Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features

Mutations that cause neurological phenotypes are highly informative with regard to mechanisms governing human brain function and disease. We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) in large kindreds initially ascertained for intellectual and developmental disability (IDD). GPT2 [also known as alanine transaminase 2 (ALT2)] is one of two related transaminases that catalyze the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and α-ketoglutarate. In addition to IDD, all affected individuals show postnatal microcephaly and ∼80% of those followed over time show progressive motor symptoms, a spastic paraplegia. Homozygous nonsense p.Arg404* and missense p.Pro272Leu mutations are shown biochemically to be loss of function. The GPT2 gene demonstrates increasing expression in brain in the early postnatal period, and GPT2 protein localizes to mitochondria. Akin to the human phenotype, Gpt2-null mice exhibit reduced brain growth. Through metabolomics and direct isotope tracing experiments, we find a number of metabolic abnormalities associated with loss of Gpt2. These include defects in amino acid metabolism such as low alanine levels and elevated essential amino acids. Also, we find defects in anaplerosis, the metabolic process involved in replenishing TCA cycle intermediates. Finally, mutant brains demonstrate misregulated metabolites in pathways implicated in neuroprotective mechanisms previously associated with neurodegenerative disorders. Overall, our data reveal an important role for the GPT2 enzyme in mitochondrial metabolism with relevance to developmental as well as potentially to neurodegenerative mechanisms.National Institute of Neurological Diseases and Stroke (U.S.) (R01NS035129)United States. National Institutes of Health (R21TW008223)National Cancer Institute (U.S.) (R01CA157996

Personality Construct Among Patients With Substance Use Disorder: An Explanatory Study In Pakistan

Objective: Many researches defined the critical predictors and significant risk factors associated with various substance use behaviors, revealing the personality traits as important determinants. Thus, the present study aimed to explore the personality constructs of individuals with a history of substance use disorder in Pakistan. Method: The Qualitative Study was conducted through purposive sampling by selecting the professionals (psychiatrists=9, clinical psychologists=4, patients with SUD = 5) with having a minimum of 5 years to a maximum of 29 years of experience working with substance use disorder patients and participants with the history of at least three years of diagnosis. A total of 18 semi-structured interviews were conducted with nine (N=13) mental health professionals and five (N=05) patients with substance use disorder. The interviews were audio-recorded and transcribed by independent researchers. The transcripts were analyzed using a systematic approach that incorporates inductive thematic analysis. Results: The themes that emerged after analyses were combined under the main three headings: Social, Cultural and Psychological/individual factors. The main results indicated that authoritative parenting style, family lifestyles, pleasure-seeking, enhanced energy, dependent personality traits, emotional instability and conflicting interpersonal relationship lead to substance use which can be addressed through early intervention