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![Brain MR images of two siblings with congenital hydrocephalus. MRI of LR12-112a1 at age 4 years includes T1-weighted mid-sagittal (a), and T2-weighted axial (b) and coronal (c) images showing hydrocephalus status post shunting. Note thinning and distortion of the corpus callosum (white arrow in a), as well as the suggestion of closed-lip schizencephaly (white arrowhead in b) attributable to distortion of cerebral folding by shunting following severe hydrocephalus. No CSF signal is visible through the cerebral aqueduct (black arrow in a). Also note crowding of the cerebellum with mild cerebellar tonsil ectopia. (d) Axial head CT image of patient LR12-112a2 on day one of life shows severe enlargement of the lateral ventricles (*) and thinning of the cerebral parenchyma. (e) Calvarial threedimensional reconstructions show marked diastasis of the sutures (double white arrows) due to hydrocephalus. (f) Coronal T2-weighted brain MR image of LR12-112a2 at age 33 months shows a cystic collection in the midline with a fluid-hematocrit level secondary to shunting complication. At age 5 years, this patient underwent another brain MRI, shown here with sagittal volumetric T2 (g), and axial (h) and coronal (i) T2-weighted images. Similar to the sibling, note the thinning and distortion of the corpus callosum (white arrow in g), absence of CSF in the cerebral aqueduct, ventriculomegaly with distortion following shunting (*), and resolution of the previously seen intraventricular hemorrhagic cyst. [Color figure can be viewed at wileyonlinelibrary.com]](profile/Chi-Cheng-8/publication/322560944/figure/fig1/AS:609559794163712@1522341788285/Brain-MR-images-of-two-siblings-with-congenital-hydrocephalus-MRI-of-LR12-112a1-at-age-4.png)
Brain MR images of two siblings with congenital hydrocephalus. MRI of LR12-112a1 at age 4 years includes T1-weighted mid-sagittal (a), and T2-weighted axial (b) and coronal (c) images showing hydrocephalus status post shunting. Note thinning and distortion of the corpus callosum (white arrow in a), as well as the suggestion of closed-lip schizencephaly (white arrowhead in b) attributable to distortion of cerebral folding by shunting following severe hydrocephalus. No CSF signal is visible through the cerebral aqueduct (black arrow in a). Also note crowding of the cerebellum with mild cerebellar tonsil ectopia. (d) Axial head CT image of patient LR12-112a2 on day one of life shows severe enlargement of the lateral ventricles (*) and thinning of the cerebral parenchyma. (e) Calvarial threedimensional reconstructions show marked diastasis of the sutures (double white arrows) due to hydrocephalus. (f) Coronal T2-weighted brain MR image of LR12-112a2 at age 33 months shows a cystic collection in the midline with a fluid-hematocrit level secondary to shunting complication. At age 5 years, this patient underwent another brain MRI, shown here with sagittal volumetric T2 (g), and axial (h) and coronal (i) T2-weighted images. Similar to the sibling, note the thinning and distortion of the corpus callosum (white arrow in g), absence of CSF in the cerebral aqueduct, ventriculomegaly with distortion following shunting (*), and resolution of the previously seen intraventricular hemorrhagic cyst. [Color figure can be viewed at wileyonlinelibrary.com]
Source publication
Congenital or infantile hydrocephalus is caused by genetic and non-genetic factors and is highly heterogeneous in etiology. In recent studies, a limited number of genetic causes of hydrocephalus have been identified. To date, recessive mutations in the CCDC88C gene have been identified as a cause of non-syndromic congenital hydrocephalus in three r...
Contexts in source publication
Context 1
... cerebral aqueduct was completely effaced in both patients on all studies, implying congenital aqueductal stenosis. LR12-112a2 also had a subdural hematoma along the midline and left side of the posterior falx with a porencephalic cyst, which were presumably consequences of rapid decompression of the lateral ventricles after shunting (Figure 1). ...
