Severe Congenital Hydrocephalus Research Articles

RGS22 maintains the physiological function of ependymal cells to prevent hydrocephalus.

Ependymal cells line the wall of cerebral ventricles and ensure the unidirectional cerebrospinal fluid (CSF) flow by beating their motile cilia coordinately. The ependymal denudation or ciliary dysfunction causes hydrocephalus. Here, we report that the deficiency of regulator of G-protein signaling 22 (RGS22) results in severe congenital hydrocephalus in both mice and rats. Interestingly, RGS22 is specifically expressed in ependymal cells within the brain. Using conditional knock-out mice, we further demonstrate that the deletion of Rgs22 exclusively in nervous system is sufficient to induce hydrocephalus. Mechanistically, we show that Rgs22 deficiency leads to the ependymal denudation and impaired ciliogenesis. This phenomenon can be attributed to the excessive activation of lysophosphatidic acid receptor (LPAR) signaling under Rgs22-/- condition, as the LPAR blockade effectively alleviates hydrocephalus in Rgs22-/- rats. Therefore, our findings unveil a previously unrecognized role of RGS22 in the central nervous system, and present RGS22 as a potential diagnostic and therapeutic target for hydrocephalus.

Generation of Periventricular Reactive Astrocytes Overexpressing Aquaporin 4 Is Stimulated by Mesenchymal Stem Cell Therapy.

Aquaporin-4 (AQP4) plays a crucial role in brain water circulation and is considered a therapeutic target in hydrocephalus. Congenital hydrocephalus is associated with a reaction of astrocytes in the periventricular white matter both in experimental models and human cases. A previous report showed that bone marrow-derived mesenchymal stem cells (BM-MSCs) transplanted into the lateral ventricles of hyh mice exhibiting severe congenital hydrocephalus are attracted by the periventricular astrocyte reaction, and the cerebral tissue displays recovery. The present investigation aimed to test the effect of BM-MSC treatment on astrocyte reaction formation. BM-MSCs were injected into the lateral ventricles of four-day-old hyh mice, and the periventricular reaction was detected two weeks later. A protein expression analysis of the cerebral tissue differentiated the BM-MSC-treated mice from the controls and revealed effects on neural development. In in vivo and in vitro experiments, BM-MSCs stimulated the generation of periventricular reactive astrocytes overexpressing AQP4 and its regulatory protein kinase D-interacting substrate of 220 kDa (Kidins220). In the cerebral tissue, mRNA overexpression of nerve growth factor (NGF), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF1α), and transforming growth factor beta 1 (TGFβ1) could be related to the regulation of the astrocyte reaction and AQP4 expression. In conclusion, BM-MSC treatment in hydrocephalus can stimulate a key developmental process such as the periventricular astrocyte reaction, where AQP4 overexpression could be implicated in tissue recovery.

A novel pathogenic deletion in ISPD causes Walker-Warburg syndrome in a Chinese family.

Walker-Warburg syndrome (WWS) is a genetically heterogeneous disease that often presents with complex brain and eye malformations and congenital muscular dystrophy. Mutations of the ISPD gene have been identified as one of the most frequent causes of WWS. The current study aimed to identify the cause of severe congenital hydrocephalus and brain dysplasia in our subject. Genomic DNA was extracted from the fetus's umbilical cord blood and peripheral venous blood of the parents. The genetic analysis included whole-exome sequencing and qPCR. Additionally, in silico analysis and cellular experiments were performed. We identified a novel homozygous deletion of exons 7 to 9 in the ISPD gene of the fetus with WWS. In silico analysis revealed a defective domain structure in the C-terminus domain of the ISPD. Analysis of the electrostatic potential energy showed the formation of a new binding pocket formation on the surface of the mutant ISPD gene (ISPD-del ex7-9). Cellular study of the mutant ISPD revealed a significant change in its cellular localization, with the ISPD-del ex7-9 protein translocating from the cytoplasm to the nucleus compared to wild-type ISPD, which is mostly present in the cytoplasm. The present study expands the mutational spectrum of WWS caused by ISPD mutations. Importantly, our work suggests that whole-exome sequencing could be considered as a diagnostic option for fetuses with congenital hydrocephalus and brainmalformations when karyotype or chromosomal microarray analysis fails to provide a definitive diagnosis.

Prenatal diagnosis of Walker-Warburg syndrome due to compound mutations in the B3GALNT2 gene.

