Genetic heterogeneity in X-linked hydrocephalus: linkage to markers within Xq27.3.

X-linked hydrocephalus is a well-defined disorder which accounts for > or = 7% of hydrocephalus in males. Pathologically, the condition is characterized by stenosis or obliteration of the aqueduct of Sylvius. Previous genetic linkage studies have suggested the likelihood of genetic homogeneity for this condition, with close linkage to the DXS52 and F8C markers in Xq28. We have investigated a family with typical X-linked aqueductal stenosis, in which no linkage to these markers was present. In this family, close linkage was established to the DXS548 and FRAXA loci in Xq27.3. Our findings demonstrate that X-linked aqueductal stenosis may result from mutations at two different loci on the X chromosome. Caution is indicated in using linkage for the prenatal diagnosis of X-linked hydrocephalus.     

Assignment of X-linked hydrocephalus to Xq28 by linkage analysis

X-linked recessive hydrocephalus (HSAS) occurs at a frequency of approximately 1 per 30,000 male births and consists of hydrocephalus, stenosis of the aqueduct of Sylvius, mental retardation, spastic paraparesis, and clasped thumbs. Prenatal diagnosis of affected males by ultrasonographic detection of hydrocephalus is unreliable because hydrocephalus may be absent antenatally. Furthermore, carrier detection in females is not possible because they are asymptomatic. Using four families segregating HSAS, we performed linkage analysis with a panel of X-linked probes that detect restriction fragment length polymorphisms. We report here that HSAS, in all tested families, is closely linked to marker loci mapping in Xq28 (DXS52, lod = 6.52 at theta of 0.03; F8, lod = 4.32 at theta of 0.00; DXS15, lod = 3.40 at theta of 0.00). These data assign HSAS to the gene-dense chromosomal band Xq28 and allow for both prenatal diagnosis and carrier detection by linkage analysis.     

A deletion of five nucleotides in the LICAM gene in a Japanese family with X-linked hydrocephalus

X-linked hydrocephalus (HSAS) is the most common form of inherited hydrocephalus characterized by hydrocephalus due to stenosis of the aqueduct of Sylvius, mental retardation, clasped thumbs, and spastic paraparesis. MASA syndrome (mental retardation, aphasia, shuffling gait and adducted thumbs) and SPG1 (X-linked complicated spastic paraplegia) are also X-linked disorders with overlapping clinical signs. Linkage analysis studies implicated the neural cell adhesion molecule L1 (LICAM) gene as a candidate gene for these X-linked disorders. This genetic study analyzes the LICAM gene in a Japanese family with members suffering from HSAS, and describes a deletion of five nucleotides in exon 8. Screening byBg1I digestion of polymerase chain reaction (PCR) products revealed that two siblings have the same mutation and a sister was identified as a heterozygous carrier. The 5 nucleotide deletion causes a shift of the reading frame and introduces a premature stop codon 72 nucleotides downstream, which might result in a truncated protein. The mutation identified herein is a novel L1 CAM mutation, which triggers hydrocephalus. We report a unique LlCAM mutation that causes HSAS: the first report of such a mutation in a Japanese family.     

Role of the subcommissural organ in the pathogenesis of congenital hydrocephalus in the HTx rat

The present investigation was designed to clarify the role of the subcommissural organ (SCO) in the pathogenesis of hydrocephalus occurring in the HTx rat. The brains of non-affected and hydrocephalic HTx rats from embryonic day 15 (E15) to postnatal day 10 (PN10) were processed for electron microscopy, lectin binding and immunocytochemistry by using a series of antibodies. Cerebrospinal fluid (CSF) samples of non-affected and hydrocephalic HTx rats were collected at PN1, PN7 and PN30 and analysed by one- and two-dimensional electrophoresis, immunoblotting and nanoLC-ESI-MS/MS. A distinct malformation of the SCO is present as early as E15. Since stenosis of the Sylvius aqueduct (SA) occurs at E18 and dilation of the lateral ventricles starts at E19, the malformation of the SCO clearly precedes the onset of hydrocephalus. In the affected rats, the cephalic and caudal thirds of the SCO showed high secretory activity with all methods used, whereas the middle third showed no signs of secretion. At E18, the middle non-secretory third of the SCO progressively fused with the ventral wall of SA, resulting in marked aqueduct stenosis and severe hydrocephalus. The abnormal development of the SCO resulted in the permanent absence of Reissner’s fibre (RF) and led to changes in the protein composition of the CSF. Since the SCO is the source of a large mass of sialilated glycoproteins that form the RF and of those that remain CSF-soluble, we hypothesize that the absence of this large mass of negatively charged molecules from the SA domain results in SA stenosis and impairs the bulk flow of CSF through the aqueduct.     