Context 2
... imaging of both siblings showed severe enlargement of the lateral ventricles with secondary compression of the supratentorial and infratentorial compartments causing deviation of brain tissue across the midline and cerebellar tonsillar ectopia. The corpus callosum was thin and stretched. The cerebral aqueduct was completely effaced in both patients on all studies, implying congenital aqueductal stenosis. LR12-112a2 also had a subdural hematoma along the midline and left side of the posterior falx with a porencephalic cyst, which were presumably consequences of rapid decompression of the lateral ventricles after shunting (Figure ...
Citations
... Its mutation leads to the accumulation of CSF within the ventricles [53]). Ccdc88c (coiled-coil domain containing 88 C, or Daple) is a gene whose mutation causes congenital hydrocephalus [54]. Its product interacts with and negatively regulates the cytoplasmic WNT signaling transducer disheveled, whose transcript Dvl1 was also significantly rhythmic in ChP. ...
Choroid plexus (ChP), the brain structure primarily responsible for cerebrospinal fluid production, contains a robust circadian clock, whose role remains to be elucidated. The aim of our study was to [1] identify rhythmically controlled cellular processes in the mouse ChP and [2] assess the role and nature of signals derived from the master clock in the suprachiasmatic nuclei (SCN) that control ChP rhythms. To accomplish this goal, we used various mouse models (WT, mPer2Luc, ChP-specific Bmal1 knockout) and combined multiple experimental approaches, including surgical lesion of the SCN (SCNx), time-resolved transcriptomics, and single cell luminescence microscopy. In ChP of control (Ctrl) mice collected every 4 h over 2 circadian cycles in darkness, we found that the ChP clock regulates many processes, including the cerebrospinal fluid circadian secretome, precisely times endoplasmic reticulum stress response, and controls genes involved in neurodegenerative diseases (Alzheimer’s disease, Huntington’s disease, and frontotemporal dementia). In ChP of SCNx mice, the rhythmicity detected in vivo and ex vivo was severely dampened to a comparable extent as in mice with ChP-specific Bmal1 knockout, and the dampened cellular rhythms were restored by daily injections of dexamethasone in mice. Our data demonstrate that the ChP clock controls tissue-specific gene expression and is strongly dependent on the presence of a functional connection with the SCN. The results may contribute to the search for a novel link between ChP clock disruption and impaired brain health.
... Interestingly, deletion of mouse Afadin/AFD-1 and mutations in human L1CAM/SAX-7 or CCDC88C/GRDN-1 all cause a shared phenotype: hydrocephalus, or enlargement of the ventricles in the brain (Adle-Biassette et al., 2013;Drielsma et al., 2012;Ekici et al., 2010;Ruggeri et al., 2018;Yamamoto et al., 2013). In the afadin conditional knockout mouse, hydrocephalus arises from loss of . ...
Adherens junctions (AJs) are a fundamental organizing structure for multicellular life. Although AJs are studied mainly in epithelia, their core function - stabilizing cell contacts by coupling adhesion molecules to the cytoskeleton - is important in diverse tissues. We find that two C. elegans sensory neurons, URX and BAG, require conserved AJ proteins for dendrite morphogenesis. We previously showed that URX and BAG dendrites attach to the embryonic nose via the adhesion molecule SAX-7/L1CAM, acting both in neurons and glia, and then extend by stretch during embryo elongation. Here, we find that a PDZ-binding motif (PB) in the SAX-7 cytoplasmic tail acts with other interaction motifs to promote dendrite extension. Using pull-down assays, we find that the SAX-7 PB binds the multi-PDZ scaffolding protein MAGI-1, which bridges it to the cadherin-catenin complex protein HMP-2/β-catenin. Using cell-specific rescue and depletion, we find that both MAGI-1 and HMR-1/Cadherin act in glia to non-autonomously promote dendrite extension. Double mutant analysis indicates that each protein can act independently of SAX-7, suggesting a multivalent adhesion complex. The SAX-7 PB motif also binds AFD-1/Afadin, loss of which further enhances sax-7 BAG dendrite defects. As MAGI-1, HMR-1, and AFD-1 are all found in epithelial AJs, we propose that an AJ-like complex in glia promotes dendrite extension.
