An Amish founder variant consolidates disruption of CEP55 as a cause of hydranencephaly and renal dysplasia.

The centrosomal protein 55 kDa (CEP55 (OMIM 610000)) plays a fundamental role in cell cycle regulation and cytokinesis. However, the precise role of CEP55 in human embryonic growth and development is yet to be fully defined. Here we identified a novel homozygous founder frameshift variant in CEP55, present at low frequency in the Amish community, in two siblings presenting with a lethal foetal disorder. The features of the condition are reminiscent of a Meckel-like syndrome comprising of Potter sequence, hydranencephaly, and cystic dysplastic kidneys. These findings, considered alongside two recent studies of single families reporting loss of function candidate variants in CEP55, confirm disruption of CEP55 function as a cause of this clinical spectrum and enable us to delineate the cardinal clinical features of this disorder, providing important new insights into early human development.

Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome or Fowler syndrome: Report of a family and insight into the disease's mechanism.

BACKGROUND: Fowler syndrome is a rare autosomal recessive disorder characterized by hydranencephaly-hydrocephaly and multiple pterygium due to fetal akinesia. To date, around 45 cases from 27 families have been reported, and the pathogenic bi-allelic mutations in FLVCR2 gene described in 15 families. The pathogenesis of this condition has not been fully elucidated so far. METHODS: We report on an additional family with two affected fetuses carrying a novel homozygous mutation in FLVCR2 gene, and describe the impact of known mutants on the protein structural and functional impairment. RESULTS: The present report confirms the genetic homogeneity of Fowler syndrome and describes a new FLVCR2 mutation affecting the protein function. The structural analysis of the present and previously published FLVCR2 mutations supports the hypothesis of a reduced heme import as the underlying disease's mechanism due to the stabilization of the occluded conformation or a protein misfolding. CONCLUSION: Our data suggest the hypothesis of heme deficiency as the major pathogenic mechanism of Fowler syndrome.

Discrepancy Between Cerebral Structure and Cognitive Functioning: A Review.

Neuroscientists typically assume that human mental functions are generated by the brain and that its structural elements, including the different cell layers and tissues that form the neocortex, play specific roles in this complex process. Different functional units are thought to complement one another to create an integrated self-awareness or episodic memory. Still, findings that pertain to brain dysplasia and brain lesions indicate that in some individuals there is a considerable discrepancy between the cerebral structures and cognitive functioning. This seems to question the seemingly well-defined role of these brain structures. This article provides a review of such remarkable cases. It contains overviews of noteworthy aspects of hydrocephalus, hemihydranencephaly, hemispherectomy, and certain abilities of "savants." We add considerations on memory processing, comment on the assumed role of neural plasticity in these contexts, and highlight the importance of taking such anomalies into account when formulating encompassing models of brain functioning.

Bilateral population receptive fields in congenital hemihydranencephaly.

PURPOSE: Congenital hemihydranencephaly (HH) is a very rare disorder characterised by prenatal near-complete unilateral loss of the cerebral cortex. We investigated a patient affected by congenital right HH whose visual field extended significantly into the both visual hemifields, suggesting a reorganisation of the remaining left visual hemisphere. We examined the early visual cortex reorganisation using functional MRI (7T) and population receptive field (pRF) modelling. METHODS: Data were acquired by means of a 7T MRI while the patient affected by HH viewed conventional population receptive field mapping stimuli. Two possible pRF reorganisation schemes were evaluated: where every cortical location processed information from either (i) a single region of the visual field or (ii) from two bilateral regions of the visual field. RESULTS: In the patient affected by HH, bilateral pRFs in single cortical locations of the remaining hemisphere were found. In addition, using this specific pRF reorganisation scheme, the biologically known relationship between pRF size and eccentricity was found. CONCLUSIONS: Bilateral pRFs were found in the remaining left hemisphere of the patient affected by HH, indicating reorganisation of intra-cortical wiring of the early visual cortex and confirming brain plasticity and reorganisation after an early cerebral damage in humans.

Hemihydranencephaly: living with half brain dysfunction.

