A case report of a patient with microcephaly, facial dysmorphism, chromosomal radiosensitivity and telomere length alterations closely resembling "Nijmegen breakage syndrome" phenotype

Genetic heterogeneity in Nijmegen breakage syndrome (NBS) is highlighted by patients showing clinical and cellular features of NBS but with no mutations in NBS1 and normal levels of nibrin. NBS is an autosomal recessive disorder, whose clinical cellular signs include growth and developmental defects, dysmorphic facies, immunodeficiency, cancer predisposition, chromosomal instability and radiosensitivity. NBS is caused by mutations in the NBS1 gene, whose product is part of the MRE11/RAD50/NBS1 complex involved in the DNA double-strand break (DSB) response pathway. Since the identification of the NBS1 gene, patients with NBS clinical signs, particularly severe congenital microcephaly, are screened for mutations in the NBS1 gene. Further analyses include X-ray-induced chromosome aberrations, telomere analysis, kinetics of DSBs repair, levels of a panel of proteins involved in the maintenance of genetic stability, radiation-induced phosphorylation of various substrates and cell cycle analysis. We describe a patient with a NBS clinical phenotype, chromosomal sensitivity to X-rays but without mutations in the whole NBS1 or in the Cernunnos gene. Enhanced response to irradiation was mediated neither by DSBs rejoining defects nor by the NBS/AT-dependent DNA-damage response pathway. Notably, we found that primary fibroblasts from this patient displayed telomere length alterations. Cross-talk between pathways controlling response to DSBs and those involved in maintaining telomeres has been shown in the present patient. Dissecting the cellular phenotype of radiosensitive NBS-like patients represents a useful tool for the research of new genes involved in the cellular response to DSBs.     

GPT2 mutations cause developmental encephalopathy with microcephaly and features of complicated hereditary spastic paraplegia

Various genetic defects can cause intellectual and developmental disabilities (IDDs). Often IDD is a symptom of a more complex neurodevelopmental or neurodegenerative syndrome. Identifying syndromic patterns is substantive for diagnostics and for understanding the pathomechanism of a disease. Recessive glutamate pyruvate transaminase (GPT2) mutations have recently been associated with IDD in 4 families. Here, we report a novel recessive GPT2 stop mutation p.Gln24* causing a complex IDD phenotype in a homozygous state in 5 patients from 2 consanguineous Arab families. By compiling clinical information of these individuals and previously described GPT2 patients a recognizable neurodevelopmental and potentially neurodegenerative phenotype can be assigned consisting of intellectual disability, pyramidal tract affection with spastic paraplegia, microcephaly and frequently epilepsy. Because of the consistent presence of pyramidal tract affection in GPT2 patients, we further suggest that GPT2 mutations should be considered in cases with complex hereditary spastic paraplegia.     

主动脉缩窄合并右弓右降及多囊状动脉瘤的影像诊断

目的 研究主动脉缩窄合并右弓右降及多囊状动脉瘤的的影像学表现。方法 回顾性分析2例主动脉缩窄合并右弓右降及多囊状动脉瘤x线胸片、超声心动图、心血管造影、三维动态增强磁共振造影(3DDCEMRA)资料并与手术病理结果对照。结果 两例均为镜面右位主动脉弓(Ⅰ型)、主动脉缩窄、主动脉弓部多囊状动脉瘤。结论 心血管造影是诊断该类复杂畸形最可靠的方法，三维动态增强磁共振造影(3DDCEMRA)在一定程度上可以替代心血管造影，能为临床手术提供明确的定位与定性诊断。     

75例先天性心脏病感染性心内膜炎的临床分析

目的：探讨先天性心脏病(先心病)感染性心内膜炎(IE)的临床特点。方法：回顾性分析75例住院患者中各类先心病IE的并发率、临床特点、血培养、心内膜受累和治疗情况。结果：①先心病IE中主动脉瓣病变发病率最高(6．2％)；②手术证实累及多个瓣膜。病变多样；③尿检查改变、肝大和脾大的发生率及血培养阳性率(35．7％)较文献报道下降，可能与抗生素广泛应用和感染的主要致病微生物与过去不同有关；①手术治疗45例，治愈44例(97．8％)，死亡1例，内科治疗30例，治愈13例(43．3％)，因动脉栓塞或心功能恶化而出院14例，死亡3例。结论：适当的内科治疗与积极的外科治疗相结合对提高先心病IE存活率、降低病死率有重要意义。     

