Deletion 18q21.2q21.32 involving TCF4 in a boy diagnosed by CGH-array

We report on a 12 year-old boy presenting with severe developmental delay, dysmorphic features, limb anomalies, growth retardation, hypoplastic vermis and corpus callosum. Conventional and high-resolution cytogenetic analyses were normal. CGH-array allowed characterisation of a de novo 6.2 Mb 18q21.2q21.32 interstitial deletion involving TCF4, the recently identified gene responsible for Pitt-Hopkins syndrome (PHS). No tachypnoea-apnoea paroxysms were observed. We discuss the dysmorphic features particularly involving the ears, which might be helpful towards PHS and 18q21 deletion diagnosis.     

Characterization by array-CGH of an interstitial de novo tandem 6p21.2p22.1 duplication in a boy with epilepsy and developmental delay

We report on a 6-years-old boy with psychomotor retardation, mild dysmorphic features and behavioral disturbances associated with epilepsy. Conventional cytogenetic analysis concluded to an interstitial de novo 6p21.2p22.3 duplication. Molecular cytogenetic analysis, including array-CGH technology, allows characterization of this 7.3Mb interstitial tandem duplication. The phenotype of this small 6p duplication reported to date is compared to other cases in the literature. Presence of epilepsy, although rare in patients with 6p duplication may be linked to genes involved in brain function and synaptic transmission in the 6p21.2p22.1 duplicated region (GABBR1, BRD2 and GRM4).     

The TRPV4 channel: structure-function relationship and promiscuous gating behaviour

Transient receptor potential (TRP) channels provide an enormous variability of Ca(2+) influx mechanisms triggered by a wide range of stimuli. In this review, we discuss the activation properties of the Ca(2+)- and Mg(2+)-permeable TRP channel of the vanilloid subfamily TRPV4. This channel is activated by various physical and chemical stimuli, such as cell swelling, heat, phorbols and, probably, by endogenous ligands, which are able to induce Ca(2+) entry. Not much is known about the regulation of this channel. We will refer only to a mechanism of Ca(2+)-dependent inhibition of TRPV4. Possible functional roles of this channel will be correlated with its observed expression pattern. Finally, we discuss the structural determinants of TRPV4 channel function.     

Randomized controlled trial evaluating the clinical benefit of montelukast for treating spring seasonal allergic rhinitis.

BACKGROUND: Symptoms of allergic rhinitis are mediated in part by cysteinyl leukotrienes. OBJECTIVE: To evaluate the clinical benefit of montelukast, a cysteinyl leukotriene receptor antagonist, administered once daily for treating seasonal allergic rhinitis. METHODS: This multicenter, randomized, double-blind, placebo- and active-controlled study enrolled 1,214 healthy, nonsmoking outpatients aged 15 to 85 years with spring allergic rhinitis, positive skin test to a spring allergen, and predefined daytime nasal symptoms. After a 3- to 5-day placebo run-in period, patients were randomly assigned to treatment with montelukast 10 mg (n = 522), loratadine 10 mg (n = 171), or placebo (n = 521) once daily at bedtime for 2 weeks. During the run-in and treatment periods, symptoms were evaluated in a daily diary using a 0 (best) to 3 (worst) scale. RESULTS: Baseline characteristics of randomized patients were clinically similar in the three treatment groups. Montelukast was significantly more effective than placebo (P = 0.003) in improving the daytime nasal symptoms score (difference in least square means, -0.09; 95% confidence interval, -0.16, -0.03) averaged over 2 weeks of therapy. The treatment effect of montelukast was significantly greater (P < 0.05), relative to placebo, for all secondary endpoints, including nighttime symptoms and daytime eye symptoms, patient and physician global evaluations of allergic rhinitis, and rhinoconjunctivitis quality of life. Loratadine, which served as a positive control, was significantly more effective than placebo for most endpoints, validating the study results. Both montelukast and loratadine were well tolerated. CONCLUSION: Therapy with montelukast significantly improves assessments of symptom severity as well as quality-of-life parameters for patients with seasonal allergic rhinitis.     

