Sex Hormone Decline and Amyloid ß Synthesis, Transport and Clearance in the Brain.

Sex hormones (SH) are essential regulators of the central nervous system. The decline in SH levels along with ageing may contribute to compromised neuroprotection and set the grounds for neurodegeneration and cognitive impairments. In Alzheimer's disease, besides other pathological features, there is an imbalance between amyloid ß (Aß) production and clearance, leading to its accumulation in the brain of older subjects. Aß accumulation is a primary cause for brain inflammation and degeneration, as well as concomitant cognitive decline. There is mounting evidence that SH modulate Aß production, transport and clearance. Importantly, SH regulate most of the molecules involved in the amyloidogenic pathway, their transport across brain barriers for elimination, and their degradation in the brain interstitial fluid. This review brings together data on the regulation of Aß production, metabolism, degradation and clearance by SH.

A novel microdeletion affecting the CETP gene raises HDL-associated cholesterol levels.

We describe a novel, inherited 16q13 microdeletion that removes cholesteryl ester transfer protein (CETP) and several nearby genes. The proband was originally referred for severe childhood-onset obesity and moderate developmental delay, but his fasting lipid profile revealed relatively high levels of high density lipoprotein cholesterol (HDL-C) and relatively low levels of low density lipoprotein cholesterol (LDL-C) for age, despite his obesity. Testing of first-degree relatives identified two other microdeletion carriers. Functional assays in affected individuals showed decreased CETP mRNA expression and enzymatic activity. This microdeletion may or may not be pathogenic for obesity and developmental delay, but based on the lipid profile, the functional studies, and the phenotype of other patients with loss-of-function mutations of CETP, we believe this microdeletion to be antipathogenic for cardiovascular disease.

Clinical application of 2.7M Cytogenetics array for CNV detection in subjects with idiopathic autism and/or intellectual disability.

Higher resolution whole-genome arrays facilitate the identification of smaller copy number variations (CNVs) and their integral genes contributing to autism and/or intellectual disability (ASD/ID). Our study describes the use of one of the highest resolution arrays, the Affymetrix(®) Cytogenetics 2.7M array, coupled with quantitative multiplex polymerase chain reaction (PCR) of short fluorescent fragments (QMPSF) for detection and validation of small CNVs. We studied 82 subjects with ASD and ID in total (30 in the validation and 52 in the application cohort) and detected putatively pathogenic CNVs in 6/52 cases from the application cohort. This included a 130-kb maternal duplication spanning exons 64-79 of the DMD gene which was found in a 3-year-old boy manifesting autism and mild neuromotor delays. Other pathogenic CNVs involved 4p14, 12q24.31, 14q32.31, 15q13.2-13.3, and 17p13.3. We established the optimal experimental conditions which, when applied to select small CNVs for QMPSF confirmation, reduced the false positive rate from 60% to 25%. Our work suggests that selection of small CNVs based on the function of integral genes, followed by review of array experimental parameters resulting in highest confirmation rate using multiplex PCR, may enhance the usefulness of higher resolution platforms for ASD and ID gene discovery.

Isodicentric Yp: prenatal diagnosis and outcome in 12 cases.

OBJECTIVES: 1. To present the prenatal cytogenetic findings and postnatal outcome of 12 cases with an isodicentric chromosome composed of the short arm of the Y chromosome.2. To review the literature and provide recommendations for cytogenetic analysis and counseling. METHODS: Prenatal and postnatal cytogenetic data and clinical findings of isodicentric Yp ascertained in six institutions were gathered and reviewed. RESULTS: Nine of the twelve cases were referred for advanced maternal age (AMA), one of which was a twin pregnancy with one twin having an increased nuchal translucency measurement. The remaining cases were referred owing to a family history of hemophilia and an abnormal maternal serum screen, respectively. Nine of these pregnancies resulted in the birth of a normal-appearing male infant with subsequent normal growth and psychomotor development. Follow-up ranged from birth to 7 years. In two cases, the pregnancy was terminated and the fetuses showed male external genitalia. In the case ascertained because of an increased nuchal translucency measurement, the prenatal diagnosis of 45,X was made. At birth, there were ambiguous genitalia, and postnatal cytogenetic studies found an isodicentric Yp. In 11 of the 12 cases, mosaicism was present. CONCLUSION: Our cases show that the prenatal finding of an isodicentric Yp, with or without 45,X mosaicism, is compatible with normal male phenotype in most cases, particularly in the absence of other anomalies. To ensure accuracy in cytogenetic reporting and prenatal counseling, the identification of a structurally abnormal or small Y chromosome, either alone or in the presence of 45,X colonies, should be followed immediately by confirmatory molecular cytogenetic investigations as well as by ultrasound determination of the phenotypic sex of the fetus.