Hemi-hydranencephaly is a very rare condition characterized by complete or almost near-complete unilateral absence of the cortical cortex, which is filled by a sac of cerebrospinal fluid. Prenatal vascular disruption with occlusion of the carotid artery territories ipsilateral to the damaged brain is the presumed pathogenesis.We have selected nine cases that fit the clinical and pathologic characteristics of hemi-hydranencephaly, demonstrating that destruction of one hemisphere may be not always associated with severe neurologic impairment and may allow an almost normal life. This disorder is an example of a possible prenatal re-organization in which the right and left cerebral hemispheres present functional potentiality to make up the damaged brain.The cases reported in the literature are discussed, including a patient previously reported and followed-up for 10 years. A review of the cases is performed with an evaluation of the most important aspect of this rare and mysterious disorder.

Hemihydranencephaly syndrome: case report and review.

BACKGROUND: Hemihydranencephaly (HHDNC) is a rare disorder with complete or almost complete unilateral absence of cerebral cortex. METHODS: This study describes a 27 months-old girl presenting with developmental delay and generalized weakness more on the left side. Bilateral blindness was noted since the age of 6 months. RESULTS: Her fundus examination revealed bilateral optic atrophy, dilated tortuous retinal veins with increased intra-ocular tension. She had polyuria and recurrent attacks of dehydration due to neurogenic diabetes insipidus. Her blood protein S was deficient. Her magnetic resonance imaging (MRI) demonstrated HHDNC with nearly complete absence of the right cerebral hemisphere. Her MR-Arteriography demonstrated total occlusion of right middle and anterior cerebral arteries and attenuated and beaded right posterior cerebral artery. Diffusion tensor MR imaging revealed complete absence of right cortico-spinal and optic tracts with deficient left sided tracts. CONCLUSION: In contrast to the good outcome of the few reported cases of HHDNC, this case had severe global disabilities.

The presence of consciousness in the absence of the cerebral cortex.

Hydranencephaly is a rare neurological condition in which the cerebral hemispheres are either absent or severely compromised. It is widely believed that children with hydranencephaly are not conscious; and therefore, are routinely classified into the diagnostic criteria of vegetative state. However, there are several pieces of behavioral evidence clearly indicating the presence of consciousness in such patients. Here, I review these behavioral evidence and argue how misclassification of these patients and assigning them a lack of consciousness have far-reaching implications in terms of both clinical and theoretical neuroscience.

Residual visual function after loss of both cerebral hemispheres in infancy.

PURPOSE: To investigate whether and what kind of visual function is still present in the absence of both cerebral hemispheres. METHODS: Binocular visual function of five children who had suffered the loss of both cerebral hemispheres and the visual fields of 30 controls 5 to 12 months of age were examined according to a perimetric method based on forced-choice, preferential-looking methods. RESULTS: Results show that after the destruction of both cerebral hemispheres, a stimulus presented binocularly beyond 5 degrees eccentricity did not elicit a response. However, two children were still able to fixate steadily and to follow a stimulus presented binocularly within the central 5 degrees , with eye and head movements despite the absence of both cerebral hemispheres. One child responded only to a moving face or a moving drum with black and white stripes presented binocularly within the central 5 degrees but not to a moving spot of light. The binocular visual field of 30 controls 5 to 12 months of age almost reached the dimensions of the adult binocular visual field. CONCLUSIONS: Neural structures in the midbrain, including the superior colliculi and the pretectum, seem to be able to mediate visual function in the foveal and macular regions. These structures are, however, unable to mediate the presence of a functional visual field beyond 5 degrees eccentricity.

Brainstem mediation of the stapedius muscle reflex in hydranencephaly.