BackgroundCongenital hydrocephalus is one of the symptoms of Walker–Warburg syndrome that is attributed to the disruptions of the genes, among which the B3GALNT2 gene is rarely reported. A diagnosis of the Walker–Warburg syndrome depends on the clinical manifestations and the whole‐exome sequencing after birth, which is unfavorable for an early diagnosis.MethodsWalker–Warburg Syndrome was suspected in two families with severe fetal congenital hydrocephalus. Whole‐exome sequencing and Sanger sequencing were performed on the affected fetuses.ResultsThe compound heterozygous variants c.1A>G p.(Met1Val) and c.1151+1G>A, and c.1068dupT p.(D357*) and c.1052 T>A p.(L351*) in the B3GALNT2 gene were identified, which were predicted to be pathogenic and likely pathogenic, respectively. Walker–Warburg syndrome was prenatally diagnosed on the basis of fetal imaging and whole‐exome sequencing.ConclusionsOur findings expand the spectrum of pathogenic mutations in Walker–Warburg syndrome and provide new insights into the prenatal diagnosis of the disease.

A novel nonsense mutation in the L1CAM gene responsible for X-linked congenital hydrocephalus.

Congenital hydrocephalus is a descriptive diagnosis of symptoms, that are present for numerous reasons, including chromosomal disorders, genetic mutations, intrauterine infection and hemorrhage, amongst other factors. Mutation of L1CAM gene is the most frequent cause of congenital hydrocephalus, contributing to approximately 30% of X-linked congenital hydrocephalus. In the present study, we used whole-exome sequencing and Sanger sequencing to investigate an aborted male fetus present with severe congenital hydrocephalus at 24 weeks of gestation, whose mother had a history of two previous voluntary terminations of pregnancies as a result of hydrocephalus. Magnetic resonance imaging, an autopsy and electron microscopy were performed and the phenotypic changes were described. Whole-exome sequencing in the fetus, as well as variant segregation analysis, revealed a novel maternally derived hemizygous nonsense mutation (c.2865G>A; p. Y955*) in exon 21 of the L1CAM gene (NM_000425.4). Severe hydrocephalus was observed along with marked dilatation of lateral ventricles. An electron micrograph of the surface of lateral ventricle walls revealed a lack of ependymal cilia. The present study suggests that L1CAM mutation screening should be considered for a male fetus with isolated hydrocephalus, especially with a family history, which could facilitate prenatal diagnosis in a subsequent pregnancy.

Neocortical tissue recovery in severe congenital obstructive hydrocephalus after intraventricular administration of bone marrow-derived mesenchymal stem cells

BackgroundIn obstructive congenital hydrocephalus, cerebrospinal fluid accumulation is associated with high intracranial pressure and the presence of periventricular edema, ischemia/hypoxia, damage of the white matter, and glial reactions in the neocortex. The viability and short time effects of a therapy based on bone marrow-derived mesenchymal stem cells (BM-MSC) have been evaluated in such pathological conditions in the hyh mouse model.MethodsBM-MSC obtained from mice expressing fluorescent mRFP1 protein were injected into the lateral ventricle of hydrocephalic hyh mice at the moment they present a very severe form of the disease. The effect of transplantation in the neocortex was compared with hydrocephalic hyh mice injected with the vehicle and non-hydrocephalic littermates. Neural cell populations and the possibility of transdifferentiation were analyzed. The possibility of a tissue recovering was investigated using 1H High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance (1H HR-MAS NMR) spectroscopy, thus allowing the detection of metabolites/osmolytes related with hydrocephalus severity and outcome in the neocortex. An in vitro assay to simulate the periventricular astrocyte reaction conditions was performed using BM-MSC under high TNFα level condition. The secretome in the culture medium was analyzed in this assay.ResultsFour days after transplantation, BM-MSC were found undifferentiated and scattered into the astrocyte reaction present in the damaged neocortex white matter. Tissue rejection to the integrated BM-MSC was not detected 4 days after transplantation. Hyh mice transplanted with BM-MSC showed a reduction in the apoptosis in the periventricular neocortex walls, suggesting a neuroprotector effect of the BM-MSC in these conditions. A decrease in the levels of metabolites/osmolytes in the neocortex, such as taurine and neuroexcytotoxic glutamate, also indicated a tissue recovering. Under high TNFα level condition in vitro, BM-MSC showed an upregulation of cytokine and protein secretion that may explain homing, immunomodulation, and vascular permeability, and therefore the tissue recovering.ConclusionsBM-MSC treatment in severe congenital hydrocephalus is viable and leads to the recovery of the severe neurodegenerative conditions in the neocortex. NMR spectroscopy allows to follow-up the effects of stem cell therapy in hydrocephalus.