Novel case of del(17)(q23.1q23.3) further highlights a recognizable phenotype involving deletions of chromosome (17)(q21q24).

We report on a girl with a phenotype and developmental profile initially suggestive of Angelman syndrome. Subsequently she was shown to have an interstitial deletion of the long arm of chromosome 17; [del(17)(q23.1q23.3)], the smallest unique cytogenetic deletion in this region documented to date. These findings and those of 4 others from the literature, with overlapping deletions of 17q and breakpoints between 17q21-17q24, are reviewed and compared. Similar phenotypic findings include growth retardation, global developmental delay, and specific musculoskeletal and craniofacial anomalies. The size of the specific deletion, and the proximal and distal breakpoints at this region of chromosome 17q, appear to be important in determining morbidity from cardiac involvement and may affect the extent of developmental delay.

Complex karyotypic alterations in an endometrial stromal sarcoma.

Cytogenetic investigation of a low-grade endometrial stromal sarcoma (ESS) revealed structural rearrangements of chromosomes 3, 6, and 7. The karyotypic findings in the few cases of ESS reported reveal recurrent involvement of both homologues of chromosome 7, with less consistent changes affecting chromosomes 6 and 17. The cytogenetic and histologic features of these uterine stromal tumors require further study.

Cytogenetic findings in seven lacrimal gland neoplasms.

We have undertaken cytogenetic investigation of seven benign and malignant lacrimal gland neoplasms. This study showed recurrent chromosomal abnormalities involving chromosomes 3, 8, 9, and 12. These features are similar to those found in benign and malignant salivary gland tumors, which suggests possible common mechanisms involved in the neoplastic proliferation of these histologically related tumors.

Partial duplication of 3q (q25.1-->q26.1) without the Brachmann-de Lange phenotype.

Partial duplications of chromosome 3 have previously been reported to have phenotypic characteristics similar to Brachmann-de Lange syndrome (BDLS). We present the case of a 13-year-old girl with an apparent duplication in the 3q25.1-->q26.1 region but none of the manifestations commonly seen in BDLS. The chromosome 3 duplication was confirmed with a FISH painting probe of the involved region. These results suggest that the region critical for Brachmann-de Lange syndrome is not within the duplicated region of 3q25.1-->q26.1.

Cardio-facio-cutaneous (CFC) syndrome in a child carrying an inherited inversion of chromosome 7.

We describe a 6 1/2-year-old girl with the cardio-facio-cutaneous (CFC) syndrome. She presents with most of the characteristics of this condition: typical facial changes, congenital heart defect, slow growth, ectodermal dysplasia, and developmental delay. Chromosome analysis disclosed a 46,XX,inv(7)(q21.2q31.2) mat karyotype.

Bilateral striatal necrosis in hemolytic-uremic syndrome.

A 41-year old resident of a nursing home presented with bloody diarrhea, and subsequently developed hemolytic-uremic syndrome. E. coli serotype O157:H7 was isolated from the stool culture. At autopsy she was found to have bilateral symmetrical striatal necrosis involving mainly the putamen and lateral globus pallidus. The main microscopic findings consisted of coagulative necrosis, endothelial damage and microthrombosis. Scattered microscopic lesions of similar appearances were noted in the parietal cortex, external capsule and fornix. This case is of particular interest because of the rarity of bilateral striatal necrosis in hemolytic-uremic syndrome and the recent experimental data which implicate E. coli endotoxin in the pathogenesis of cerebral lesions in this syndrome.