Exome sequencing of 118 patients with neurodevelopmental disorders shows that this technique is useful for identifying new pathogenic mutations and for correcting diagnosis in ~10% of cases.
Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acids synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenosine and guanine nucleotides. We describe a new distinct early-onset neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH), due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a new, potentially treatable early-onset neurodegenerative disease.
An increased incidence of sister chromatid exchanges (SCEs) in peripheral lymphocytes of operating room personnel exposed to waste anesthetic gases has been reported. We investigated whether the increase of SCEs in anesthesiologists was reversible. Twenty-five anesthesiologists exposed to waste anesthetic gases such as sevoflurane and nitrous oxide were compared with nonexposed internists working in the same hospital. The concentrations of sevoflurane and nitrous oxide in the operating rooms were measured. The incidence of SCE was measured in lymphocytes cultures of anesthesiologists before and after a 2-mo leave from the operating room. These values of SCE were compared with those of nonexposed physicians. Occupational exposure to sevoflurane and nitrous oxide in the operating rooms were above the threshold values. There was a significant difference in SCE values of the anesthesiologists compared with the nonexposed physicians (11.9 +/- 4.4 versus 4.2 +/- 1.1, P < 0.001). After a 2-mo leave from the operating room, the SCE values of the anesthesiologists were significantly lower compared with those taken before the leave (4.8 +/- 1.8 and 11.9 +/- 4.4, respectively, P < 0.001). We conclude that the increase of SCE in anesthesiologists exposed to increased environmental concentrations of waste anesthetics gases, such as sevoflurane and nitrous oxide, are reversible if they work free from exposure for 2 mo.
We report six patients with Cockayne syndrome type B without photosensitivity. The patients are from the same inbred family and exhibit variable clinical features. The main clinical manifestations were progressive encephalopathy including intracranial calcification and white-matter lesions, dwarfism without growth hormone deficiency, senile appearance, mental and motor retardation, atrophy of subcutaneous fat tissue, severe pectus carinatus, and spasticity. Clinical photosensitivity was not observed in any patient. Other clinical findings were cataract, pigmentary retinopathy, and peripheral neuropathy. The onset of the disease was between 3 and 6 months of age. Molecular genetic analyses in the family established linkage to ERCC6, the gene responsible for Cockayne syndrome type B, confirming the clinical diagnosis.
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