Recessive Inheritance of Congenital Hydrocephalus With Other Structural Brain Abnormalities Caused by Compound Heterozygous Mutations in ATP1A3.

BackgroundATP1A3 encodes the α3 subunit of the Na+/K+ ATPase, a fundamental ion-transporting enzyme. Primarily expressed in neurons, ATP1A3 is mutated in several autosomal dominant neurological diseases. To our knowledge, damaging recessive genotypes in ATP1A3 have never been associated with any human disease. Atp1a3 deficiency in zebrafish results in hydrocephalus; however, no known association exists between ATP1A3 and human congenital hydrocephalus (CH).MethodsWe utilized whole-exome sequencing (WES), bioinformatics, and computational modeling to identify and characterize novel ATP1A3 mutations in a patient with CH. We performed immunohistochemical studies using mouse embryonic brain tissues to characterize Atp1a3 expression during brain development.ResultsWe identified two germline mutations in ATP1A3 (p. Arg19Cys and p.Arg463Cys), each of which was inherited from one of the patient’s unaffected parents, in a single patient with severe obstructive CH due to aqueductal stenosis, along with open schizencephaly, type 1 Chiari malformation, and dysgenesis of the corpus callosum. Both mutations are predicted to be highly deleterious and impair protein stability. Immunohistochemical studies demonstrate robust Atp1a3 expression in neural stem cells (NSCs), differentiated neurons, and choroid plexus of the mouse embryonic brain.ConclusionThese data provide the first evidence of a recessive human phenotype associated with mutations in ATP1A3, and implicate impaired Na+/K+ ATPase function in the pathogenesis of CH.

Показатели соматического статуса у больных с врожденной гидроцефалией

The paper studies the state of somatic status in 57 patients with General and internal congenital hydrocephalus in children from 3 months to 3 years. In addition to computerized tomography, magnetic resonance imaging, electroencephalogram, ultrasound investigation in different groups of patients studied, the intensity of psychosomatic condition, in particular depending on the stage, severity and form of dysgenesis (mono– and poly dysgenesis). The main neurological syndromes of the disease with disorders of nervous innervation, cardiovascular system, mental development. Depending on the severity of the pathology, the effectiveness of the developed treatment approaches has been established. The possibility of recovering psychosomatic status from the progredience of the course of the disease has been clarified.. The study of the immediate and in some patients with catamnesis showed that as a result of treatment, mental development was most fulfilled in patients with moderately active congenital hydrocephalus, among whom the proportion of patients with a normal level of intellectual development was about two thirds (p<0.01) due to a significant reduction in the number of children with mental retardation (p<0.01). Among patients with severe active congenital hydrocephalus, there was a significant decrease in the number of patients with mental retardation (p<0.01) and an increase in the number of children with intellectual disabilities (p<0.01), due to the maturation of patients and the expansion in the process of complex treatment and dynamic observation of opportunities to clarify the degree of mental insufficiency, rather than progredience of the disease.

A novel ISLR2-linked autosomal recessive syndrome of congenital hydrocephalus, arthrogryposis and abdominal distension.

ISLR2 (immunoglobulin superfamily containing leucine-rich repeat 2), encodes a protein involved in axon guidance in brain development (hence the other name leucine-rich repeat domain- and immunoglobulin domain-containing axon extension proteins; LINX). A recently described mouse knockout displays hydrocephalus. However, the corresponding phenotype in humans is unknown. Here, we describe a multiplex consanguineous family in which a homozygous truncating variant in ISLR2 segregates with severe congenital hydrocephalus, arthrogryposis multiplex congenita and abdominal distension. We suggest this syndrome may represent the human "knockout" phenotype for ISLR2.

