.48%) of cases with abnormal mitochondrial neuropathology. Our results show that a non-invasive, bigenomic sequencing (BGS) approach (using both a nWES and optimized mtDNA analysis to include large deletions) should be the first step in investigating for mitochondrial diseases. There may still be a role for tissue biopsy in unsolved cases or when the diagnosis is still not clear after NGS studies.

Most Children With Epilepsy Experience Postictal Phenomena, Often Preventing a Return to Normal Activities of Childhood.

BACKGROUND: After a seizure, individuals with epilepsy have reported diverse symptoms in the postictal period, especially motor and cognitive dysfunction. However, these phenomena have not been well characterized in children, and their impact on patient well-being is not understood. We hypothesized that in a subset of epilepsy patients, postictal symptoms would affect their ability to return to normal childhood activities. METHODS: To test our hypothesis, a survey-based approach was used to characterize the type, frequency, and duration, as well as the impact of these symptoms on the ability of these children to return to their normal activities. RESULTS: In this prospective study, data were analyzed from 208 patients seen in the pediatric neurology outpatient clinic at the Alberta Children's Hospital. We found that 86% (179 out of 208) of respondents reported postictal symptoms, with the most common symptom category being fatigue, sleepiness, and/or tiredness (90%; 161 of 179). The greatest impact resulted from weakness or being unable to move normally, which prevented 78% of those affected (71 of 91) from returning to normal activities after a seizure. Children who had focal seizures were more likely to experience postictal fatigue, sleepiness, or tiredness (P = 0.01; Bonferroni corrected), but no other postictal symptoms were significantly associated with a specific seizure type or epilepsy syndrome. CONCLUSIONS: The results of this study further our understanding of the frequency, type, and duration of symptoms experienced in the postictal period and how these symptoms impact children with epilepsy. It is clear that postictal phenomena often occur after epileptic seizures and have a significant impact on the lives of children with epilepsy.