Morphological and behavioral changes in the pathogenesis of a novel mouse model of communicating hydrocephalus

The Ro1 model of hydrocephalus represents an excellent model for studying the pathogenesis of hydrocephalus due to its complete penetrance and inducibility, enabling the investigation of the earliest cellular and histological changes in hydrocephalus prior to overt pathology. Hematoxylin and eosin staining, immunofluorescence and electron microscopy were used to characterize the histopathological events of hydrocephalus in this model. Additionally, a broad battery of behavioral tests was used to investigate behavioral changes in the Ro1 model of hydrocephalus. The earliest histological changes observed in this model were ventriculomegaly and disorganization of the ependymal lining of the aqueduct of Sylvius, which occurred concomitantly. Ventriculomegaly led to thinning of the ependyma, which was associated with periventricular edema and areas of the ventricular wall void of cilia and microvilli. Ependymal denudation was subsequent to severe ventriculomegaly, suggesting that it is an effect, rather than a cause, of hydrocephalus in the Ro1 model. Additionally, there was no closure of the aqueduct of Sylvius or any blockages within the ventricular system, even with severe ventriculomegaly, suggesting that the Ro1 model represents a model of communicating hydrocephalus. Interestingly, even with severe ventriculomegaly, there were no behavioral changes, suggesting that the brain is able to compensate for the structural changes that occur in the pathogenesis of hydrocephalus if the disorder progresses at a sufficiently slow rate.     

磁共振三维稳态进动快速成像序列诊断脑积水的临床价值

摘要 目的：分析磁共振三维稳态进动快速成像(3D-FIESTA)序列诊断脑积水的临床价值。方法：选择我院2015年3月~2016年3月收治的手术病理确诊的120例脑积水患者,术前均行磁共振常规序列及3D-FIESYA序列扫描,比较其检查结果。结果：磁共振常规序列提示有23例交通性脑积水,有73例梗阻性脑积水,其中有24例中脑导水管完全梗阻,有20例中脑导水管狭窄,有16例四脑室流出道梗阻,有13例桥前池囊肿阻塞双侧室间孔,有24例未检出。3D-FIESTA序列提示有34例交通性脑积水,有83例梗阻性脑积水,其中有34例中脑导水管完全梗阻,有19例中脑导水管狭窄,有18例四脑室流出道梗阻,有12例桥前池囊肿阻塞双侧室间孔,有3例未检出。3D-FIESTA序列对脑积水的检出率高于磁共振常规序列,差异有统计学意义(P<0.05)。结论：3D-FIESTA序列能够客观反映脑脊液循环通路的状态,利于脑积水类型的鉴别,为临床治疗提供更全面、确切的影像学参考。     

Computational investigation of subject-specific cerebrospinal fluid flow in the third ventricle and aqueduct of Sylvius

The cerebrospinal fluid flow in the third ventricle of the brain and the aqueduct of Sylvius was studied using computational fluid dynamics (CFD) based on subject-specific boundary conditions derived from magnetic resonance imaging (MRI) scans. The flow domain geometry was reconstructed from anatomical MRI scans by manual image segmentation. The movement of the domain boundary was derived from MRI brain motion scans. Velocimetric MRI scans were used to reconstruct the velocity field at the inferior end of the aqueduct of Sylvius based on the theory of pulsatile flow in pipes. A constant pressure boundary condition was assigned at the foramina of Monro. Three main flow features were observed: a fluid jet emerging from the aqueduct of Sylvius, a moderately mobile recirculation zone above the jet and a mobile recirculation below the jet. The flow in the entire domain was laminar with a maximum Reynolds number of 340 in the aqueduct. The findings demonstrate that by combining MRI scans and CFD simulations, subject-specific detailed quantitative information of the flow field in the third ventricle and the aqueduct of Sylvius can be obtained.     