Surprisingly good outcome in antenatal diagnosis of severe hydrocephalus related to CCDC88C deficiency

Non-syndromic congenital hydrocephalus is aetiologically diverse and while a genetic cause is frequently suspected, it often cannot be confirmed. The most common genetic cause is L1CAM-related X-linked hydrocephalus and that explains only 5%–10% of all male cases. This underlines a current limitation in our understanding of the genetic burden of non-syndromic congenital hydrocephalus, especially for those cases with likely autosomal recessive inheritance. Additionally, the prognosis for most cases of severe congenital hydrocephalus is poor, with most of the surviving infants displaying significant intellectual impairment despite surgical intervention. It is for this reason that couples with an antenatal diagnosis of severe hydrocephalus are given the option, and may opt, for termination of the pregnancy. We present two families with CCDC88C-related recessive congenital hydrocephalus with children who had severe hydrocephalus. Those individuals who were shunted within the first few weeks of life, who did not require multiple surgical revisions, and who had a more distal truncating variant of the CCDC88C gene met their early childhood developmental milestones in some cases. This suggests that children with CCDC88C-related autosomal recessive hydrocephalus can have normal developmental outcomes under certain circumstances. We recommend CCDC88C analysis in cases of severe non-syndromic congenital hydrocephalus, especially when aqueduct stenosis with or without a medial diverticulum is seen, in order to aid prognosis discussion.

The genetic landscape of familial congenital hydrocephalus.

Congenital hydrocephalus is an important birth defect, the genetics of which remains incompletely understood. To date, only 4 genes are known to cause Mendelian diseases in which congenital hydrocephalus is the main or sole clinical feature, 2 X-linked (L1CAM and AP1S2) and 2 autosomal recessive (CCDC88C and MPDZ). In this study, we aimed to determine the genetic etiology of familial congenital hydrocephalus with the assumption that these cases represent Mendelian forms of the disease. Exome sequencing combined, where applicable, with positional mapping. We identified a likely causal mutation in the majority of these families (21 of 27, 78%), spanning 16 genes, none of which is X-linked. Ciliopathies and dystroglycanopathies were the most common etiologies of congenital hydrocephalus in our cohort (19% and 26%, respectively). In 1 family with 4 affected members, we identified a homozygous truncating variant in EML1, which we propose as a novel cause of congenital hydrocephalus in addition to its suggested role in cortical malformation. Similarly, we show that recessive mutations in WDR81, previously linked to cerebellar ataxia, mental retardation, and disequilibrium syndrome 2, cause severe congenital hydrocephalus. Furthermore, we confirm the previously reported candidacy of MPDZ by presenting a phenotypic spectrum of congenital hydrocephalus associated with 5 recessive alleles. Our study highlights the importance of recessive mutations in familial congenital hydrocephalus and expands the locus heterogeneity of this condition. Ann Neurol 2017;81:890-897.

Holoprosencephaly and Recurrent Episodes of Severe Neurogenic Hypernatremia

Holoprosencephaly (HPE) is a severe and complex malformation caused by incomplete cleavage of the prosencephalon and incomplete development of paramedian structures. Many causes have been recognized as responsible for this malformation including maternal diabetes, chromosomal abnormalities, and heterozygous mutations, involving four major genes ( SHH , Z1C2 , SIX3 , and TGIF ) and other less frequently reported genes. HPE has frequently been reported as a feature of complex malformative syndromes such as Smith–Lemli–Opitz syndrome, CHARGE syndrome (acronym of Coloboma, Heart defects, choanal Atresia, Retardation of growth and/or development, Genitourinary malformation and Ear abnormalities), and Rubinstein–Taybi syndrome. Moreover, children with HPE may present with other anomalies aside from those of the brain and face, including endocrine disorders such as diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia, and growth hormone deficiency. We report a boy with typical clinical signs of HPE including neuroradiologic findings resembling severe congenital hydrocephalus. The patient also presented with a specific metabolic anomaly consisting of recurrent episodes of hypernatremia.

Repeated autologous umbilical cord blood infusions are feasible and had no acute safety issues in young babies with congenital hydrocephalus.

Babies with congenital hydrocephalus often experience developmental disabilities due to brain injury associated with prolonged increased pressure on the developing brain parenchyma. Umbilical cord blood (CB) infusion has favorable effects in animal models of brain hypoxia and stroke and is being investigated in clinical trials of brain injury in both children and adults. We sought to establish the safety and feasibility of repeated intravenous infusions of autologous CB in young babies with congenital hydrocephalus. Infants with severe congenital hydrocephalus and an available qualified autologous CB unit traveled to Duke for evaluation and CB infusion. When possible, the CB unit was utilized for multiple infusions. Patient and CB data were obtained at the time of infusion and analyzed retrospectively. From October 2006 to August 2014, 76 patients with congenital hydrocephalus received 143 autologous CB infusions. Most babies received repeated doses, for a total of two (n = 45), three (n = 18), or four (n = 4) infusions. There were no infusion-related adverse events. As expected, all babies experienced developmental delays. Cryopreserved CB products may be effectively manipulated to provide multiple CB doses. Repeated intravenous infusion of autologous CB is safe and feasible in young babies with congenital hydrocephalus.

