LARP7 variants and further delineation of the Alazami syndrome phenotypic spectrum among primordial dwarfisms: 2 sisters

Alazami syndrome (AS) (MIM# 615071) is an autosomal recessive microcephalic primordial dwarfism (PD) with recognizable facial features and severe intellectual disability due to depletion or loss of function variants in LARP7. To date, 15 patients with AS have been reported. Here we describe two consanguineous Algerian sisters with Alazami PD due to LARP7 homozygous pathogenic variants detected by whole exome sequencing. By comparing these two additional cases with those previously reported, we strengthen the key features of AS: severe growth restriction, severe intellectual disability and some distinguishing facial features such as broad nose, malar hypoplasia, wide mouth, full lips and abnormally set teeth. We also report significant new findings enabling further delineation of this syndrome: disproportionately mild microcephaly, stereotypic hand wringing and severe anxiety, thickened skin over the hands and feet, and skeletal, eye and heart malformations. From previous reviews, we summarize the main etiologies of PD according to the involved mechanisms and cellular pathways, highlighting their clinical core features.     

Interaction of Shigella flexneri IpaC with model membranes correlates with effects on cultured cells

Invasion of enterocytes by Shigella flexneri requires the properly timed release of IpaB and IpaC at the host-pathogen interface; however, only IpaC has been found to possess quantifiable activities in vitro. We demonstrate here that when added to cultured cells, purified IpaC elicits cytoskeletal changes similar to those that occur during Shigella invasion. This IpaC effect may correlate with its ability to interact with model membranes at physiological pH and to promote entry by an ipaC mutant of S. flexneri.     

Hearing impairment as an early sign of alpha‐mannosidosis in children with a mild phenotype: Report of seven new cases

Alpha‐mannosidosis (AM) is a very rare (prevalence: 1/500000 births) autosomal recessive lysosomal storage disorder. It is characterized by multi‐systemic involvement associated with progressive intellectual disability, hearing loss, skeletal anomalies, and coarse facial features. The spectrum is wide, from very severe and lethal to a milder phenotype that usually progresses slowly. AM is caused by a deficiency of lysosomal alpha‐mannosidase. A diagnosis can be established by measuring the activity of lysosomal alpha‐mannosidase in leucocytes and screening for abnormal urinary excretion of mannose‐rich oligosaccharides. Genetic confirmation is obtained with the identification of MAN2B1 mutations. Enzyme replacement therapy (LAMZEDE^R) was approved for use in Europe in August 2018. Here, we describe seven individuals from four families, diagnosed at 3–23 years of age, and who were referred to a clinical geneticist for etiologic exploration of syndromic hearing loss, associated with moderate learning disabilities. Exome sequencing had been used to establish the molecular diagnosis in five cases, including a two‐sibling pair. In the remaining two patients, the diagnosis was obtained with screening of urinary oligosaccharides excretion and the association of deafness and hypotonia. These observations emphasize that the clinical diagnosis of AM can be challenging, and that it is likely an underdiagnosed rare cause of syndromic hearing loss. Exome sequencing can contribute significantly to the early diagnosis of these nonspecific mild phenotypes, with advantages for treatment and management.     

Préparation et identification de copolyamides alternés du type ω-aminoacide

The hydrochlorides of p-nitrophenyl 6-aminocaproate ( 4a ), p-nitrophenyl 12-aminododecanoate ( 4b ), and p-nitrophenyl 12-(6-aminocaproylamino)dodecanoate ( 6 ) were prepared and polycondensed in 1,2,4-trichlorobenzene in the presence of tributylamine under different conditions. The polycondensation of 6 at 128°C gave the alternating copolyamide (PA 6, 12). The polymers were identified by DTA and by ¹³C NMR.     

Cloning and expression of surface antigens from occult chronic hepatitis B virus infections and their recognition by commercial detection assays

Occult hepatitis B virus (HBV) infections show little or no serological markers of viral infection, including the absence of hepatitis B surface antigen (HBsAg) which is the main marker of ongoing HBV infection. Such infections can be important in the context of blood and/or organ donations. To study whether mutations contribute to HBsAg seronegativity, S gene sequences from such patients were amplified and cloned. Sequencing revealed 12 clones from seven different patients which contained potentially important mutations. The sequences were subcloned into an expression vector and mutant HBsAgs were expressed in cell culture. The capacity of three HBsAg detection assays to recognise the mutant HBsAgs was studied. Three categories were found: mutant HBsAgs that are not recognised by the assays, those that are recognised as well as wild-type (WT) antigen and an intermediate category where detection of the mutant HBsAgs is reduced with respect to WT. Most of the isolates fall into the second category. Mutations can therefore contribute to HBsAg seronegativity in occult HBV infections, but in most cases the explanation is probably the low level of viral replication.     

