Cerebellar Cortical Dysplasia Research Articles

Morphological and Calcium Signaling Alterations of Neuroglial Cells in Cerebellar Cortical Dysplasia Induced by Carmustine.

Cortical dysplasias are alterations in the organization of the layers of the brain cortex due to problems in neuronal migration during development. The neuronal component has been widely studied in experimental models of cortical dysplasias. In contrast, little is known about how glia are affected. In the cerebellum, Bergmann glia (BG) are essential for neuronal migration during development, and in adult they mediate the control of fine movements through glutamatergic transmission. The aim of this study was to characterize the morphology and intracellular calcium dynamics of BG and astrocytes from mouse cerebellum and their modifications in a model of cortical dysplasia induced by carmustine (BCNU). Carmustine-treated mice were affected in their motor coordination and balance. Cerebellar dysplasias and heterotopias were more frequently found in lobule X. Morphology of BG cells and astrocytes was affected, as were their spontaneous [Ca2+]i transients in slice preparation and in vitro.

FUKUYAMA CONGENITAL MUSCULAR DYSTROPHY: P.343Complications of Fukuyama congenital muscular dystrophy revealed from a nationwide registry

Clinical characteristics Fukuyama congenital muscular dystrophy (FCMD) is characterized by hypotonia, symmetric generalized muscle weakness, and CNS migration disturbances that result in changes consistent with cobblestone lissencephaly with cerebral and cerebellar cortical dysplasia. Mild, typical, and severe phenotypes are recognized. Onset typically occurs in early infancy with poor suck, weak cry, and floppiness. Affected individuals have contractures of the hips, knees, and interphalangeal joints. Later features include myopathic facial appearance, pseudohypertrophy of the calves and forearms, motor and speech delays, intellectual disability, seizures, ophthalmologic abnormalities including visual impairment and retinal dysplasia, and progressive cardiac involvement after age ten years. Swallowing disturbance occurs in individuals with severe FCMD and in individuals older than age ten years, leading to recurrent aspiration pneumonia and death. Diagnosis/testing The diagnosis of FCMD is established in a proband by identification of biallelic pathogenic variants in FKTN on molecular genetic testing. Management Treatment of manifestations: Physical therapy and stretching exercises, treatment of orthopedic complications, assistance devices such as long leg braces and wheelchairs, use of noninvasive respiratory aids or tracheostomy, prompt treatment of acute respiratory tract infections, antiepileptic drugs, medical and/or surgical treatment for gastroesophageal reflux, gastrostomy tube placement when indicated to assure adequate caloric intake, cardiomyopathy treatment as per cardiologist. Surveillance: Monitor: Respiratory function in individuals with advanced disease; For myocardial involvement by chest x-ray, ECG, and echocardiography in individuals older than age ten years; Gastrointestinal function, and for signs/symptoms of gastroesophageal reflux; For foot deformities and scoliosis. Genetic counseling FCMD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

Tracking the source of cerebellar epilepsy: Hemifacial seizures associated with cerebellar cortical dysplasia

Traditionally, subcortical structures such as the cerebellum are supposed to exert a modulatory effect on epileptic seizures, rather than being the primary seizure generator. We report a 14-month old girl presenting, since birth, with seizures symptomatic of a right cerebellar dysplasia, manifested as paroxystic contralateral hemifacial spasm and ipsilateral facial weakness. Multimodal imaging was used to investigate both anatomical landmarks related to the cerebellar lesion and mechanisms underlying seizure generation. Electric source imaging (ESI) supported the hypothesis of a right cerebellar epileptogenic generator in concordance with nuclear imaging findings; subsequently validated by intra-operative intralesional recordings. Diffusion spectrum imaging-related tractography (DSI) showed severe cerebellar structural abnormalities confirmed by histological examination. We suggest that hemispheric cerebellar lesions in cases like this are likely to cause epilepsy via an effect on the facial nuclei through ipsilateral and contralateral aberrant connections.

Disorganized Foliation of Unilateral Cerebellar Hemisphere as Cerebellar Cortical Dysplasia in Patients with Recurrent Seizures: A Case Report

Technological advances in magnetic resonance (MR) imaging allow improved visualization of posterior fossa structures. In previous studies, several forms of cerebellar cortical dysplasia including disorganized foliation have been reported in congenital muscular dystrophy and in related disorders (1-3). However, abnormal pattern of cerebellar folia without such disorders is extremely rare and there are only a few reports of this finding in the literature (3-5). In this paper, we present a case of abnormal foliation of unilateral cerebellar hemisphere, and review relevant literatures on this abnormality.