Camk2a-Cre-mediated conditional deletion of chromatin remodeler Brg1 causes perinatal hydrocephalus

Mammalian SWI/SNF-like BAF chromatin remodeling complexes are essential for many aspects of neural development. Mutations in the genes encoding the core subunit Brg1/SmarcA4 or other complex components cause neurodevelopmental diseases and are associated with autism. Congenital hydrocephalus is a serious brain disorder often experienced by these patients. We report a role of Brg1 in the pathogenesis of hydrocephalus disorder. We discovered an unexpected early activity of mouse Camk2a-Cre transgene, which mediates Brg1 deletion in a subset of forebrain neurons beginning in the late embryonic stage. Brg1 deletion in these neurons led to severe congenital hydrocephalus with enlargement of the lateral ventricles and attenuation of the cerebral cortex. The Brg1-deficient mice had significantly smaller subcommissural organs and narrower Sylvian aqueducts than mice that express normal levels of Brg1. Effects were non-cell autonomous and may be responsible for the development of the congenital hydrocephalus phenotype. Our study provides evidence indicating that abnormalities in Brg1 function result in defects associated with neurodevelopmental disorders and autism.

Choroid plexus coagulation in infants with extreme hydrocephalus or hydranencephaly.

OBJECT.: Severe hydrocephalus and hydranencephaly are common congenital conditions in Kenya. In patients with these conditions, ventriculoperitoneal (VP) shunts are associated with appreciable complications and endoscopic third ventriculostomies (ETVs) have limited success. Endoscopic choroid plexus coagulation (CPC) to diminish CSF production is a potential treatment option. The purpose of this study was to evaluate the effect of CPC without ETV in infants with severe hydrocephalus or hydranencephaly. Medical records of infants with severe congenital hydrocephalus or hydranencephaly who underwent CPC in Kijabe Hospital from November 2010 to April 2013 were reviewed retrospectively. Thirty-three patients with complete medical records and preoperative radiographic images were identified. After CPC, the infants were followed in the Kijabe Hospital outpatient department, in mobile clinics, or by telephone. Success of the CPC was defined as resolution of preoperative symptoms, stabilization of head size, and avoidance of VP shunt placement. Patients were followed from 30 to 608 days (median of 120 days). Three patients were lost to follow-up. Of the 30 evaluable patients, CPC was considered to be successful in 13 (43.3%), including 8 of 20 patients with severe hydrocephalus and 5 of 10 with hydranencephaly. Failure of CPC was evident from increased head circumference in 14 (82%) of 17 patients and from CSF leakage in 3. Of the 17 failures, 13 occurred within 3 months of surgery. Six patients died: 3 whose CPC procedures were failures, 2 whose CPC was successful, and 1 postoperatively. Of the 17 in whom CPC failed, 10 subsequently underwent VP shunt insertion. CPC stabilizes macrocephaly in approximately 40% of infants with severe congenital hydrocephalus and hydranencephaly and can be considered as an alternative to VP shunt placement.

Ultrastructural alterations of human cortical capillary basement membrane in human brain oedema.

The capillary basement membranes are examined in severe traumatic brain injuries, vascular malformation, congenital hydrocephalus and brain tumours. They exhibit homogeneous and nodular thickening, vacuolization, rarefaction, reduplication, and deposition of collagen fibers. Their average thickness varied according to the aetiology and severity of brain oedema. In moderate brain oedema the thickness ranged from 71.97 to 191.90 nm in width, and in patients with severe brain oedema it varied from 206.66 to 404.22 nm. The basement membrane complex appears apparently intact in moderate oedema, and shows glio-basal dissociation in severe oedema. In areas of highly increased cerebro-vascular permeability, the basement membrane shows matrix disorganization, reduplication, and bifurcations protruding toward the endothelial cells, and acting as abluminal transcapillary channels. In regions of total brain necrosis, its structural stability is lost showing loosening, dissolution and rupture. Basement membrane swelling is due to overhydration of its protein-complex glycoprotein matrix. The thickening, rarefaction and vacuolization are induced by the increased vacuolar and vesicular transendothelial transport. The degenerated basement membrane areas exhibit a finely granular precipitate interpreted as protein, proteoglycan, glycoprotein, and agrin degraded matrix.