Strain difference of the mouse in manifestation of hydrocephalus following prenatal methylmercury exposure

Genetic background may influence susceptibility to hydrocephalus. In the present experiment we compared the manifestation of hydrocephalus following prenatal methylmercury exposure among strains of mice which sporadically develop or never develop spontaneous hydrocephalus. Pregnant mice of the B10.D2 congenic strain were given a single oral dose of 10 mg/kg methylmercuric chloride on one of days 14 through 17 of pregnancy and allowed to give birth and rear their litters. The incidence of grossly apparent hydrocephalus in the offspring at 30 days of age following treatment on day 14, 15, 16, or 17 of pregnancy was 67, 88, 75, and 48%, respectively; that of sham-treated and untreated offspring was 5 and 4%, respectively. In addition, there were some brains showing slight dilatation of the lateral ventricles. Pregnant females of C57BL/10 (B10) or DBA/2 (D2) strain were also treated with 10 mg/kg methylmercury on day 15 of pregnancy. The incidence of hydrocephalus at 30 days of age in untreated and dosed B10 mice was 0.8 and 54%, respectively. Hydrocephalus failed to develop in D2 mice. The hydrocephalus is a communicating type. Occlusion of the cerebral aqueduct with glial reaction and caudal displacement of the cerebellum are considered to be secondary changes. The results indicate that the susceptibility to methylmercury-induced hydrocephalus is under genetic control in mice.     

Craniofacial configuration and postcranial development of a hydrocephalic child (ca. 2500 B.C.-500 A.D.): with a review of cases and comment on diagnostic criteria

Hydrocephalus is a severe disorder of the central nervous system characterized by absorption blockage of the cerebral spinal fluid (CSF). The archaeological record of the condition ranges in time from 10,000 B.C. to 1670 A.D. and consists of 30 possible cases worldwide. A review of this material reveals that diagnostic criteria which fully delineate the condition have not been established. Previously, no attempt has been made to differentiate the two major categories of hydrocephalus and their subgroupings, or to identify other conditions which might result in similar morphologies. A partial child's skeleton from the Middle Period (ca. 2500 B.C. to 500 A.D.) of Central California Prehistory is described in light of an extensive clinical literature. Examination of this individual reveals a unique craniofacial configuration and malformed postcrania. Bony criteria for a differential diagnosis of hydrocephalus are established and applied to this individual. Based on these criteria, the individual is diagnosed as having a chronic form of noncommunicating hydrocephalus. Blockage of the CSF pathway most likely occurred in the aqueduct of Sylvius with a partial occlusion of the foramen of Monro or a frontal cyst. In addition, femoral development is suggestive of partial paralysis.     

Detection of chromosomal abnormalities using cordocentesis]

Four cases of cytogenetic prenatal diagnosis of fetuses with chromosomal aberrations are presented: (1) the Patau syndrome; (2) and (4) the Down syndrome; (3) the Klinefelter syndrome. Cordocentesis has been shown to be expedient for rapid and accurate determination of fetus karyotype. Indicative for cytogenetic examination were ultrasonic data, maternal age, the values of AFP, HGG and nonconjugated estreol in maternal serum. Comparison of ultrasonic examination of fetuses with the data on abortus autotopsia was undertaken. The results demonstrate importance of ultrasonic, cytogenetic, biochemical and morphological research in prenatal malformation diagnosis.     