Modulation of acetylcholine release in the ventral striatum by histamine receptors

Inflammation Research -     

Effects of sleep on pain-related somatosensory evoked potentials in humans

We investigated effects of sleep on pain-related somatosensory evoked potentials (SEP) following painful electrical stimulation of the left index finger. The biggest advantage of this method is that signals ascending through both A-beta fibers relating to touch and A-delta fibers relating to pain can be recorded simultaneously. While the subject was awake, non-painful stimulation evoked early- and middle latency components, N20, P30 and N60, at the C4 electrode, and painful stimulation evoked not only early- and middle latency components at the C4 but also later pain-specific components, N130 and P240, at the Cz electrode. During sleep, N20 and P30 did not show a significant change in amplitude, N60 showed a slight but significant amplitude reduction, and N130 and P240 significantly decreased in amplitude or disappeared, as compared with those while awake. Therefore, we speculate on the mechanisms generating each component as follows; (1) N20 and P30 are the primary components generated in SI ascending through A-beta fibers. (2) N60 is the secondary component generated in SI involving cognitive function to some degree. (3) N130-P240 are the pain-specific components ascending through A-delta fibers, and closely related to cognitive function, because they were much affected by consciousness, different from the components ascending through A-beta fibers.     

Molecular epidemiology of hepatitis B, C, D and E viruses among children in Moscow, Russia.

BACKGROUND: It is known that the prevalence of HBV and HCV infections vary according to geographical areas. However, in Russia, an adequate level of information on the molecular epidemiology of hepatitis viruses has not been available so far. OBJECTIVES: To investigate the characterization of various hepatitis viruses in Russia, we conducted molecular-based epidemiological survey of hepatitis viruses including hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV) and hepatitis E virus (HEV) among children in Moscow, Russia. STUDY DESIGN: The study population of 374 subjects (ranging in age from 1 to 14 years old) consisted of 195 patients with liver diseases and 179 patients without liver diseases. Viral DNA/RNA was determined by nested PCR. Genotyping of HBV and HCV were examined by PCR using type-specific primers. Anti-HEV antibody was assayed by ELISA. RESULTS: The infection rate of each virus among patients with liver diseases including acute hepatitis, chronic hepatitis or cirrhosis was 65.6% for HBV and 15.9% for HCV. In contrast, among non-liver disease patients, the infection rates were 14.4% for HBV and 0.6% for HCV, respectively. The most common viral genotypes were type D (85%) of HBV and type 1b (79.3%) of HCV. HDV RNA was detected in 7 of 149 (4.7%) HBV DNA-positive children tested. Moreover, testing for HEV among 341 subjects resulted in the detection of anti-HEV IgG in 62 cases (18.2%). CONCLUSIONS: Our results suggest that HBV infection is widespread in Moscow and have led to a high incidence of acute and chronic liver diseases among children in this region.     

Comparative study on deletions of the dystrophin gene in three Asian populations

The frequency and distribution of deletions of 19 deletion-prone exons clustered in two hot spots in the proximal and central regions of the dystrophin gene were compared in three populations from Singaporean, Japan, and Vietnam. DNA samples obtained from 105 Singaporean, 86 Japanese, and 34 Vietnamese Duchenne muscular dystrophy patients were examined by polymerase chain reaction amplification. Deletions of the examined exons were found in 51.2% of Japanese patients but in 40.0% or less of the Singaporeans and Vietnamese. About two thirds of the deletions were localized in the central region and the remaining deletions were clustered at the proximal region. The most commonly deleted exons at the central deletion hot spot were exon 50 in the Singaporean, exons 49 and 50 in the Japanese, and exon 51 in the Vietnamese population. At the proximal deletion hot spot, the most commonly deleted exons were exons 6 and 8 in the Singaporeans, exons 12 and 17 in the Japanese, and exons 8 and 12 in the Vietnamese. Two cases each from Singapore and Japan had large-scale gross mutations spanning both deletion hot spots. Our results suggest that, although the presence and frequency of the two deletion hot spots may be similar in the three Asian populations analyzed, the distribution and frequency of deletions among the different exons can vary as a result of population-specific intronic sequences that predispose individuals to preferential deletion breakpoints. Received: May 20, 2002 / Accepted: July 1, 2002