CADASIL: new cases and new questions

We described the first two unrelated Polish families with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). In the morphological examination with light microscopy, two kinds of changes were observed: (1) panarteritis nodosa-like changes with eosinophilic fibrinoid necrosis of the vessel wall and perivascular inflammatory infiltrates and (2) basophilic granular material in the tunica media characteristic of CADASIL. At electron microscopy, we found deposits of granular osmophilic material (GOM) within the wall of arteries, veins and capillary vessels. Our findings imply two questions requiring further investigation: Why in the genetically determined vascular disorder are the features of systemic inflammatory vascular disease present? Why in capillary walls deprived of smooth muscle cells are deposits of GOM present?     

Understanding and treating kleptomania: new models and new treatments

Kleptomania, characterized by repetitive, uncontrollable stealing of items not needed for personal use, is a disabling disorder that often goes unrecognized in clinical practice. Although originally conceptualized as an obsessive compulsive spectrum disorder, emerging evidence (clinical characteristics, familial transmission, and treatment response) suggests that kleptomania may have important similarities to both addictive and mood disorders. In particular, kleptomania frequently co-occurs with substance use disorders, and it is common for individuals with kleptomania to have first-degree relatives who suffer from a substance use disorder. Additionally, there is some suggestion that selective serotonin reuptake inhibitors, the treatment of choice for obsessive compulsive disorder, may lack efficacy for kleptomania. Instead, other medications (lithium, anti-epileptics, and opioid antagonists) have shown early promise in treating kleptomania. Evidence suggests that there may be subtypes of kleptomania that are more like OCD, whereas others have more similarities to addictive and mood disorders. Subtyping of individuals with kleptomania may be a useful way to better understand this behavior and decide on effective treatment interventions.     

Psychiatry, molecular genetics and ethics: the new discoveries and the new issues

Recent developments in molecular genetics are examined with particular reference to psychiatry. The new technologies available have allowed significant advances in the understanding of certain illnesses such as familial Alzheimer's disease and Huntington's chorea, and will provide powerful tools to explore many other important psychiatric illnesses. The area of genetic counselling is already characterized by complex ethical issues. We can expect that as the new technologies provide the prospect of positive germ line genetic engineering, these ethical issues will become more complex. It is important that psychiatrists prepare themselves for these future developments and take an active role in leading the debate.     

Old syndromes and new cytogenetics

This annotation has been confined to well-established clinical syndromes with recently discovered chromosomal etiologies. It deliberately omits retinoblastoma, the oft-cited paradigm of a contiguous gene syndrome, since it is usually inherited as a Mendelian single gene disorder. However, it was recognition of both the deletion of band q14 of chromosome 13 in mentally retarded children with retinoblastoma, and the linkage of retinoblastoma with the genetic marker esterase D, which resulted in the eventual cloning of the gene. Also omitted are microdeletions of the X chromosome. These disorders are seen primarily in males, who manifest the phenotypic effects of the deletion of the loci of various combinations of adjacent genes: Duchenne muscular dystrophy, glycerol kinase deficiency, adrenal hypoplasia, optic albinism, hypogonadotropic hypogonadism and anosmia (Kallman syndrome), chondrodysplasia punctata and ichthyosis. Many are also mentally retarded. The third group omitted are Mendelian disorders occurring with atypical mental retardation (not usually part of the disorder), the presumption being that they include small deletions. It is expected that other contiguous gene syndromes will be recognized eventually; Rubinstein-Taybi and Cornelia de Lange syndromes are prime candidates. Why do deletions have such dramatic consequences when a normal homologue of the region is present? If their effects were due to the uncovering of recessive genes, we would expect to see greater variations in phenotype among carriers, including normal individuals whose deletions were masked by the protective effects of dominant alleles in the homologous regions. Imprinting--the 'stamping' of a gene as it passes through the germ line--provides a more satisfactory explanation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epilepsy and the new cytogenetics

We set out to review the extent to which molecular karyotyping has overtaken conventional cytogenetics in applications related to epilepsy. Multiplex ligase-dependent probe amplification (MLPA) targeted to predetermined regions such as SCN1A and KCNQ2 has been effectively applied over the last half a decade, and oligonucleotide array comparative genome hybridization (array CGH) is now well established for genome-wide exploration of microchromosomal variation. Array CGH is applicable to the characterization of lesions present in both sporadic and familial epilepsy, especially where clinical features of affected cases depart from established syndromes. Copy number variants (CNVs) associated with epilepsy and a range of other syndromes and conditions can be recurrent due to nonallelic homologous recombination in regions of segmental duplication. The most common of the recurrent microdeletions associated with generalized epilepsy are typically seen at a frequency of ～ 1% at 15q13.3, 16p13.11, and 15q11.2, sites that also confer susceptibility for intellectual disability, autism, and schizophrenia. Incomplete penetrance and variable expressivity confound the established rules of cytogenetics for determining the pathogenicity for novel CNVs; however, as knowledge is gained for each of the recurrent CNVs, this is translated to genetic counseling. CNVs play a significant role in the susceptibility profile for epilepsies, with complex genetics and their comorbidities both from the "hotspots" defined by segmental duplication and elsewhere in the genome where their location and size are often novel.     

Tardive dyskinesia and new antipsychotics

PURPOSE OF REVIEW: To provide an update on tardive dyskinesia rates in patients treated with first-generation or second-generation antipsychotics in studies published since the last systematic review in 2004. RECENT FINDINGS: Across 12 trials (n = 28 051, age 39.7 years, 59.7% male, 70.9% white, followed for 463 925 person-years), the annualized tardive dyskinesia incidence was 3.9% for second-generation antipsychotics and 5.5% for first-generation antipsychotics. Stratified by age, annual tardive dyskinesia incidence rates were 0.35% with second-generation antipsychotics in children, 2.98% with second-generation antipsychotics versus 7.7% with first-generation antipsychotics (P < 0.0001) in adults, and 5.2% with second-generation antipsychotics versus 5.2% with first-generation antipsychotics (P = 0.865) in the elderly (based almost exclusively on one retrospective cohort study). In four adult studies (n = 2088, age 41.2 years, 71.2% male, 62.0% white), tardive dyskinesia prevalence rates were 13.1% for second-generation antipsychotics, 15.6% for antipsychotic-free patients, and 32.4% for first-generation antipsychotics (P < 0.0001). SUMMARY: Current evidence supports a lower tardive dyskinesia risk for second-generation antipsychotics than for first-generation antipsychotics. Tardive dyskinesia incidence was higher with second-generation antipsychotics than previously reported, possibly due to recent studies with relatively short mean durations and use of nonstandard tardive dyskinesia definitions.