Expanding horizons: ciliary proteins reach beyond cilia.

Once obscure, the cilium has come into the spotlight during the past decade. It is now clear that aside from generating locomotion by motile cilia, both motile and immotile cilia serve as signaling platforms for the cell. Through both motility and sensory functions, cilia play critical roles in development, homeostasis, and disease. To date, the cilium proteome contains more than 1,000 different proteins, and human genetics is identifying new ciliopathy genes at an increasing pace. Although assigning a function to immotile cilia was a challenge not so long ago, the myriad of signaling pathways, proteins, and biological processes associated with the cilium have now created a new obstacle: how to distill all these interactions into specific themes and mechanisms that may explain how the organelle serves to maintain organism homeostasis. Here, we review the basics of cilia biology, novel functions associated with cilia, and recent advances in cilia genetics, and on the basis of this framework, we further discuss the meaning and significance of ciliary connections.

Ciliopathies and the Kidney: A Review.

Primary cilia are specialized sensory organelles that protrude from the apical surface of most cell types. During the past 2 decades, they have been found to play important roles in tissue development and signal transduction, with mutations in ciliary-associated proteins resulting in a group of diseases collectively known as ciliopathies. Many of these mutations manifest as renal ciliopathies, characterized by kidney dysfunction resulting from aberrant cilia or ciliary functions. This group of overlapping and genetically heterogeneous diseases includes polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome as the main focus of this review. Renal ciliopathies are characterized by the presence of kidney cysts that develop due to uncontrolled epithelial cell proliferation, growth, and polarity, downstream of dysregulated ciliary-dependent signaling. Due to cystic-associated kidney injury and systemic inflammation, cases result in kidney failure requiring dialysis and transplantation. Of the handful of pharmacologic treatments available, none are curative. It is important to determine the molecular mechanisms that underlie the involvement of the primary cilium in cyst initiation, expansion, and progression for the development of novel and efficacious treatments. This review updates research progress in defining key genes and molecules central to ciliogenesis and renal ciliopathies.

Diagnostic use of computational retrotransposon detection: Successful definition of pathogenetic mechanism in a ciliopathy phenotype.

Among more than 5,000 human monogenic disorders with known causative genes, transposable element insertion of a Long Interspersed Nuclear Element 1 (LINE1, L1) is known as the mechanistic basis in only 13 genetic conditions. Meckel-Gruber syndrome is a rare ciliopathy characterized by occipital encephalocele and cystic kidney disease. Here, we document a boy with occipital encephalocele, post-axial polydactyly, and multicystic renal disease. A medical exome analysis detected a heterozygous frameshift mutation, c.4582_4583delCG p.(Arg1528Serfs*17) in CC2D2A in the maternally derived allele. The further use of a dedicated bioinformatics algorithm for detecting retrotransposon insertions led to the detection of an L1 insertion affecting exon 7 in the paternally derived allele. The complete sequencing and sequence homology analysis of the inserted L1 element showed that the L1 element was classified as L1HS (L1 human specific) and that the element had intact open reading frames in the two L1-encoded proteins. This observation ranks Meckel-Gruber syndrome as only the 14th disorder to be caused by an L1 insertion among more than 5,000 known human genetic disorders. Although a transposable element detection algorithm is not included in the current best-practice next-generation sequencing analysis, the present observation illustrates the utility of such an algorithm, which would require modest computational time and resources. Whether the seemingly infrequent recognition of L1 insertion in the pathogenesis of human genetic diseases might simply reflect a lack of appropriate detection methods remains to be seen.

Expanding the allelic disorders linked to TCTN1 to include Varadi syndrome (Orofaciodigital syndrome type VI).

Varadi syndrome is a subtype of orofaciodigital syndrome (OFDS) that combines the typical features of OFDS and the posterior fossa features of Joubert syndrome. The only gene known to be mutated in Varadi syndrome is C5ORF42. In this report, we describe the phenotype of a patient with Varadi syndrome who is homozygous for a previously reported mutation in TCTN1 (NM_001082538.2:c.342-2A>G, p.Gly115Lysfs*8) and suggest that allelic disorders linked to TCTN1 include Varadi syndrome, in addition to Joubert syndrome and Meckel-Gruber syndrome.