... It was suggested that the described CCDC88C mutations may cause a loss of protein function through the truncation of binding motifs vital to the noncanonical Wnt pathway [4,15,16] or by modulating the phosphorylation status of the JNK pathway, thereby inducing caspase-3 cleavage and triggering apoptosis [3,5,6,17]. According to the literature, cellular functions, such as protein trafficking and cilium formation, are also affected by these mutations. ...
Spinocerebellar ataxia (SCA) 40 is an extremely rare subtype of the phenotypically and genetically diverse autosomal dominant ataxias caused by mutations of the CCDC88C gene. Most reported cases of SCA40 are characterized by late-onset cerebellar ataxia and variable extrapyramidal features; however, there is a report of a patient with early-onset spastic paraparesis as well. Here, we describe a novel missense CCDC88C mutation (p.R203W) in the hook domain of the DAPLE protein encoded by the CCDC88C gene that was identified in a female patient who developed late-onset ataxia, dysmetria and intention tremor. To explore the molecular consequences of the newly identified and previously described CCDC88C mutations, we carried out in vitro functional tests. The CCDC88C alleles were expressed in HEK293 cells, and the impact of the mutant DAPLE protein variants on JNK pathway activation and apoptosis was assessed. Our results revealed only a small-scale activation of the JNK pathway by mutant DAPLE proteins; however, increased JNK1 phosphorylation could not be detected. Additionally, none of the examined mutations triggered proapoptotic effect. In conclusion, we identified a novel mutation of the CCDC88C gene from a patient with spinocerebellar ataxia. Our results are not in accord with previous observations and do not support the primary role of the CCDC88C mutations in induction of JNK pathway activation in ataxia. Therefore, we propose that CCDC88C mutations may exert their effects through different and possibly in much broader, yet unexplored, biological processes.
... Now, it can be detected during pregnancy using ultrasonography, allowing care to begin as soon as possible [2]. It is related to both genetic and non-genetic factors, also in recent studies, there are few reports of hereditary causes of hydrocephalus [3]. It's possible to be nonsyndromic or syndromic, depending on the underlying cause and related malformations identified using clinical, cytogenetic, and molecular examinations [4]. ...
... , two genes previously implicated in neurodevelopmental disorders but associated with phenotypes different than the one found in our proband. Bi-allelic variants in CCDC88C were associated with a form of congenital hydrocephalus [21][22][23] , while variants in ZNF407 have been recently implicated in an AR form of ID with microcephaly, short stature, hypotonia, and ocular anomalies 24,25 . ...
Intellectual disability (ID) is a highly heterogeneous disorder with hundreds of associated genes. Despite progress in the identification of the genetic causes of ID following the introduction of high-throughput sequencing, about half of affected individuals still remain without a molecular diagnosis. Consanguineous families with affected individuals provide a unique opportunity to identify novel recessive causative genes. In this report, we describe a novel autosomal recessive neurodevelopmental disorder. We identified two consanguineous families with homozygous variants predicted to alter the splicing of ATP9A which encodes a transmembrane lipid flippase of the class II P4-ATPases. The three individuals homozygous for these putatively truncating variants presented with severe ID, motor and speech impairment, and behavioral anomalies. Consistent with a causative role of ATP9A in these patients, a previously described Atp9a−/− mouse model showed behavioral changes.
... 52 Through positional cloning and targeted sequencing of a consanguineous family, the authors identified a novel splice-site mutation in CCDC88C resulting in a consistent complex hydrocephalic brain malformation with associated craniofacial abnormalities. 52,53 WES-mediated studies, by comparison, are faster and able to identify single CH disease genes from complex multisyndromic or pleiotropic phenotypes. Slavotinek et al. reported exome sequencing of 5 probands from 3 nonconsanguineous families with cerebral ventriculomegaly, echogenic kidneys, and histopathological findings of congenital nephrosis to identify novel deleterious autosomal recessive variants in CRMB2 in all sequenced probands. ...