Hydranencephaly is a rare condition in which the cerebral hemispheres are absent at birth and are replaced by membranous sacs in a cerebrospinal fluid-filled cranium. Surviving hydranencephalic patients have a functional brainstem and possible remnants of the cerebral cortex. This case report examines hearing function and the integrity of the brainstem mediated stapedius muscle reflex (SMR) in an adult with hydranencephaly, using middle ear impedance change measures. The brainstem mediated ipsilateral and cross-brainstem contralateral SMRs were elicited in the right ear at normal threshold levels for noise bands of 0.25-1.0, 1.0-4.0, and 0.25-4.0 kHz (broadband), and at the sinusoidal frequencies of 0.5, 1.0, and 2.0 kHz. The ipsilateral and contralateral SMR decay rates were normal. The growth in the SMR amplitude in response to noise and pure tone stimuli from threshold to saturation over a 15-20 dB range was normal and showed essentially sigmoidal curves. The normal ipsilateral and crossed brainstem contralateral electrophysiological SMR in this hydranencephalic patient demonstrated the preservation of peripheral hearing reception and functional brainstem auditory afferent and efferent tracts and nuclei in the absence of corticofugal influence.

Electroencephalography, Doppler vascular scanning, and single photon emission computed tomography in a child with hydranencephaly and intractable seizures.

In a child with hydranencephaly and refractory seizures, the electroencephalogram showed a flat isoelectric pattern with no significant slow waves or epileptiform activity; cranial computed tomography, magnetic resonance imaging, Doppler vascular scanning, and single photon emission computed tomography (SPECT) were done to define the pathogenesis of the seizures. The investigations were suggestive of a lack of significant cortical, subcortical, or thalamic structures with hypoplasia of the vermis and cerebellum. SPECT showed little activity in the base of the brain and cerebellum. The cause of the seizures remained unclear in spite of the investigations.

Auditory behaviors and auditory brainstem responses of infants with hypogenesis of cerebral hemispheres.

Three infants with an almost complete absence of the cerebral hemispheres as a result of brain anomalies were studied both audiologically and neurologically. The brain anomalies were diagnosed by means of MRI and CT scans. Behavioral audiometry revealed reactions only to loud sound stimulations but auditory brainstem responses showed wave configurations and thresholds compatible with the ages of the infants. There were significant differences in the thresholds obtained by behavioral audiometry and auditory brainstem responses. It can be considered that these auditorily stimulated behavioral responses are evoked by auditory motor reflexes originating in the brainstem, but not by auditory perception.

Hemihydranencephaly: case report and literature review.

Hydranencephaly is a severe brain condition characterized by complete or almost complete absence of cerebral cortex with preservation of meninges, basal ganglia, pons, medulla, cerebellum, and falx. It has been ascribed to different causes (infections, irradiations, fetal anoxia, medications, twin-twin transfusion), all leading to vascular disruption. Hemihydranencephaly is an extremely rare condition in which the vascular anomaly is unilateral. We report on a patient who was suspected to have hydrocephalus in utero; a brain magnetic resonance imaging scan showed left-sided hydranencephaly with preservation of basal ganglia. The patient developed signs of right hemiparesis but notably has only mild language delay. The available literature on hemihydranencephaly is reviewed.

The novel genetic disorder microhydranencephaly maps to chromosome 16p13.3-12.1.

We studied a large consanguineous Anatolian family with children who exhibited hydranencephaly associated with microcephaly. The children were severely affected. This novel genetic disorder is autosomal recessive. We used autozygosity mapping to identify a locus at chromosome 16p13.3-12.1; it has a LOD score of 4.11. The gene locus is within a maximal 11-cM interval between markers D16S497 and D16S672 and within a minimal critical region of 8 cM between markers D16S748 and D16S490.

Brain functions of an infant with hydranencephaly revealed by auditory evoked potentials.

Hydranencephaly is a severe condition of brain characterized by the almost complete absence of the cerebral hemispheres with the thalamus, cerebellum and brainstem being preserved. This paper reports hydranencephaly in a 3-month-old boy. Cranial magnetic resonance imaging (MRI) revealed the condition and an auditory evoked potential study which was performed in order to investigate residual brain function. They showed normal auditory brainstem function but no appearance of other auditory evoked potentials originating from the higher brain.

[Mismatch negativity of patients with hydranencephaly].