Adams Oliver syndrome: Description of a new phenotype with cerebellar abnormalities in a family

SummaryBackgroundTo describe cerebellar abnormalities in a family composed by a father and two affected sibs with Adams Oliver syndrome (AOS) (OMIM 100300).Material/MethodsBrain MRI and MR angiography were performed at 1.5T.ResultsThe siblings presented cerebellar cortex dysplasia characterized by the presence of cysts.ConclusionsAbnormalities of CNS are an unusual manifestation of AOS. To our knowledge, this is the first report of cerebellar cortical dysplasia in a family with AOS.

G.P.12 Eye abnormalities in children with congenital muscular dystrophy due to mutations in FKRP

Mutations in the FKRP gene account for a broad spectrum of patients ranging from CMD to a much milder LGMD2I. The involvement of the eyes can be variable with most patients having normal eye examination. We describe eye abnormalities in a child with Walker–Warburg phenotype due to a novel FKRP gene mutation in exon 3 and compare these with other reported cases with FKRP mutation. A boy was born to a G6P3L2 woman from Ghana. The couple was non-consanguineous and a previous pregnancy was interrupted for occipital encephalocele. Antenatal ultrasound showed severe hydrocephalus and delivery was by caesarian section at term. He had hypotonia, bilateral elbow contractures and very limited spontaneous movements. His creatine kinase was 6664IU/L. Brain MRI showed massive hydrocephalus, diffuse cobblestone lissencephaly, hypomyelination, cerebellar cortical dysplasia, hypoplastic pons and deformed brainstem with fusion of colliculi. Eye examination revealed right micropthalmia, nonreactive pupils, absent red reflex, very deep anterior chamber with retrolental fibrovascular tissue. B scan showed closed funnel and total retinal unattachment. The left eye had shallow anterior chamber, tunica vasculosa lentis and clear lens, persistent vascular membrane, hypoplastic optic nerve, retinal pigmentary epithelium and vitreous hemorrhage. Fluorescein angiography revealed large areas of capillary dropouts and non perfusion ischemic retina. DNA testing showed two mutations in the FKRP gene: Exon 3:c.558dupC (p.Ala187fs) and Exon 3:c.1418T>G (p.Phe473cys).Patients with FKRP gene mutation have no or mild eye involvement (strabismus) with very few cases reported with moderate to severe eye involvement. Our patient represents one of the most severe phenotypes described in regards to eye involvement.

Prenatal diagnosis of cerebellar cortical dysplasia associated with abnormalities of foliation

Prenatal diagnosis of cerebellar cortical dysplasia associated with abnormalities of foliation

Cerebellar cortical dysplasia, chronic headache, and tremor in Proteus syndrome

The patient was a 19-year-old woman with chronic head-ache, hand tremor, and school difficulties. The examination revealed large subcutaneous nodules, epidermal nevus, gi-gantism of the feet, hypertrophy of the hemibody, and mild postural hand tremor. The magnetic resonance imaging (MRI) showed distortion in the morphology of cerebellar fo-lia, increased size of the cerebellum, and foci hypersignal on T2 (Figure). Based on diagnostic criteria published, this per-son has Proteus syndrome

Neuropsychological evaluation and follow-up of children with cerebellar cortical dysplasia

To describe neuropsychological disturbances and the developmental course associated with cerebellar cortical dysplasia (CCD). The neuroimaging findings from 10 children (five males, five females; aged 3-10 y) with CCD were reviewed and classified. These children all underwent clinical neurological examination and neuropsychological assessment (NPA) on admission, then were followed for an average of 6 years using the cognitive Wechsler Scale, Vineland Adaptive Behavior Scales, and Rey-Osterrieth Complex Figure/McCarthy Drawing subtests. Based on magnetic resonance imaging, CCD was categorized as minor (n = 4), moderate (n = 1), and severe (n = 5). The first NPA disclosed mental retardation* in six (profound, three; moderate, one; mild, two) and normal intelligence in four (low, two; average, one; high, one), but with verbal/performance dissociation in three cases. Socio-adaptive functions were altered in all children except one. Visuospatial abilities were delayed in eight children. In the follow-up, no progression was observed in the three cases with profound mental retardation, whereas the remainder showed homogeneous or disharmonic progression, including improvement or deterioration of verbal/performance function. Cognitive impairment and evolution was not associated with the degree of cerebellar involvement. The neuropsychological profile and evolution associated with CCD do not appear to be predictable, and some features might improve over time.