The relationship between hydrocephalus and Chiari type II malformation in the experimental rat fetuses with Arnold-Chiari malformation

Spina bifida, Chiari type II malformation, cerebral aqueduct stenosis and hydrocephalus are the most frequent association anomalies in the congenital malformation of the central nervous system (Warkany et al., 1958). They are potentially treatable and of clinical importance. But the relationship between hydrocephalus and Chiari type II malformation is still a controversial subject. A single oral dose of 240 mg/kg of ethylenethiourea (ETU) was given to Sprague Dawley (SD) rats on the 11th day of gestation. Fetuses were removed in the 20th day of gestation by cesarean sections; high incidence of spinal dysraphism associated with hindbrain crowding was found in these fetuses. They are similar to Arnold-Chiari malformation in humans. We used these experimental models to analyze the relationship between hydrocephalus and Chiari type II malformation. From the present investigation, no hydrocephalus or cerebral aqueduct stenosis was found in the experimental rat fetuses with the Arnold-Chiari malformation. So we do not consider the hydrodynamic theory that Chiari type II malformation was induced by increasing intracranial pressure in hydrocephalus. Hydrocephalus in the Arnold-Chiari malformation may not be the primary disorder but seems to be caused by plugging the foramen magnum in Chiari type II malformation. So the cerebrospinal fluid in the spinal subarachnoid space can not move upward to the cranial subarachnoid space for absorption to venous return. Cerebral aqueduct stenosis may be secondarily compressed by hydrocephalus and not be the primary development anomaly or acquired occlusion due to gliosis. This is in accord with the theory proposed by Russell and Donald (1935).(ABSTRACT TRUNCATED AT 250 WORDS)     

The Diagnosis of Mitral Stenosis

The diagnosis of classical mitral stenosis is easy, but many pitfalls lead to over-diagnosis or under-diagnosis. These have been considered in detail and variations in symptoms and signs have been illustrated by case histories. Such variations include: (1) Embolism producing the Leriche syndrome; (2) mitral stenosis with insignificant hemodynamic effect; (3) myxoma masquerading as mitral stenosis; (4) mitral stenosis without apical murmurs, and (5) mitral stenosis with a systolic murmur predominant or alone. In cases of combined mitral and aortic stenosis, the history, radiographic configuration, and incidence of hemoptysis, edema, bronchitis, embolism and atrial fibrillation resemble such findings in cases of isolated mitral stenosis, but the auscultatory signs of the latter may be obscured. The degree of aortic stenosis is difficult to determine in cases of combined stenosis. In the diagnosis of re-stenosis the condition of the valve at the first commissurotomy, the precise procedure performed and the degree of regurgitation produced are of prime importance. Congenital mitral stenosis is rare and is associated with a high incidence of other defects.     

Prenatal diagnosis and genetic counseling of a Chinese Alport syndrome kindred

Alport syndrome (AS) is a progressive renal disease characterized by hematuria and progressive renal failure. X-linked dominant AS (XLAS) is the major inheritance form, accounting for almost 80% of the cases, caused by mutations in COL4A5 gene. An accurate genetic diagnosis of AS is very important for genetic counseling and even prenatal diagnosis. In this study we detected mutation of COL4A5 by amplifying the entire coding sequence mRNA of peripheral blood lymphocytes using nested PCR in a Chinese XLAS family, and then performed the first prenatal diagnosis of AS in China. Mutation analysis of the fetus was performed on both cDNA-based level and DNA-based level of amniocytes. Fetus sex was determined by PCR amplification of SRY and karyotypes analysis. Maternal cell contamination was excluded by linkage analysis. There was a G-to-A substitution at position 4,271 in exon 46 of COL4A5 gene (c.G4271A) in the pregnant woman; this genetic variant has not been described previously and was a novel missense mutation. The fetus did not carry the same mutation as the mother. PCR amplification product of SRY and karyotypes analysis revealed a male fetus. Linkage analysis showed that there was no contamination of maternal cells in amniocytes.     

