Leigh syndrome (LS) is a progressive neurodegenerative disorder of infancy and early childhood. It is clinically diagnosed by typical manifestations and characteristic computed tomography (CT) or magnetic resonance imaging (MRI) studies. Unravelling mitochondrial respiratory chain (MRC) dysfunction behind LS is essential for deeper understanding of the disease, which may lead to the development of new therapies and cure. The aim of this study was to evaluate the clinical validity of various diagnostic tools in confirming MRC disorder in LS and Leigh-like syndrome (LL). The results of enzyme assays, molecular analysis, and cellular oxygen consumption rate (OCR) measurements were examined. Of 106 patients, 41 were biochemically and genetically verified, and 34 had reduced MRC activity but no causative mutations. Seven patients with normal MRC complex activities had mutations in the MT-ATP6 gene. Five further patients with normal activity in MRC were identified with causative mutations. Conversely, 12 out of 60 enzyme assays performed for genetically verified patients returned normal results. No biochemical or genetic background was confirmed for 19 patients. OCR was reduced in ten out of 19 patients with negative enzyme assay results. Inconsistent enzyme assay results between fibroblast and skeletal muscle biopsy samples were observed in 33% of 37 simultaneously analyzed cases. These data suggest that highest diagnostic rate is reached using a combined enzymatic and genetic approach, analyzing more than one type of biological materials where suitable. Microscale oxygraphy detected MRC impairment in 50% cases with no defect in MRC complex activities.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-017-0042-6) contains supplementary material, which is available to authorized users.

Significantly more children with ALRI who needed supplementary oxygen and ventilator management were vitamin D deficient. These findings suggest that the immunomodulatory properties of vitamin D may influence the severity of ALRI.

Leigh syndrome is a major phenotype of mitochondrial diseases in children. With new therapeutic options being proposed, assessing the mortality and clinical condition of Leigh syndrome patients is crucial for evaluating therapeutics. As data are scarce in Japan, we analysed the mortality rate and clinical condition of Japanese Leigh syndrome patients that we diagnosed since 2007. Data from 166 Japanese patients diagnosed with Leigh syndrome from 2007 to 2017 were reviewed. Patients' present status, method of ventilation and feeding, and degree of disability as of April 2018 was analysed. Overall, 124 (74.7%) were living, 40 (24.1%) were deceased, and 2 (1.2%) were lost to follow‐up. Median age of living patients was 8 years (1‐39 years). Median length of disease course was 91 months for living patients and 23.5 months for deceased patients. Nearly 90% of deaths occurred by age 6. Mortality rate of patients with onset before 6 months of age was significantly higher than that of onset after 6 months. All patients with neonatal onset were either deceased or bedridden. MT‐ATP6 deficiency caused by m.8993T>G mutation and MT‐ND5 deficiency induced a severe form of Leigh syndrome. Patients with NDUFAF6 , ECHS1 , and SURF1 deficiency had relatively mild symptoms and better survival. The impact of onset age on prognosis varied across the genetic diagnoses. The clinical condition of many patients was poor; however, few did not require mechanical ventilation or tube‐feeding and were not physically dependent. Early disease onset and genetic diagnosis may have prognostic value.

SUMMARY The authors studied age‐related correlations of auditory event‐related potentials (ERPs) using the conventional ‘oddball’ paradigm and reaction time in 175 normal subjects, aged between four and 21 years. From four years, the latencies of N100, N200 and P300 in ERP progressively shortened until about 16 to 17 years, after which they reached adult level, but with a slight tendency to prolongation towards 20 years; there was no trend for amplitude changes. The reaction time was more rapid than that of P300 latency. These findings indicate that the cognitive function of children improves rapidly until 16 to 17 years. A reduced difference between P300 latency and reaction time with age implies additional progress in motor skill. Combining P300 latency and reaction‐time studies may provide more detailed information for the evaluation of the development of cognitive function and motor skill. RÉSUMÉ Potentiels auditifs d'evénements et temps de reaction chez les enfanis: évaluation du développement cognitif Les auteurs ont étudié la corrélation avec I'ǎge de potentiels auditifs reliés aux événements (ERPs) en utilisant des modèles farfelus conventionnels, et le temps de réaction chez 175 sujets normaux ǎgés de quatre á 21 ans. Après quatre ans, les latences de N100, N200 et P300 de I'ERP diminuaient progressivement jusqu’à 16 ou 17 ans, après quoi elles atteignaient le niveau adulte, avec une légère tendance à I'allongement vers 20 ans; il n'y avait pas d'indication de modification d'amplitude. Le temps de réaction était plus faible que la latence P300. Ces données indiquent que la fonction cognitive des enfants s'accroit rapidement jusquà 16 ou 17 ans. Un raccourcissement du délai entre la latence P300 et le temps de réaction avec I'ǎge implique un progres complémentaire de I'habileté gestuelle. Les études combinées de la latence P300 et du temps de reaction peuvent fournir des informations plus détaillées pour I‘évaluation de la fonction cognitive en développement et I'habileté gestuelle. ZUSAMMENFASSUNG Auditory event‐related Potentials und Reaktionszeit bei Kindern: Beurteilung der kognitiven Entwicklung Die Autoren untersuchten bei 175 gesunden Personen im Alter zwischen vier und 21 Jahren alterstypisshe Korrelationen der auditory event‐related Potentials (ERPs) unter Verwendung des conventional oddball paradigm und der Reaktionszeit. Vom vierten bis ungefähr zum 16–17. Lebensjahr nahmen die Latenzen von N100, N200 und P300 im ERP fortlaufend ab, danach erreichten sie Erwachsenenwerte, jedoch mit einer leichten Verlängerungstendenz zum 20. Lebensjahr hin; es gab keinen Trend für Amplitudenveränderungen. Die Reaktionszeit war kürzer als die der P300 Latenz. Diese Befunde zeigen, daβ die kognitive Funktion der Kinder sich bis zum 16–17. Lebensjahr schnell vervollkommnet. Der mit dern Alter geringer werdende Unterschied zwischen der P300 Latenz und Reaktionszeit bedeutet einen zusätzlichen Fortschritt bei den motorischen Fähigkeiten. Die Verbindung der Untersuchungen von P300 Latenzen un...

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