MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation.

To identify genes that affect body mass index (BMI) in American Indians who are predominately of Pima Indian heritage, we previously completed a genome-wide association study in 1120 American Indians. That study also included follow-up genotyping for 9 SNPs in 2133 additional subjects. A comprehensive follow-up study has subsequently been completed where 292 SNPs were genotyped in 3562 subjects, of which 128 SNPs were assessed for replication in 3238 additional subjects. In the combined subjects (n = 6800), BMI associations for two SNPs, rs12882548 and rs11652094, approached genome-wide significance (P = 6.7 × 10(-7) and 8.1 × 10(-7), respectively). Rs12882548 is located in a gene desert on chromosome 14 and rs11652094 maps near MAP2K3. Several SNPs in the MAP2K3 region including rs11652094 were also associated with BMI in Caucasians from the GIANT consortium (P = 10(-2)-10(-5)), and the combined P-values across both American Indians and Caucasian were P = 10(-4)-10(-9). Follow-up sequencing across MAP2K3 identified several paralogous sequence variants indicating that the region may have been duplicated. MAP2K3 expression levels in adipose tissue biopsies were positively correlated with BMI, although it is unclear if this correlation is a cause or effect. In vitro studies with cloned MAP2K3 promoters suggest that MAP2K3 expression may be up-regulated during adipogenesis. Microarray analyses of mouse hypothalamus cells expressing constitutively active MAP2K3 identified several up-regulated genes involved in immune/inflammatory pathways and a gene, Hap1, thought to play a role in appetite regulation. We conclude that MAP2K3 is a reproducible obesity locus that may affect body weight via complex mechanisms involving appetite regulation and hypothalamic inflammation.

Acute Toxic Cerebellar Leukoencephalopathy in an Eight-Year-Old Child Following Illicit Fentanyl and Cocaine Ingestion: A Case Report of Full Clinical Recovery.

During the current opioid epidemic, the number of children with illicit toxic ingestions is increasing. Children presenting with altered mental status and neurologic, particularly cerebellar symptoms of unclear etiology, should be considered to undergo brain imaging as well as toxicology screening to not miss the possible complication of acute toxic leukoencephalopathy. We report the case of an eight-year-old child who presented with somnolence and respiratory depression of unclear etiology, responding profoundly to naloxone, quickly raising concern for drug ingestion. The toxicology screen was positive for fentanyl, cocaine metabolites, caffeine, and diphenhydramine, but not available until day 3 of the hospital stay. In the interim, head CT and brain MRI findings revealed concerning bilateral cerebellar hypodensities, suggestive of opioid-induced leukoencephalopathy. This condition has been described as potentially malignant and fatal, but very few cases of this pathology have been described in children so far. Fortunately, all neurological symptoms in our patient, including altered mental status, respiratory depression, atactic gait, blurry vision, and lower extremity pain, completely resolved within five days of presentation and the patient seemingly underwent a full clinical recovery without residual symptoms. Awareness and prompt recognition of acute toxic leukoencephalopathy in children presenting with altered mental status or neurological symptoms of unclear etiology is of utmost importance to prevent deterioration and optimize treatment, especially during times of a worsening opioid epidemic in our country.