Microcephaly,intractable seizures and developmental delay caused by biallelic variants in TBCD: further delineation of a new chaperone‐mediated tubulinopathy

Microtubule dynamics play a crucial role in neuronal development and function, and several neurodevelopmental disorders have been linked to mutations in genes encoding tubulins and functionally related proteins. Most recently, variants in the tubulin cofactor D (TBCD) gene, which encodes one of the five co‐chaperones required for assembly and disassembly of α/β‐tubulin heterodimer, were reported to underlie a recessive neurodevelopmental/neurodegenerative disorder. We report on five patients from three unrelated families, who presented with microcephaly, intellectual disability, intractable seizures, optic nerve pallor/atrophy, and cortical atrophy with delayed myelination and thinned corpus callosum on brain imaging. Exome sequencing allowed the identification of biallelic variants in TBCD segregating with the disease in the three families. TBCD protein level was significantly reduced in cultured fibroblasts from one patient, supporting defective TBCD function as the event underlying the disorder. Such reduced expression was associated with accelerated microtubule re‐polymerization. Morpholino‐mediated TBCD knockdown in zebrafish recapitulated several key pathological features of the human disease, and TBCD overexpression in the same model confirmed previous studies documenting an obligate dependency on proper TBCD levels during development. Our findings confirm the link between inactivating TBCD variants and this newly described chaperone‐associated tubulinopathy, and provide insights into the phenotype of this disorder.     

Zika virus: A new threat to human reproduction

Zika virus (ZIKV) was first isolated in 1947 in a rhesus monkey from the Zika forest of Uganda. Until 2007, only 14 human cases were reported. The first large human outbreak occurred in 2007 (Yap Island, Federated States of Micronesia, Pacific) followed by French Polynesia in 2013 and Brazil in 2015. The virus is mainly transmitted through Aedes mosquito bites, but sexual and post‐transfusion transmissions have been reported. Symptoms include low‐grade fever, maculopapular rash, conjunctivitis, myalgia, arthralgia, and asthenia. During the recent outbreaks in French Polynesia and Brazil, ZIKV infection has been associated with two major complications: microcephaly and Guillain–Barré syndrome. Since fetal infection includes other birth defects, congenital Zika syndrome has been used to define in utero infection. The majority of sexual transmission occurred from a symptomatic male to a female, but female‐to‐male and male‐to‐male transmission have been reported. Asymptomatic male‐to‐female transmission has also been described. Importantly, ZIKV RNA can persist at least 6 months in semen. The male urogenital tract may therefore act as a reservoir for the virus. ZIKV RNA was detected in a cervical swab of a patient 3 days after presenting the classic symptoms suggesting a potential tropism for the female genital tract. Long‐lasting presence of ZIKV RNA might not indicate that the individual is infectious but makes recommendation for couples potentially exposed to the virus and willing to conceive difficult. It will also be important to determine whether genital ZIKV infection might have a deleterious effect on male and female fertility.     

Zika and pregnancy: A comprehensive review

Zika virus (ZIKV) infection is a well‐nurtured topic for healthcare personnel nowadays. Central nervous system involvement including microcephaly and ocular involvements has already been reported in neonates of affected pregnant ladies. In this article, we have discussed these effects on the newborns of ZIKV‐infected mothers. The proposed pathogenesis, modes of transmission of this infection from mothers to the fetuses, diagnosis of the cases and precaution for the pregnant ladies have also been discussed. We have gathered the recently available data on the risk of ZIKV for expectant mothers from PubMed, https://www.gov.uk/guidance/zika-virus as well as from centers for disease control and prevention websites.