No abstract

KBG syndrome (OMIM 148050) is a very rare genetic disorder characterized by macrodontia, distinctive craniofacial abnormalities, short stature, intellectual disability, skeletal, and neurologic involvement. Approximately 60 patients have been reported since it was first described in 1975. Recently mutations in ANKRD11 have been documented in patients with KBG syndrome, and it has been proposed that haploinsufficiency of ANKRD11 is the cause of this syndrome. In addition, copy number variation in the 16q24.3 region that includes ANKRD11 results in a variable phenotype that overlaps with KBG syndrome and also includes autism spectrum disorders and other dysmorphic facial features. In this report we present a 2½-year-old African American male with features highly suggestive of KBG syndrome. Genomic microarray identified an intragenic 154 kb deletion at 16q24.3 within ANKRD11. This child's mother was mosaic for the same deletion (present in approximately 38% of cells) and exhibited a milder phenotype including macrodontia, short stature and brachydactyly. This family provides additional evidence that ANKRD11 causes KBG syndrome, and the mild phenotype in the mosaic form suggests that KBG phenotypes might be dose dependent, differentiating it from the more variable 16q24.3 microdeletion syndrome. This family has additional features that might expand the phenotype of KBG syndrome.

hypoglycemia͞hypoxia ͉ neuroprotection ͉ PAN-811͞Triapine ͉ oxidative ͉ calcium

Oxidative stress plays a significant role in neurotoxicity associated with a variety of neurodegenerative diseases including Alzheimer's disease (AD). Increased oxidative stress has been shown to be a prominent and early feature of vulnerable neurons in AD. Olfactory neuroepithelial cells are affected at an early stage. Exposure to oxidative stress induces the accumulation of intracellular reactive oxygen species (ROS), which in turn causes cell damage in the form of protein, lipid, and DNA oxidations. Elevated ROS levels are also associated with increased deposition of amyloid-beta and formation of senile plaques, a hallmark of the AD brain. If enhanced ROS exceeds the basal level of cellular protective mechanisms, oxidative damage and cell death will result. Therefore, substances that can reduce oxidative stress are sought as potential drug candidates for treatment or preventative therapy of neurodegenerative diseases such as AD. PAN-811, also known as 3-aminopyridine-2-carboxaldehyde thiosemicarbazone or Triapine, is a small lipophilic compound that is currently being investigated in several Phase II clinical trials for cancer therapy due to its inhibition of ribonucleotide reductase activity. Here we show PAN-811 to be effective in preventing or reducing ROS accumulation and the resulting oxidative damages in both AD-derived and age-matched olfactory neuroepithelial cells.

Abstract:Hydrogen peroxide (H 2 O 2 ), a major non-radical reactive oxygen species (ROS) could elicit intracellular oxidative damage and/or cause extracellular free calcium influx by activating the NMDA receptor or through calcium channels. In the present study, NMDA receptor antagonist MK-801 fully blocked H 2 O 2 -induced neuronal cell death, whereas green tea (GT) extract containing-antioxidants only partially suppressed the neurotoxicity of H 2 O 2 . These suggest that majority of ROS overproduction is downstream of H 2 O 2 -induced calcium influx. A novel neuroprotectant PAN-811 was previously demonstrated to efficiently attenuate ischemic neurotoxicity. PAN-811 hereby fully blocks H 2 O 2 -elicited neuronal cell death with a more advanced neuroprotective profile than that of GT extract. PAN-811 was also shown to protect against CaCl 2 -elicited neurotoxicity. Efficient protection against oxidative stress-induced neurotoxicity by PAN-811 indicates its potential application in treatment of ROS-mediated neurodegenerative diseases.