Mosaic marker chromosome 16 resulting in 16q11.2–q12.1 gain in a child with intellectual disability, microcephaly, and cerebellar cortical dysplasia

Proximal duplications of the long arm of chromosome 16 are rare and only a few patients have been reported. Clinically, the patients do not have a distinctive syndromic appearance; however they all show some degree of intellectual disability and most have severely delayed speech development. We report on a child presenting with mild-to-moderate intellectual disability, microcephaly, language dyspraxia, and mild dysmorphisms who was found to have a mosaic gain of chromosome 16q (16q11.2-16q12.1). Magnetic resonance imaging done at the age of 4 years demonstrated cerebellar cortical dysplasia involving the vermis and hemispheres. This is the first report of cerebellar anomalies in a patient with partial trisomy 16q. The genes ZNF423 and CBLN1 found in the duplicated region play a role in the development of the cerebellum and may be responsible for the cerebellar cortical dysplasia.

P2.20 Fukuyama congenital muscle dystrophy: A rare mutation

The dystroglycanopathies comprise a clinically and genetically heterogeneous group of muscular dystrophies characterized by deficient glycosylation of alpha-dystroglycan. Mutations in the fukutin (FKTN) gene have primarily been identified among patients with classic Fukuyama congenital muscular dystrophy (FCMD), a severe form of dystroglycanopathy. Young girl 30 months old with moderate limb-girdle muscle weakness and history of congenital hip dislocation, from a non consanguineous family, without history of muscle disease. She never achieved independent walk, and clinical examination revealed a predominance of scapular weakness, a myopathic face and a severe mental retardation. Cardiac and ophthalmological evaluations were normal. Investigation performed showed creatine kinase 6777 IU/L; muscle histopathology and immunofluorescence suggestive of an a-dystroglycan glycosylation abnormality. MRI showed cerebellar cists, leukodystrophy and cortical dysplasia (polymicrogyria). POMGnT1 was negative. Fukutine gene was performed and revealed a rare mutation, not previously reported, which was confirmed in muscle and in parents ADN. In this report the diagnosis suspicion was based on MRI achievements, which showed in one child all the mainly image phenotypes described in FCMD.

Brain Regional Glucose Uptake Changes in Isolated Cerebellar Cortical Dysplasia: Qualitative Assessment Using Coregistrated FDG-PET/MRI

We aimed to assess brain regional glucose uptake (rGlcU) changes in children with isolated cerebellar cortical dysplasia (CCD) using 18-fluoro-deoxy-glucose positron emission tomography (FDG-PET). Six children aged 9 months to 11 years at the time of diagnosis, carrying isolated CCD (with no other associated posterior fossa or supratentorial malformation) underwent a brain FDG-PET and a subsequent 3DT1-weighted MRI for coregistration. The MRIs acquired previously at the time of diagnosis were reviewed to record the cerebellar dysplastic features and classify the patients as having minor, moderate, or severe CCD. The individual rGlcU was assessed qualitatively on coregistrated FDG maps. Clinical data from birth, including neurological and neuropsychological (verbal and motor skills) disturbances, were recorded. We found rGlcU changes within the cerebellum of four patients matching with the location and extent of structural abnormalities: hypometabolism in three patients with severe CCD involving the vermis and both cerebellar hemispheres and focal hypermetabolism in one patient with moderate CCD associated with a nodular heterotopic gray matter. No obvious rGlcU changes were found in the two patients with minor CCD involving the vermis only. Supratentorial rGlcU changes found commonly involved the basal ganglia bilaterally. Coregistrated FDG-PET/MRI technique is useful in detecting cerebellar cell dysfunction associated with isolated CCD. Our results enhance the need for multimodal and quantitative studies to better evaluate local and remote functional disturbances caused by CCD.

Bilateral Perysilvian Polymicrogyria With Cerebellar Dysplasia and Ectopic Neurohypophysis

Polymicrogyria (involving or not the sylvian scissure) with cerebellar cortical dysplasia or vermis hypoplasia has been reported in few cases. In addition, the association between ectopic neurohypophysis and other cortical malformations, including bilateral perisylvian polymicrogyria, has been documented. We describe a girl affected by focal epilepsy since the age of 2 years. Magnetic resonance imaging (MRI) at 11 and 22 years of age showed bilateral perisylvian polymicrogyria, dysplasia of the left cerebellar hemisphere, and ectopic neurohypophysis. Genetic tests, including fluorescent in situ hybridization 22q11.2 and array-comparative genomic hybridization, and pituitary hormones (at the age of 20 years) were normal. The patient is now 22 years old, and she is seizure free under therapy with lamotrigine and levetiracetam. To the best of our knowledge, this is the first description of this complex cerebral malformation. This finding confirms that bilateral perisylvian polymicrogyria can be associated with other cerebral malformations; cerebellum and neurohypophysis must be carefully evaluated in patients with polymicrogyria.