Mutation in MPDZ causes severe congenital hydrocephalus

BackgroundCongenital hydrocephalus is an important birth defect that is heterogeneous in aetiology and clinical presentation. Although genetics is believed to play an important role in the aetiology of non-syndromic congenital...

Interstitial 9q34.11–q34.13 deletion in a patient with severe intellectual disability, hydrocephalus, and cleft lip/palate

Interstitial deletions of chromosome bands 9q34.11-q34.13 are rare. We report on a 16-year-old female patient with severe intellectual disability, congenital hydrocephalus, cleft lip and palate, talipes equinovarus, epilepsy, kyphoscoliosis, convergent strabismus, severe short stature, dystrophy, and facial dysmorphic signs. Array analysis revealed a 3.7 Mb interstitial deletion in 9q34.11-q34.13. The deletion harbors more than 60 genes, including SPTAN1, DYT1/TOR1A, ABL1, ASS1, LAMC3, POMT1, DOLK, and GLE1, mutations in which have previously been associated with monogenic disorders. This is the first patient with a deletion of this size and position in 9q34.11-q34.13. Reports of additional patients with aberrations in this region will be needed to establish karyotype-phenotype correlations and to gain information on the contribution of individual genes for the clinical manifestations.

Hydrocephalus with Hirschsprung disease: Severe end of X‐linked hydrocephalus spectrum

L1CAM molecule is a cell adhesion molecule in nervous and enteric systems and is responsible for X-linked hydrocephalus (XLH) spectrum, which is a rare condition with severe congenital hydrocephalus, dysgenesis of the corpus callosum, intellectual disability, spasticity, and adducted thumbs. Several cases of XLH accompanied by Hirschsprung disease (HSCR) have been reported in the literature, but whether HSCR results from a gain-of-function mutation in cases with XLH, i.e., a neomorphic mutation, or the severe end of the L1CAM mutation spectrum remains unclear. The present patient was a Japanese boy with severe congenital hydrocephalus with aqueductal stenosis as well as hypoplasia of the corpus callosum. HSCR had been confirmed by a biopsy. A mutation analysis of the L1CAM gene showed a C61T mutation in exon 1, resulting in a truncating nonsense mutation at amino acid position 21 and producing an extremely short protein that was unlikely to interact with other proteins. These findings suggest that XLH-HSCR represents the severe end of the XLH spectrum, rather than a neomorphic mutation. A thorough abdominal investigation to rule out HSCR should be considered in patients with XLH accompanied by severe constipation.

Acute encephalopathy in two cases with severe congenital hydrocephalus

We report acute encephalopathy in two cases with severe congenital hydrocephalus. Case 1 was a 23-month-old girl, born at of 36 weeks gestation and delivered by cesarean section due to congenital hydrocephalus. Magnetic resonance imaging (MRI) showed prominent ventricular dilation associated with hydrocephalus, Dandy–Walker variant and cortical malformation. The blood test for toxoplasmosis, syphilis, varicella-zoster, rubella, cytomegalovirus, and herpes simplex virus (TORCH) complex and various metabolic tests of blood and urine specimens yielded unremarkable results. She was admitted to our hospital for respiratory failure with fever and her clinical course deteriorated, progressing to hemiconvulsion hemiplegia epilepsy syndrome. Case 2 was a 17-month-old boy, born by spontaneous vertex delivery at 39 weeks. Severe, asymmetrical ventricular dilation associated with hydrocephalus, cerebellar and brainstem hypoplasia, and punctuate calcifications of the thalamus, third and fourth ventricles, around the aqueduct, were observed on computed tomography (CT). The blood test for TORCH complex and various metabolic tests of blood and urine specimens yielded unremarkable results. He was admitted to our hospital for status epilepticus with fever and his clinical course progressed to hemorrhagic shock and encephalopathy syndrome. In patients with brain disorders, diagnosis and treatment are likely to be delayed and prognosis may thereby be worsened. When status epileptics or prolonged coma manifests even in patients with severe brain disorders, we must consider encephalopathy in the differential diagnosis.