Early milestones and neurodevelopment in children with mitochondrial disease

AIM: To quantify neurodevelopmental functioning in children with primary mitochondrial disease (MtD), and to assess relationships with other clinical data. METHOD: This study was performed as a cross-sectional analysis of a longitudinal cohort. Inclusion criteria were age over 12 months, genetically confirmed MtD. Clinical data were obtained by caregiver interview and medical records abstraction. Measures included IQ, Vineland Adaptive Behavior Scales, Third Edition, the International Pediatric Mitochondrial Disease Scale (IPMDS), and Gross Motor Functional Classification System (GMFCS) level. An exploratory approach analyzed the relationship between clinical data and other measures, using Vineland Adaptive Behavior Scales, Third Edition as a dependent variable. RESULTS: The cohort included 32 children, mean age 7 years (SD = 3 years 6 months). The most common genotypes included MT-ATP6 (n = 6) and the mitochondrial aminoacyl tRNA synthetase family of genes. Regarding phenotype, 15 out of 32 (47%) met clinical criteria for Leigh syndrome. Clinical descriptors of disability included 18 out of 32 (56%) with intellectual disability/global developmental delay; 13 out of 32 (40%) were non-ambulatory and 6 out of 32 (19%) reported developmental regression, primarily in the motor domain. The mean Full Scale IQ was 54 (SD = 27) and adaptive behavior composite (ABC) standard score was 66 (SD = 20) with motor subscale lower than other domains. The ABC was negatively associated with IPMDS, GMFCS, and seizures. Of those who walked and talked by 24 months and had neuroimaging with zero or one brain region affected (n = 9), eight (89%) had adaptive function in the average range. INTERPRETATION: Children with MtD exhibit a wide range of neurodevelopmental function. Overall MtD adaptive function was low, with motor-predominant disability, and correlated negatively with other measures of severity. Episodic developmental regression occurred in a minority of this cohort but primarily affected motor skills.