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.

Comparison of risperidone, olanzapine and quetiapine: effects on body weight, serum blood glucose and prolactin.

Schizophrenia is a chronic illness with a lifetime prevalence of 1% and with serious physical, social and economic consequences. Over the past decade, atypical antipsychotic medications have become the first-line treatment for schizophrenia (Breier et al, 2005).

A 12-year follow-up of a sample of patients dependent upon heroin.

Heroin addiction is a chronic, relapsing and remitting condition. Each year 2-5% of addicts discontinue drug use permanently and 1-2% die, mostly of overdose (Robins, 1993). A study of 129 opiate-addicted patients on a monthly maintenance regimen found that those with a family history of opium use had an earlier age at onset (Chaudhry et al, 1991). Long-term follow-up studies of people who misuse opiates have revealed that opioid dependence appears to run a chronic, relapsing and remitting course with a significant mortality (10-15%) over 10 years (Robson, 1992). Metrebian et al (1998) reported that long-term heroin abstinence was associated with less criminality, psychological distress and morbidity; Hser et al (2001) reported it was associated with higher employment rates.