Chiari Type 1 Deformity in Children: Pathogenetic, Clinical, Neuroimaging, and Management Aspects.

Our understanding of cerebellar tonsillar herniation evolved over time and nowadays various pathomechanisms have been proposed. Causes of tonsillar herniation share a discrepancy between content (fore- and hindbrain) and container (supratentorial cranial vault, posterior fossa), may be associated with abnormalities of the craniocervical junction, and may have a developmental or acquired nature. In tonsillar herniation, the hindbrain is not malformed but deformed. Accordingly, "Chiari type 1 deformity," not "Chiari type 1 malformation" is the correct term to characterize primary tonsillar herniation. Chiari type 1 deformity is commonly seen in pediatric neurology, neuroradiology, and neurosurgery and may have various clinical presentations depending on patient age. In addition, Chiari type 1 deformity is increasingly found by neuroimaging studies as an incidental finding in asymptomatic children. An accurate and reliable selection of patients based on clinical and neuroimaging findings is paramount for the success of neurosurgical treatment. Future studies are needed to provide selection criteria with a higher sensitivity and specificity.

[Prenatal diagnosis of Meckel-Gruber syndrome. Case report and literature review]. / Diagnóstico prenatal de síndrome de Meckel-Gruber. Reporte de un caso y revisión de la bibliografía.

BACKGROUND: Meckel-Gruber syndrome is a ciliopathy, a lethal autosomal recessive disorder that occurs in all races and ethnicities; it is characterized by central nervous system abnormalities, resulting in mental retardation, bilateral renal cystic dysplasia and malformations of hands and feet. To date there have been only about 200 cases reported worldwide. It is a disease with a recurrence rate of 25% whose most reliable method for diagnosis is prenatal ultrasound. The mortality rate is 100% and in view of the high index of recurrence, subsequent pregnancies should be investigated appropriately with genetic counseling. CLINIC CASE: We present the case of a 15 years-old mother with 30.2 weeks pregnancy resulting from rape by consanguinity (grandfather), without prenatal care. On admission HD ultrasound study is performed finding fetus fetometria average 26.2 weeks (for discordant fetometria head circumference 187.5 mm to 21.0 weeks gestation -3DE-) lost in the skull shape of the shell line is observed winding mean; not cut down, cavum septum pellucidum or herniated sac cerebellum and occipital level (encephalocele) are evident. It starts cervical ripening with prostaglandins for 24 hours to conduct further labor with oxytocic and delivery care where a fetus death, female, 1516 g is obtained. Fetal autopsy family is authorized; however, it not has done because it is legal and only medical geneticist obtains medical case assessment. CONCLUSIONS: The Meckel-Gruber syndrome is a very rare condition that occurs in cases of consanguinity occasions. Mortality occurs in 100% of cases, so you should talk to parents and explain the best maternal prognosis, with abortion in the early stages and subsequent genetic counseling.

[HIGH INCIDENCE AND BROAD GENETIC VARIABILITY OF MECKEL-GRUBER SYNDROME IN THE ARAB POPULATION RESIDING IN NORTH-EAST ISRAEL].

BACKGROUND: Meckel-Gruber syndrome (MKS) is a lethal rare inherited autosomal recessive disease. The syndrome is characterized by multiple congenital anomalies including polycystic kidneys, occipital encephalocele and polydactyly. The presence of two out of these anomalies is sufficient for a definitive diagnosis. At least 11 genes have been reported to-date to underlie MKS. METHODS: In the current study we have retrospectively analyzed all the families at the Ha'Emek Medical Center in which the diagnosis of MKS was determined. RESULTS: In total, 17 affected individuals are reported, originating from 12 sibships. The diagnoses were conducted or suspected by prenatal sonography, and some of the newborns were examined. Polycystic kidneys were present in 94% of cases, occipital encephalocele in 82% and polydactyly in about half of all cases. The underlying genetic cause was identified in 11 of our families, comprising mutations in 7 different genes, revealing high genetic heterogeneity. CONCLUSION: The identification of the genetic basis of MKS in our region allows focused and data-based genetic counseling and serves as an important tool for reproductive decisions, including the prevention of recurrence of pregnancies affected with this lethal syndrome. In the near future we plan to study the prevalence of the different MKS mutations found in each community in order to consider the expansion of national genetic screening in high risk populations.

