De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.

EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

A Community-based Healthy Living Promotion Program Improved Self-esteem Among Minority Children.

OBJECTIVES: Improving self-esteem, dietary habits, and physical activity is essential for long-term success in childhood obesity prevention. The aim is to evaluate the effects of a healthy living promotion program, Healthy Kids-Houston, on BMI, dietary habits, self-esteem, and physical activity among minority children. METHODS: The after-school program was implemented at community centers in low-income neighborhoods with close proximity to public schools. The program consisted of 3 6-week sessions. Each week, children attended 2 2-hour sessions. Each 2-hour session in the intervention included 90 minutes of structured physical activities and 30 minutes of nutrition and healthy habit lessons. The control group received typical enrichment programs. Outcomes were measured before the intervention and at the end of each 6-week session. RESULTS: We enrolled 877 children (age 10.2 ±â€Š0.1 years (mean ±â€ŠSE); body mass index z score: 1.49 ±â€Š0.1; 52.0% boys; 72.6% Hispanic) in the program with 524 children received the intervention at 14 community centers and 353 children served as control at 10 community centers. The intervention led to no improvements in BMI z score (P = 0.78) and dietary habits (P = 0.46). Significant improvements (P ≤ 0.02) were detected in the amount of exercise that a child perceived to be required to offset a large meal and in several key self-esteem scores. No improvements were detected in physical activities (P ≥ 0.21). CONCLUSIONS: The improvement in some key self-esteem scores and nutrition knowledge may act as a mediator to motivate these children to adopt a healthier lifestyle in the future.