Bilateral Cerebellar Cortical Dysplasia without Other Malformations: A Case Report

Recent advances in MRI have revealed congenital brain malformations and subtle developmental abnormalities of the cerebral and cerebellar cortical architecture. Typical cerebellar cortical dysplasia as a newly categorized cerebellar malformation, has been seen in patients with Fukuyama congenital muscular dystrophy. Cerebellar cortical dysplasia occurs at the embryonic stage and is often observed in healthy newborns. It is also incidentally and initially detected in adults without symptoms. To the best of our knowledge, cerebellar dysplasia without any related disorders is very rare. We describe the MRI findings in one patient with disorganized foliation of both cerebellar hemispheres without a related disorder or syndrome.

Neuroprotective effects of melatonin upon the offspring cerebellar cortex in the rat model of BCNU-induced cortical dysplasia

Cortical dysplasia is a malformation characterized by defects in proliferation, migration and maturation. This study was designed to evaluate the alterations in offspring rat cerebellum induced by maternal exposure to carmustine-[1,3-bis (2-chloroethyl)-1-nitrosoure] (BCNU) and to investigate the effects of exogenous melatonin upon cerebellar BCNU-induced cortical dysplasia, using histological and biochemical analyses. Pregnant Wistar rats were assigned to five groups: intact-control, saline-control, melatonin-treated, BCNU-exposed and BCNU-exposed plus melatonin. Rats were exposed to BCNU on embryonic day 15 and melatonin was given until delivery. Immuno/histochemistry and electron microscopy were carried out on the offspring cerebellum, and levels of malondialdehyde and superoxide dismutase were determined. Histopathologically, typical findings were observed in the cerebella from the control groups, but the findings consistent with early embryonic development were noted in BCNU-exposed cortical dysplasia group. There was a marked increase in the number of TUNEL positive cells and nestin positive cells in BCNU-exposed group, but a decreased immunoreactivity to glial fibrillary acidic protein, synaptophysin and transforming growth factor β1 was observed, indicating a delayed maturation, and melatonin significantly reversed these changes. Malondialdehyde level in BCNU-exposed group was higher than those in control groups and melatonin decreased malondialdehyde levels in BCNU group ( P < 0.01), while there were no significant differences in the superoxide dismutase levels between these groups. These data suggest that exposure of animals to BCNU during pregnancy leads to delayed maturation of offspring cerebellum and melatonin protects the cerebellum against the effects of BCNU.

Neuropathological analysis of an asymptomatic adult case with Dandy–Walker variant

The Dandy-Walker (DW) complex is a rare posterior fossa malformation, usually observed during the prenatal period or the early infancy. Clinically, it is characterized by mental retardation, seizures, cerebellar ataxia as well as symptoms of hydrocephalus. Structural imaging reveal a hypoplasia or agenesis of the cerebellar vermis, enlargement of the fourth ventricle with a posterior fossa cyst. Additional neurodevelopmental changes such as agenesis of the corpus callosum, lissencephaly and cortical dysplasia are also present. We report the first neuropathological analysis of an adult asymptomatic DW case. Brain computerized tomography showed a massive posterior fossa cyst and hypoplasia of the cerebellum. An Ehlers-Danlos syndrome type IV characterized by repetitive intestinal perforations and a saccular aneurysm on the left posterior communicating artery was also present. Macroscopic brain examination revealed hypoplasia of both cerebellar hemispheres and posterior part of the vermis, as well as dilatation of the fourth ventricle without hydrocephalus. The posterior fossa cyst wall was formed by an external arachnoid layer, middle layer with loose connective tissue and an internal layer of ependymal cells. There were two foci of cerebellar cortical dysplasia but no ectopic neurons, neuronal loss or gliosis in both cerebellum and cerebral cortex. No vascular or significant neurodegenerative lesions were observed. In comparison with previous reports in DW infants, this adult case displayed milder brain abnormalities compatible with a diagnosis of DW variant. The preservation of the cortical cytoarchitecture as well as the paucity of additional neurodevelopmental changes may explain the absence of clinical expression.