Usher syndrome protein network functions in the retina and their relation to other retinal ciliopathies.

The human Usher syndrome (USH) is the most frequent cause of combined hereditary deaf-blindness. USH is genetically and clinically heterogeneous: 15 chromosomal loci assigned to 3 clinical types, USH1-3. All USH1 and 2 proteins are organized into protein networks by the scaffold proteins harmonin (USH1C), whirlin (USH2D) and SANS (USH1G). This has contributed essentially to our current understanding of the USH protein function in the eye and the ear and explains why defects in proteins of different families cause very similar phenotypes. Ongoing in depth analyses of USH protein networks in the eye indicated cytoskeletal functions as well as roles in molecular transport processes and ciliary cargo delivery in photoreceptor cells. The analysis of USH protein networks revealed molecular links of USH to other ciliopathies, including non-syndromic inner ear defects and isolated retinal dystrophies but also to kidney diseases and syndromes like the Bardet-Biedl syndrome. These findings provide emerging evidence that USH is a ciliopathy molecularly related to other ciliopathies, which opens an avenue for common therapy strategies to treat these diseases.

Tension pneumocephalus as a result of endonasal surgery: an uncommon intracranial complication.

Tension pneumocephalus (TP) is a clinical entity characterized by continued build-up of air within the cranial cavity, leading to abnormal pressure exerted upon the brain and subsequent neurologic deterioration, due to development of a mass effect and potentially a herniation syndrome. Intracranial complications of endoscopic sinus surgery (ESS) and other endonasal procedures are fortunately very rare, occurring in less than 3% of cases. We report 4 cases of small bone defects (<3 mm) in the anterior cranial base accompanied by TP, caused by ESS and other endonasal procedures. The pathophysiology and management of this clinical entity is discussed with a pertinent literature. Four patients with small (<3 mm) skull base defects were identified. All patients presented with active cerebrospinal fluid leaks. CT scans showed intracranial tension pneumocephalus. Using image-guided endoscopic techniques, all defects were addressed with multi-layer repair. Closure was achieved in all patients on the first attempt, with an average follow-up of 36 months. Tension pneumocephalus is a rare event that can occur as a result of traumatic or iatrogenic violation of the dura and should be considered in all patients presenting with altered mental status after endoscopic sinus surgery or other surgical and diagnostic procedures that violate either the cranial or spinal dura. Because of the potential for rapid clinical deterioration and death, prompt brain imaging is warranted to rule out the diagnosis, and urgent neurosurgical consultation is indicated for definitive management.

Neuraxial anesthesia in parturients with intracranial pathology: a comprehensive review and reassessment of risk.

Parturients with intracranial lesions are often assumed to have increased intracranial pressure, even in the absence of clinical and radiographic signs. The risk of herniation after an inadvertent dural puncture is frequently cited as a contraindication to neuraxial anesthesia. This article reviews the relevant literature on the use of neuraxial anesthesia in parturients with known intracranial pathology, and proposes a framework and recommendations for assessing risk of neurologic deterioration, with epidural analgesia or anesthesia, or planned or inadvertent dural puncture. The authors illustrate these concepts with numerous case examples and provide guidance for the practicing anesthesiologist in determining the safety of neuraxial anesthesia.

Continuous electroencephalography (cEEG) changes precede clinical changes in a case of progressive cerebral edema.

BACKGROUND: Continuous electroencephalogram (cEEG) is tightly linked to cerebral metabolism and is sensitive to cerebral ischemia and hypoxia. The severity of cerebral ischemia can be seen on cEEG as changes in morphology, amplitude, or frequency, and cEEG may detect neuronal dysfunction at a reversible stage. METHODS: Case report and imaging. RESULTS: We present a case of focal cerebral edema with changes seen on cEEG 24 h before clinical signs of increased intracranial pressure. cEEG showed developing asymmetry in the left hemisphere followed by burst suppression. The right hemisphere showed similar progression to burst suppression. Complete suppression of both hemispheres was noted 6 h before clinical signs of herniation. Computed tomography (CT) head confirmed a large left parietal intracerebral hematoma with mass effect. CONCLUSIONS: cEEG has applications in monitoring cerebral dysfunction in addition to detecting seizure activity in the intensive care unit. It may serve a vital role in multi-modality monitoring for early recognition of neurological complications from brain injuries that may not be noticed clinically, which is paramount to early intervention.