We examined auditory evoked potentials and passive event-related potentials in two patients with hydranencephaly. In the middle latency response, a Na component was observed in both cases. Mismatch negativity was elicited in response to tone bursts and three patterns of vowel sounds in Patient 1, and three patterns of vowel stimuli in Patient 2. These results implicate the subcortical components of the auditory system in the generation of mismatch negativity.

Polygraphic characterization of the sleep-epilepsy patterns in a hydranencephalic child with severe generalized seizures of the Lennox-Gastaut syndrome.

This is the report of a hydranencephalic child with severe generalized seizures of the Lennox-Gastaut Syndrome (LGS) who lacked the development of the entire cerebral hemispheres and had preserved the brain stem, cerebellum, hypothalamus and a portion of the thalamus as evidenced by radiological and/or physiological studies. Conventional polygraphic sleep studies in these patients showed presence of scalp EEG and other peripheral, somatic and vegetative signs characterizing the wakefulness, quiet sleep and active sleep stages. Absence of the vertex waves and disrupted sleep spindles were the major qualitative EEG abnormalities. In contrast, quantitative abnormalities in duration, latency and number of sleep cycles found in this patient were similar to those found in other children with Idiopathic Lennox-Gastaut Syndrome (ILGS). A substantial reduction in the number of interictal EEG spikes and a shortening of the ictal clonic EEG activities without concomitant EMG jerks were the most distinct epileptiform abnormalities in this child. In contrast, his basic polygraphic patterns of the tonic and apneic seizures were similar to those found in other children with ILGS. Data obtained from this child suggest that both the sleep stages and the generalized seizures of the ILGS basically depend more on the integrity of the brain stem than on the telencephalic structures.

Polygraphic characterization of the sleep-epilepsy patterns in a hydranencephalic child with severe generalized seizures of the lennox-gastaut syndrome

This is the report of a hydranenecephalic child with severe generalized seizures of the Lennox-Gastaut Syndrome (LGS) who lacked the development of the entire cerebral hemispheres and had preserved the brain stem, cerebellum, hypothalamus and a portion of the thalamus as evidenced by radiological and/or physiological studies. Conventional polygraphic sleep studies in these patients showed presence of scalp EEG and other peripheral, somatic and vegetative signs characterizing the wakefulness, quiet sleep and active sleep stages. Absence of the vertex waves and disrupted sleep spindles were the major qualitative EEG abnormalities. In contrast, quantitative abnormalities in duration, latency and number of sleep cycles found in this patient were similar to those found in other children with Idiopathic Lennox-Gastaut Syndrome (ILGS). A substantial reduction in the number of interictal EEG spikes and a shortening of the ictal clonic EEG activities without concomitant EMG jerks were the most distinct epileptiform abnormalities in this child. In contrast, his basic polygraphic patterns of the tonic and apneic seizures were similar to those found in other children with ILGS. Data obtained from this child suggest that both the sleep stages and the generalized seizures of the ILGS basically depend more on the integrity of the brain stem than on the telecephalic structures

Experimental hydranencephaly in the ovine fetus.

Hydranencephaly is defined as the replacement of a previously normal brain, in whole or in part, by membranous fluid-filled sacs. The etiology is not well understood, and the time course of development is unknown. Fifteen ovine fetuses were chronically cannulated and had both carotid arteries ligated at 100 days of gestation (term is 145-150 days). They were killed at 1 (n = 4), 2 (n = 6) and 4 (n = 5) weeks post-surgery, and the findings compared with those of 25 age-matched controls. By 2 weeks post-surgery the entire cerebral hemispheres and diencephalon had been replaced by fluid closely resembling cerebrospinal fluid. The choroid plexus, pituitary and brain stem remained outwardly normal, but the cerebellum showed signs of damage. Fetuses maintained normal values for blood gases and hematocrit up to 4 weeks post-surgery, and grew normally. Light microscopy of the brain stem showed significant losses of cell populations in the medulla by 4 weeks. Vascular casting and acute blood flow studies in an additional group of fetuses showed that the entire brain was perfused via the vertebral-occipital anastomosis immediately after acute bilateral carotid clamping, but that the blood flow rate was insufficient to maintain adequate oxygen delivery.