Neuropathological analysis of an asymptomatic adult case of Dandy-Walker Syndrome

Case Report The Dandy-Walker (DW) complex is a rare posterior fossa malformation, usually observed during the prenatal period or the early infancy. It consists of hypoplasia or agenesis of the cerebellar vermis, enlargement of the fourth ventricle with a posterior fossa cyst, and often hydrocephalus. The rare adult cases reported were characterized by late-onset symptoms, increased intracranial pressure and consistent presence of hydrocephalus. We report the first neuropathological analysis of an adult asymptomatic case of DW syndrome where the diagnosis was made incidentally, while searching for possible brain metastases of a breast tumor. An Ehlers-Danlos syndrome type IV characterized by repetitive intestinal perforations and a saccular aneurysm on the left posterior communicating artery was also present. Macroscopic examination revealed hypoplasia of both cerebellar hemispheres and posterior part of the vermis, dilatation of the IV ventricle without hydrocephalus and an arachnoid cyst in the posterior fossa. Histologically, there were two foci of cerebellar cortical dysplasia. In contrast, no ectopic neurons, neuronal loss or gliosis were observed in cerebral cortex and cerebellum. Mild neurofibrillary tangle formation was confined to the entorhinal cortex and CA1 field of the hippocampus. In agreement with the structural imaging data reported in adult DW cases, the neuropathological study of this case demonstrates the presence of milder brain abnormalities compared to DW infants. In this context, the preserved cortical cytoarchitecture and the rarity of additional neurodevelopmental changes may explain the absence of clinical expression from International Society on Brain and Behaviour: 2nd International Congress on Brain and Behaviour Thessaloniki, Greece. 17–20 November 2005

Prenatal diagnosis of Fukuyama congenital muscular dystrophy

Fukuyama congenital muscular dystrophy (FCMD) is characterized by infantile hypotonia, symmetrical generalized muscle weakness, and neuronal migration disturbances that result in changes consistent with cobblestone lissencephaly with cerebral and cerebellar cortical dysplasia. FCMD is recognized as an autosomal recessive genetic defect. Genetic counselling is recommended for parents at risk of having a child with FCMD. Given the high risk and overwhelming prospect of having another child with this incurable devastating condition leads many couples to consider prenatal diagnosis. In Japanese families, haplotype analysis using microsatellite markers is available. In non-Japanese families, DNA sequence analysis is available. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Supratentorial functional disturbances in two children with cerebellar cortical dysplasia

When evaluating children with mental retardation, subtle cerebral and cerebellar morphologic anomalies are often noted at Magnetic Resonance Imaging (MRI). Some, such as cerebellar cortical dysplasia (CCD), have been considered as subtle markers of cerebral dysgenesis. Their functional significance and their effect on brain function, remain unknown. To study supratentorial functional disturbances related to CCD we performed Positron-Emission-Tomography (PET) studies in two children with isolated CCD, in order to investigate the degree of involvement of supratentorial structures. One had developmental delay, motor disturbances and ataxia, and the other one only had mental retardation. PET studies revealed hypoperfusion and hypometabolism within the vermis, thalamus and the right striatum in one case, and hypometabolism in the basal ganglia and cerebellar deep grey nuclei in the other case. Our results could lead to a hypothesis explaining motor disturbances as well as cognitive impairment, and could suggest a pathological functional significance of CCD. Nevertheless, the relationship between these findings and mental retardation needs further investigation.

Dysplasie du cortex cérébelleux : aspects en IRM et signification

Because it is now possible to obtain high-resolution multiplanar MR imaging of the cerebellum and because of the developing interest on the role of the cerebellum on higher brain functions, we have decided to study the process of cerebellar fissuration. All brain MRI examinations performed in children for varied neurological and neurosurgical indications, especially children with non-specific mental retardation and patients with cerebral malformation detected at initial imaging work-up, were reviewed. Fissuration and lobulation anomalies (abnormal orientation of fissures, pseudopolymicrogyria, cortical thickening, subcortical cysts and heterotopia) were identified that we called cerebellar cortical dysplasia (CCD). In order to better understand the origin of this malformation, current data on cerebellar embryogenesis and histogenesis will be reviewed, and the pathological and radiological features will be illustrated. Milder forms of CCD represent a distinct group of anomalies that should be distinguished from other types of cerebellar dysplasia (agenesis, hypoplasia or complex dysplasia with involvement of the cerebellar vermis (rhombencephalosynapsis)) or combined cerebellar and cerebral dysplasia (muscular dystrophies and lissencephaly). Recognition of cerebellar cortical dysplasia could be a first step towards a broader understanding of its pathogenesis and significance.