Congenital hydrocephalus (CH), characterized by incomplete clearance of CSF and subsequent enlargement of brain ventricles, is the most common congenital brain disorder. The lack of curative strategies for CH reflects a poor understanding of the underlying pathogenesis. Herein, the authors present an overview of recent findings in the pathogenesis of CH from human genetic studies and discuss the implications of these findings for treatment of CH. Findings from these omics data have the potential to reclassify CH according to a molecular nomenclature that may increase precision for genetic counseling, outcome prognostication, and treatment stratification. Beyond the immediate patient benefits, genomic data may also inform future clinical trials and catalyze the development of nonsurgical, molecularly targeted therapies. Therefore, the authors advocate for further application of genomic sequencing in clinical practice by the neurosurgical community as a diagnostic adjunct in the evaluation and management of patients diagnosed with CH.
... CCDC88C variants in CH have been identified by multiple groups [26][27][28][29] (Table 1). Encoding the DVL1binding protein DAPLE, CCDC88C functions as a negative regulator of the WNT signaling pathway [29]. ...
Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of pathological cerebrospinal fluid (CSF) accumulation and, therefore, treated largely by neurosurgical CSF diversion. The persistence of ventriculomegaly and poor neurodevelopmental outcomes in some post-surgical patients highlights our limited knowledge of disease mechanisms. Recent whole-exome sequencing (WES) studies have shown that rare, damaging de novo and inherited mutations with large effect contribute to ~ 25% of sporadic CH. Interestingly, multiple CH genes are key regulators of neural stem cell growth and differentiation and converge in human transcriptional networks and cell types pertinent to fetal neurogliogenesis. These data implicate genetic disruption of early brain development as the primary pathomechanism in a substantial minority of patients with sporadic CH, shedding new light on human brain development and the pathogenesis of hydrocephalus. These data further suggest WES as a clinical tool with potential to re-classify CH according to a molecular nomenclature of increased precision and utility for genetic counseling, outcome prognostication, and treatment stratification.
... DAPLE contains a PDZ-binding motif at its C-terminus which contributes to ependymal cell planar polarity by inhibiting the non-canonical Wnt signaling pathway through its interaction with Dishevelled, leading to Rho-ROCK and Rac-JNK activation [10,19]. In the past 10 years, pathogenic variants in CCDC88C have been documented but the neuropathology of the disease remains virtually unknown [4,6,13,20]. We report herein the prenatal phenotype and neuropathological lesions in two fetuses from one family, which harboured two novel compound heterozygous variants in the CCDC88C gene. ...
... Similarly to families with recurrent hydrocephalus, non-syndromic hydrocephalus is rare in patients with sporadic hydrocephalus. To date, only 6 CCDC88C homozygous pathogenic variants have been identified in 14 patients with non-syndromic hydrocephalus from 6 unrelated families, including three frameshift, one splice site, and two nonsense mutations [4,6,13,20]. Conversely, CCDC88C heterozygous gain-of-function variations have been reported in patients without hydrocephalus who suffered from adultonset spinocerebellar ataxia SCA40 [10,19]. ...
The prevalence of congenital hydrocephalus has been estimated at 1.1 per 1000 infants when including cases diagnosed before 1 year of age after exclusion of neural tube defects. Classification criteria are based either on CSF dynamics, pathophysiological mechanisms or associated lesions. Whereas inherited syndromic hydrocephalus has been associated with more than 100 disease-causing genes, only four genes are currently known to be linked to congenital hydrocephalus either isolated or as a major clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C . In the past 10 years, pathogenic variants in CCDC88C have been documented but the neuropathology remains virtually unknown. We report the neuropathology of two foetuses from one family harbouring two novel compound heterozygous pathogenic variants in the CCDC88C gene: a maternally inherited indel in exon 22, c.3807_3809delinsACCT;p.(Gly1270Profs*53) and a paternally inherited deletion of exon 23, c.3967-?_c.4112-?;p.(Leu1323Argfs*10). Medical termination of pregnancy was performed at 18 and 23 weeks of gestation for severe bilateral ventriculomegaly. In both fetuses, brain lesions consisted of multifocal atresia-forking along the aqueduct of Sylvius and the central canal of the medulla, periventricular neuronal heterotopias and choroid plexus hydrops. The second fetus also presented lumbar myelomeningocele, left diaphragmatic hernia and bilateral renal agenesis. CCDC88C encodes the protein DAPLE which contributes to ependymal cell planar polarity by inhibiting the non-canonical Wnt signaling pathway and interacts with MPDZ and PARD3. Interestingly, heterozygous variants in PARD3 result in neural tube defects by defective tight junction formation and polarization process of the neuroepithelium. Besides, during organ formation Wnt signalling is a prerequisite for planar cell polarity pathway activation, and mutations in planar cell polarity genes lead to heart, lung and kidney malformations. Hence, candidate variants in CCDC88C should be carefully considered whether brain lesions are isolated or associated with malformations suspected to result from disorders of planar cell polarity.