Threshold for toxicity from hyperammonemia in critically ill children.

BACKGROUND & AIMS: Hyperammonemia results from reduction of hepatocyte function or enzyme of urea cycle deficiency. Hyperammonemia contributes to cerebral edema that may lead to cerebral herniation. The threshold of toxicity of ammonemia is unknown. METHODS: We conducted a retrospective observational study in our pediatric intensive care unit. All children who developed hyperammonemia from January 2000 to April 2009 were included. Clinical and laboratory data at admission, specific treatments implemented, and ammonemias the first 7 days after inclusion were collected. The outcome assessed was 28 day mortality. Risk of mortality was estimated by a logistic regression model. RESULTS: Ninety patients with liver failure (63.3%) and primary or secondary urea cycle defect (23.3%) were included. Patients with urea cycle defects were more likely to receive ammonia scavengers than patients with liver failure (47.6% versus 3.5%). The 28 day mortality rate was 31.1%. Risk of mortality increased according to the ammonemia within 48 h: odds ratio 1.5, 1.9, 3.3, 2.4 for ammonemia above 100, 150, 200, and 300 µmol/L, respectively. Peak ammonemia ≥200 µmol/L within the first 48 h was an independent risk factor for mortality, with greater risk found in liver failure than in urea cycle defect. CONCLUSIONS: Our study identifies a threshold of exposure to ammonia (≥200 µmol/L) above which mortality increases significantly, especially in liver failure. Specific treatments of hyperammonemia are rarely used in liver failure when compared with urea cycle defect even though use of ammonia scavengers may help to decrease ammonemia.

Neural tract injuries by brain herniations after head trauma.

OBJECTIVES: : Little is known about the usefulness and findings of brain herniation on diffusion tensor tractography (DTT). Using DTT, we demonstrated neural tract injuries in 2 patients who showed subfalcine and trasntentorial herniations after subdural hematoma resulting from motor vehicle accident. DESIGN: : Two patients and 6 age- and sex-matched, healthy volunteers were recruited for this study. SETTING: : An inpatient rehabilitation unit. MAIN OUTCOME MEASURES: : Diffusion tensor tractography for the patients was performed 5 weeks after onset. RESULTS: : Diffusion tensor tractography of patient 1 showed complete injury of both cingulums at or around the rostrum of the corpus callosum, the fornix at the anterior and posterior body, and both corticospinal tracts at the pons. In addition, partial injury of both somatosensory tracts at the midbrain was also observed. Patient 2 showed complete injury of both cingulums above the body of the corpus callosum, the fornix at the anterior and posterior body, and right corticospinal tracts at the pons level and partial injury of the right somatosensory tract. We found that the fractional anisotropy values of all neural tracts, except fornix, in both patients and left somatosensory tract in patient 2 and voxel number for left somatosensory tract in patient 2 were decreased 2 SDs below that of normal controls. CONCLUSIONS: : We determined that DTT would be a good technique for use in the detection of underlying lesions in patients with brain herniation.

Encephalocystocele - uncommon diagnosis in prenatal medicine.

Encephalocystocele is a developmental malformation characterized by brain herniation accompanied with extracranial cystic protrusion of the ventricular system. This nosological unit is often overlooked and insufficiently classified merely as encephalocele. Herein, two exceptionally clear cases of the parieto-occipital cranioschisis with encephalocystocele and congenital hydrocephalus of the lateral ventricles are documented with 2-dimensional/3-dimensional sonographic images and the corresponding MRI findings. In both cases, prenatal diagnosis was confirmed by autopsy.

Hypopituitarism in a patient with transsphenoidal cephalocele: longitudinal changes in endocrinological abnormalities.

