Aberrant protein processing with tissue deposition is associated with many common neurodegenerative disorders; however, the complex interplay of genetic and environmental factors has made it difficult to decipher the sequence of events linking protein aggregation with clinical disease. Substantial progress has been made toward understanding the pathophysiology of prototypical conformational diseases and protein polymerization in the superfamily of serine proteinase inhibitors (serpins). Here we describe a new disease, familial encephalopathy with neuroserpin inclusion bodies, characterized clinically as an autosomal dominantly inherited dementia, histologically by unique neuronal inclusion bodies and biochemically by polymers of the neuron-specific serpin, neuroserpin. We report the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families. The significance of one mutation, S49P, is evident from its homology to a previously described serpin mutations, whereas that of the other, S52R, is predicted by modelling of the serpin template. Our findings provide a molecular mechanism for a familial dementia and imply that inhibitors of protein polymerization may be effective therapies for this disorder and perhaps for other more common neurodegenerative diseases.

Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, there has been limited replications between the various independent datasets. The current study gathered the results from all seven of the ADHD linkage scans and performed a Genome Scan Meta Analysis (GSMA) to identify the genomic region with most consistent linkage evidence across the studies. Genome-wide significant linkage (P SR =0.00034, P OR =0.04) was identified on chromosome 16 between 64 and 83 Mb. In addition there are nine other genomic regions from the GSMA showing nominal or suggestive evidence of linkage. All these linkage results may be informative and focus the search for novel ADHD susceptibility genes.

The cholesterol‐lowering “statin” drugs are contraindicated in pregnancy, but few data exist on their safety in human gestation. We reviewed case reports for patterns suggesting drug‐related effects on prenatal development and considered a variety of mechanisms by which such effects, if confirmed, might occur. This uncontrolled case series included all FDA reports of statin exposures during gestation, as well as others from the literature and from manufacturers. Exposures and outcomes were reviewed and were tabulated by individual drug. Age‐specific rates of exposure to each drug among women of child‐bearing age were estimated. Of 214 ascertained pregnancy exposures, 70 evaluable reports remained after excluding uninformative cases. Among 31 adverse outcomes were 22 cases with structural defects, 4 cases of intrauterine growth restriction, and 5 cases of fetal demise. There were two principal categories of recurrent structural defects: cerivastatin and lovastatin were associated with four reports of severe midline CNS defects; simvastatin, lovastatin, and atorvastatin were all associated with reports of limb deficiencies, including two similar complex lower limb defects reported following simvastatin exposure. There were also two cases of VACTERL association among the limb deficiency cases. All adverse outcomes were reported following exposure to cerivastatin, simvastatin, lovastatin, or atorvastatin, which are lipophilic and equilibrate between maternal and embryonic compartments. None were reported following exposure to pravastatin, which is minimally present in the embryo. Statins reaching the embryo may down‐regulate biosynthesis of cholesterol as well as many important metabolic intermediates, and may have secondary effects on sterol‐dependent morphogens such as Sonic Hedgehog. The reported cases display patterns consistent with dysfunction of cholesterol biosynthesis and Sonic Hedgehog activity. Controlled studies are needed to investigate the teratogenicity of individual drugs in this class. © 2004 Wiley‐Liss, Inc.