... 34 Patients with other less common mutations, including CCDC88C, Mpdz, Eml1, and Wdr81 mutations, have also been shown to present with more severe forms of CAS. [35][36][37][38][39] Of note, several mutations linked with congenital hydrocephalus have also been linked to ophthalmological abnormalities with different underlying mechanisms. Eml1 mutations, for instance, have been demonstrated to interfere with retinal lamination during development. ...
OBJECTIVE
Congenital aqueductal stenosis (CAS) is a common etiology of hydrocephalus that occurs in a subset of infants and may be linked to an increased incidence of ophthalmological abnormalities and delayed developmental milestones. Although hydrocephalus is common and widely studied, sparse literature exists on patients with isolated (no identifiable genetic link) CAS along with analysis of ophthalmological manifestations. In this study, the authors sought to describe the ophthalmological abnormalities and delayed developmental milestones of patients with isolated CAS.
METHODS
Data of patients with CAS were prospectively entered and monitored in a surgical database maintained by the Department of Neurological Surgery at Children’s Hospital of Pittsburgh from January 2005 to October 2016. Patients with a family history of congenital hydrocephalus, positive testing for genetic forms of aqueductal stenosis, other congenital abnormalities suggesting an underlying genetic syndrome, and stenosis/obstruction due to secondary causes were excluded from this study. Prenatal and perinatal history, CSF diversion history, and a variety of outcomes, including ophthalmological deficits and developmental milestones, were collected and analyzed.
RESULTS
A total of 41 patients with isolated CAS were identified, with a mean follow-up duration of 6 years. Among that cohort, 26 patients (63.4%) developed neuroophthalmological complications, which were further stratified. Fourteen patients (34.1%) developed strabismus and 11 (26.8%) developed astigmatism, and 1 patient (2.4%) with papilledema was recorded. Among patients with ophthalmological abnormalities, 76.9% had delayed developmental milestones (p = 0.045).
CONCLUSIONS
Patients with CAS were found to have increased risk of ophthalmological abnormalities requiring correction, along with an increased risk of delayed developmental milestones. Importantly, there was a significant correlation between the development of ophthalmological abnormalities and delayed developmental milestones that was independent of CSF diversion history. Larger patient cohort studies are required to explore whether earlier development of hydrocephalus, as is the case in CAS, causes elevated rates of neurological and ophthalmological complications, and if earlier CSF diversion correlates with improved outcomes.
... CCDC88C pathogenic variants have been described in patients with severe infantileonset HC, mild to severe intellectual delay, varying degrees of motor delay, and early-onset seizures. MPDZ pathogenic variants have been described in a few families with severe congenital HC and gray matter heterotopia, with variable penetrance of coloboma and cardiac septal defects [52]. ...
Background
Fetal ventriculomegaly (VM) is a frequent finding in prenatal ultrasound. Rather than a proper diagnosis, VM is a sonographic sign, making prenatal counseling a complex and challenging undertaking. VM can range from severe pathologic processes leading to severe neurodevelopmental delay to normal variants.DiscussionA growing number of genetic conditions with different pathophysiological mechanisms, inheritance patterns, and long-term prognosis have been associated both to isolated and complex fetal VM. These include chromosomal abnormalities, copy number variants, and several single gene diseases. In this review, we describe some of the most common genetic conditions associated with fetal VM and provide a simplified diagnostic workflow for the clinician.