We report a 21-year-old man with severe fatigue due to hypopituitarism. At the age of 6 years, he was diagnosed with short stature due to a GH deficiency accompanied by a sphenoid cystic lesion. Laboratory findings and provocative tests for pituitary hormone function revealed ACTH, LH, FSH, TSH, and GH deficiency. Computed tomography and magnetic resonance imaging revealed transsphenoidal cephalocele due to a defect in the floor of the sella turcica. At 6 years, he only had severe GH deficiency and poor response of LH to LHRH. Hypothalamic-pituitary dysfunction and pituitary herniation have progressed subsequently; we observed a longitudinal progression of hypothalamic-pituitary dysfunction caused by transsphenoidal cephalocele. This dysfunction requires the selection of a treatment that will not aggravate the condition further.

Meckel syndrome with Caroli disease and choledochal cysts.

Meckel syndrome is a lethal autosomal recessive disorder characterized by the triad of cystic renal dysplasia, occipital encephalocele, or other anomaly of the central nervous system and post-axial polydactyly. Malformation of the ductal plate is an integral component of Meckel syndrome. Ductal plate malformations include congenital hepatic fibrosis, biliary hamartoma, autosomal dominant polycystic liver disease, Caroli disease, and choledochal cyst. The occurrence of cystic hepatic disease, Caroli disease, and choledochal cyst have not been highlighted. This is a report of a 26-week fetus with features of Meckel syndrome, Caroli disease, and choledochal cyst.

Cerebellar tonsillar herniation after weight loss in a patient with idiopathic intracranial hypertension.

Acquired cerebellar tonsillar herniation is a known complication of lumboperitoneal shunt (LPS) for any indication, including idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri.(1) While the underlying pathophysiology of IIH remains unknown, increasing body mass index is a clear risk factor for the development of IIH. We describe an obese patient with IIH unresponsive to LPS who developed symptoms of intracranial hypotension and cerebellar tonsillar herniation after bariatric surgery and a 50-kg weight loss.

Mechanisms of cerebellar tonsil herniation in patients with Chiari malformations as guide to clinical management.

BACKGROUND: The pathogenesis of Chiari malformations is incompletely understood. We tested the hypothesis that different etiologies have different mechanisms of cerebellar tonsil herniation (CTH), as revealed by posterior cranial fossa (PCF) morphology. METHODS: In 741 patients with Chiari malformation type I (CM-I) and 11 patients with Chiari malformation type II (CM-II), the size of the occipital enchondrium and volume of the PCF (PCFV) were measured on reconstructed 2D-CT and MR images of the skull. Measurements were compared with those in 80 age- and sex-matched healthy control individuals, and the results were correlated with clinical findings. RESULTS: Significant reductions of PCF size and volume were present in 388 patients with classical CM-I, 11 patients with CM-II, and five patients with CM-I and craniosynostosis. Occipital bone size and PCFV were normal in 225 patients with CM-I and occipitoatlantoaxial joint instability, 55 patients with CM-I and tethered cord syndrome (TCS), 30 patients with CM-I and intracranial mass lesions, and 28 patients with CM-I and lumboperitoneal shunts. Ten patients had miscellaneous etiologies. The size and area of the foramen magnum were significantly smaller in patients with classical CM-I and CM-I occurring with craniosynostosis and significantly larger in patients with CM-II and CM-I occurring with TCS. CONCLUSIONS: Important clues concerning the pathogenesis of CTH were provided by morphometric measurements of the PCF. When these assessments were correlated with etiological factors, the following causal mechanisms were suggested: (1) cranial constriction; (2) cranial settling; (3) spinal cord tethering; (4) intracranial hypertension; and (5) intraspinal hypotension.

Traumatic occipital meningoencephalocele presenting with homonymous hemianopia in a professional driver.

BACKGROUND: This study presents the case of a 32-year-old male who is a chronic headache sufferer. He is a professional driver who presented with homonymous hemianopia secondary to a traumatic occipital meningoencephalocele. This is the first time such an association has been reported. CONCLUSIONS: The complete lack of previous visual symptoms supports the belief of late development of the hemianopia. However, the chronicity and the nature of the patients' headaches could have justified further investigations in the past.