Comparison of the results of human embryo biopsy and outcome of PGD after zona drilling using acid Tyrode medium or a laser

BACKGROUND: Zona pellucida opening for blastomere removal can be done by mechanical or chemical means, or by laser. So far, only limited data on the use of laser systems for zona drilling in cases of PGD are available. METHODS: Results of embryo biopsy and outcome of PGD in two periods were compared. In the first period, acid Tyrode medium was used for zona drilling. In the second period, zona drilling was performed by a 1.48 micro m infrared laser. RESULTS: In the first period, 59 cycles resulted in 53 biopsy procedures with 356 biopsied embryos. In the second period, these numbers were 69 cycles, 69 biopsy procedures and 402 biopsied embryos. Fewer blastomeres were intact (95.2%) after zona drilling with acid Tyrode than after laser zona drilling (98.3%, P = 0.02). Rates of positive HCG (37.5% versus 35.5%), ongoing pregnancy rates (31.3% versus 25.0%) and ongoing implantation rates (18.9% versus 14.9%) did not differ. CONCLUSIONS: The use of a laser for zona drilling in cases of PGD is an easier procedure and results in more intact blastomeres. Since similar pregnancy rates are obtained, it is advantageous to use a laser for zona drilling. Further follow-up is necessary to prove the safety of this procedure.     

Progranulin expression correlates with dense‐core amyloid plaque burden in Alzheimer disease mouse models

Amyloid‐β (Aβ) plaques are pathological hallmarks of Alzheimer disease (AD). In addition, innate inflammatory responses, such as those mediated by microglia, are integral to the pathogenesis of AD. Interestingly, only dense‐core plaques and not diffuse plaques are associated with neuritic and inflammatory pathology in AD patients as well as in mouse AD models. However, the precise neuropathological changes that occur in the brain in response to amyloid deposition are largely unknown. To study the molecular mechanism(s) responsible for Aβ‐mediated neuropathology, we performed a gene expression analysis on laser‐microdissected brain tissue of Tg2576 and APPPS1 mice that are characterized by different types of amyloid plaques and genetic backgrounds. Data were validated by image and biochemical analyses on different ages of Tg2576, APPPS1, and Aβ42‐depositing BRI‐Aβ42 mice. Consistent with an important role of inflammatory responses in AD, we identified progranulin (mouse Grn; human GRN) as one of the top ten up‐regulated molecules in Tg2576 (≈8‐fold increased) and APPPS1 (≈2‐fold increased) mice compared to littermate controls, and among the eight significantly up‐regulated molecules common to both mouse models. In addition, Grn levels correlated significantly with amyloid load, especially the dense‐core plaque pathology (p < 0.001). We further showed that Grn is up‐regulated in microglia and neurons and neurites around dense‐core plaques, but not in astrocytes or oligodendrocytes, as has been shown in AD patients. Our data therefore support the ongoing use of these mouse models in drug trials, especially those with anti‐inflammatory compounds. Moreover, the correlation of Grn with increasing disease severity in AD mouse models prompts human studies exploring the viability of GRN as a disease biomarker. Because loss of GRN has recently been shown to cause frontotemporal dementia and serves as a risk factor for AD, the strong GRN reactivity around dense‐core plaques is consistent with an important role of this factor in AD pathogenesis. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Refining the locus of branchio-otic syndrome 2 (BOS2) to a 5.25 Mb locus on chromosome 1q31.3q32.1

In 1991, a large family was described with an autosomal dominant inheritance of otological and branchial manifestations which was termed branchio-otic syndrome type 2 (BOS2). This trait was mapped by linkage analysis in this family to a region of 23–31 Mb on chromosome 1q25.1q32.1. In the present report we describe the clinical features of two patients with a deletion in this region: one patient has a deletion but no otological or branchial manifestations, the other patient manifests mild conductive hearing loss resulting from bilaterally malformed middle ear ossicles, as well as a preauricular pit. Mapping of the deletion breakpoints allowed to delineate the region involved in BOS2 to a 5.25 Mb region containing 27 protein-coding genes. A detailed medical history of both patients is provided and they are compared with the literature on other detected interstitial deletions of 1q25q32. These findings will aid in the identification of the genetic cause underlying BOS2.     

Identification of Intellectual Disability Genes in Female Patients with a Skewed X‐Inactivation Pattern

Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X‐linked ID (XLID) studies focused on males because of the hemizygous state of their X chromosome. Carrier females are generally unaffected because of the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X‐inactivation would be an indicator for an X chromosomal ID cause. We analyzed the X‐inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; P = 0.029). Whole‐exome sequencing of 19 females with extreme skewing revealed causal variants in six females in the XLID genes DDX3X, NHS, WDR45, MECP2, and SMC1A. Interestingly, variants in genes escaping X‐inactivation presumably cause both XLID and skewing of X‐inactivation in three of these patients. Moreover, variants likely accounting for skewing only were detected in MED12, HDAC8, and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X‐linked variants in female patients.