产前超声诊断及漏诊胎儿肢体畸形分析

目的：探讨胎儿肢体畸形超声特征及诊断价值。方法：采用连续顺序追踪法对66342 例妊娠12-40 周孕妇行胎儿四肢畸形筛查。将产前超声诊断结果与引产或产后结果进行对比分析。结果：发生肢体畸形271 例,发生率为0.41 %（271/66342）,包括四肢短小5 例,桡骨发育不全1 例,缺肢畸形5 例,足内翻17 例,手掌畸形3 例,指趾畸形222 例及骨骼多发畸形18 例。其中产前诊断胎儿肢体畸形49 例;漏诊222 例,包括：足内翻3 例、指趾畸形218 例、多发骨骼畸形1 例。胎儿肢体畸形的出现率和产前检出率分别为：四肢短小1.84 %（5/271）、100 %（5/5）;桡骨发育不全0.36 %（1/271）、100 %（1/1）;缺肢畸形1.84 %（5/271）、100 %（5/5）;足内翻6.27 %（17/271）、82.35 %（14/17）;手掌畸形1.10 %（3/271）、100 %（3/3）;指趾畸形81.91 %（222/217）、1. 8%（4/222）;多发骨骼畸形6.64 %（18/271）、94.44 %（17/18）。结论：超声对胎儿手掌、脚掌部位以上畸形的检出率较高。指趾畸形出现率最高,但检出率最低。     

产前超声诊断及漏诊胎儿肢体畸形分析

目的:探讨胎儿肢体畸形超声特征及诊断价值。方法:采用连续顺序追踪法对66342例妊娠12-40周孕妇行胎儿四肢畸形筛查。将产前超声诊断结果与引产或产后结果进行对比分析。结果:发生肢体畸形271例,发生率为0.41%(271/66342),包括四肢短小5例,桡骨发育不全1例,缺肢畸形5例,足内翻17例,手掌畸形3例,指趾畸形222例及骨骼多发畸形18例。其中产前诊断胎儿肢体畸形49例;漏诊222例,包括:足内翻3例、指趾畸形218例、多发骨骼畸形1例。胎儿肢体畸形的出现率和产前检出率分别为:四肢短小1.84%(5/271)、100%(5/5);桡骨发育不全0.36%(1/271)、100%(1/1);缺肢畸形1.84%(5/271)、100%(5/5);足内翻6.27%(17/271)、82.35%(14/17);手掌畸形1.10%(3/271)、100%(3/3);指趾畸形81.91%(222/217)、1.8%(4/222);多发骨骼畸形6.64%(18/271)、94.44%(17/18)。结论:超声对胎儿手掌、脚掌部位以上畸形的检出率较高。指趾畸形出现率最高,但检出率最低。     

二维及实时三维超声对胎儿全前脑畸形的诊断价值探讨

目的：探讨二维及实时三维超声联合诊断胎儿全前脑畸形的价值。方法：二维超声系统检查发现胎儿颅脑结构异常者进行胎儿颅脑和颜面部实时三维成像,并将超声诊断结果与引产后尸检结果进行对照分析。结果：在20918例孕16~41周的胎儿中,经引产后尸检证实的全前脑畸形5例,其中无叶全前脑3例,半叶全前脑2例,均与产前超声检查结果相符合,二维联合实时三维超声检查对胎儿全前脑畸形诊断符合率为100%。结论：二维超声联合实时三维超声检查是诊断胎儿全前脑畸形可靠有效的方法,两者联合应用可提高产前全前脑的诊断率。     

超声检测胎儿先天性心脏病存在问题分析

目的探讨并分析产前超声筛查胎儿先天性心脏病临床应用中存在的问题。方法回顾性分析本院近三年来599例胎儿先天性心脏病超声检查情况。结果确诊49例先天性心脏病,43例于产前确诊,产前心超敏感性为87．7％。漏诊5例,漏诊率10．2％。误诊1例,误诊率2．04％。49例先心病者中,产前确诊后失访的32例,失访率高达65％。检查孕周为17周-39．5周,平均28．4周。结论虽然超声筛查胎儿先天性心脏病具有无创性、敏感性高等优点,但仍存在漏诊、误诊、诊断时间过晚等问题,值得引起注意。     

Detection of New Paternal Dystrophin Gene Mutations in Isolated Cases of Dystrophinopathy in Females

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limbgirdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here we study X-inactivation patterns of 13 female dystrophinopathy patients—10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. We show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in our assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, our results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. Our results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients.