Search

Abstract Background Despite evidence linking obesity to impaired immune function, little is known about the specific mechanisms. Because of emerging evidence that immune responses are epigenetically regulated, we hypothesized that DNA methylation changes are involved in obesity induced immune dysfunction and aimed to identify these changes. Method We conducted a genome wide methylation analysis on seven obese cases and seven lean controls aged 14 to 18 years from extreme ends of the obesity distribution and performed further validation of six CpG sites from six genes in 46 obese cases and 46 lean controls aged 14 to 30 years. Results In comparison with the lean controls, we observed one CpG site in the UBASH3A gene showing higher methylation levels and one CpG site in the TRIM3 gene showing lower methylation levels in the obese cases in both the genome wide step (P = 5 × 10-6 and P = 2 × 10-5 for the UBASH3A and the TRIM3 gene respectively) and the validation step (P = 0.008 and P = 0.001 for the UBASH3A and the TRIM3 gene respectively). Conclusions Our results provide evidence that obesity is associated with methylation changes in blood leukocyte DNA. Further studies are warranted to determine the causal direction of this relationship as well as whether such methylation changes can lead to immune dysfunction. See commentary: http://www.biomedcentral.com/1741-7015/8/88/abstract

Abstract Background Pluripotent mouse embryonic stem (ES) cells can be induced in vitro to become neural progenitors. Upon transplantation, neural progenitors migrate toward areas of damage and inflammation in the CNS. We tested whether undifferentiated and neuralized mouse ES cells migrate toward media conditioned by glioma cell lines (C6, U87 & N1321) or Stem Cell Factor (SCF). Results Cell migration assays revealed selective migration by neuralized ES cells to conditioned media as well as to synthetic SCF. Migration of undifferentiated ES cells was extensive, but not significantly different from that of controls (Unconditioned Medium). RT-PCR analysis revealed that all the three tumor cell lines tested synthesized SCF and that both undifferentiated and neuralized ES cells expressed c-kit, the receptor for SCF. Conclusion Our results demonstrate that undifferentiated ES cells are highly mobile and that neural progenitors derived from ES cells are selectively attracted toward factors produced by gliomas. Given that the glioma cell lines synthesize SCF, SCF may be one of several factors that contribute to the selective migration observed.

Central nervous system tumors are extremely rare in the pediatric population and molecularly heterogeneous. Growing scientific research and clinical practice experience are improving medical therapies to increase survival outcomes and quality of life and reduce side effects. The 2019 Neurobiology of Disease in Children Symposium, held in conjunction with the 48th annual meeting of the Child Neurology Society, aimed to (1) describe molecular advances in tumor classification, (2) better understand the evolution of targeted therapies, and (3) more clearly formulate a treatment plan for patients. The article summarizes the presentations and includes an edited transcript of a panel discussion. [ABSTRACT FROM AUTHOR]

Epileptic encephalopathies encompass a heterogeneous group of epilepsy syndromes that manifest with cognitive, behavioral, and neurologic deficits, seizures that are often intractable and multiform, aggressive electroencephalographic paroxysmal activity, and sometimes early death. As more is learned about the etiologies and manifestations of epileptic encephalopathies, progress has been made toward better treatment options. However, there is still a great need for further randomized controlled trials and research to help create clinically effective therapies. The 2015 Neurobiology of Disease in Children symposium, held in conjunction with the 44th annual meeting of the Child Neurology Society, aimed to (1) describe the clinical concerns involving diagnosis and treatment, (2) review the current status of understanding in the pathogenesis of epileptic encephalopathy, (3) discuss clinical management and therapies for epileptic encephalopathy, and (4) define future directions of research. This article summarizes the presentations and includes an edited transcript of question-and-answer sessions. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder in children is a group of neurodevelopmental disorders characterized by difficulties with social communication and behavior. Growing scientific evidence in addition to clinical practice has led the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) to categorize several disorders into the broader category of autism spectrum disorder. As more is learned about how autism spectrum disorder manifests, progress has been made toward better clinical management including earlier diagnosis, care, and when specific interventions are required. The 2014 Neurobiology of Disease in Children symposium, held in conjunction with the 43rd annual meeting of the Child Neurology Society, aimed to (1) describe the clinical concerns involving diagnosis and treatment, (2) review the current status of understanding in the pathogenesis of autism spectrum disorder, (3) discuss clinical management and therapies for autism spectrum disorder, and (4) define future directions of research. The article summarizes the presentations and includes an edited transcript of question-and-answer sessions. [ABSTRACT FROM AUTHOR]

Mitochondrial medicine provides a metabolic perspective on the pathology of conditions linked with inadequate oxidative phosphorylation. Dysfunction in the mitochondrial machinery can result in improper energy production, leading to cellular injury or even apoptosis. Clinical presentations are often subtle, so clinicians must have a high index of suspicion to make early diagnoses. Symptoms could include muscle weakness and pain, seizures, loss of motor control, decreased visual and auditory functions, metabolic acidosis, acute developmental regression, and immune system dysfunction. The 2013 Neurobiology of Disease in Children Symposium, held in conjunction with the 42nd Annual Meeting of the Child Neurology Society, aimed to (1) describe accepted clinical phenotypes of mitochondrial disease produced from various mitochondrial mutations, (2) discuss contemporary understanding of molecular mechanisms that contribute to disease pathology, (3) highlight the systemic effects produced by dysfunction within the mitochondrial machinery, and (4) introduce current strategies that are being translated from bench to bedside as potential therapeutics. [ABSTRACT FROM AUTHOR]

The goal of this project was to promote bicycle helmet use via an inpatient educational program. We hypothesized that this program would increase bicycle helmet use. One hundred twenty inpatients with history of regular (>1 time per week) bicycle riding (mean age 10.0 ± 3.6 years; 67 males, 53 females; 57 whites, 59 blacks, 4 other) were randomized to treatment (n = 58) or control (n = 62) groups. All participants received a bicycle helmet. At 1 month, 50 (92.6%) of the intervention group and 48 (82.8%) of the control group wore a helmet every bike ride (P < .07). At 3 months, 50 (96.2%) of the intervention group and 44 (80%) of the controls wore a helmet with every bike ride (P < .03). The study proved feasible, requiring trained personnel to deliver the intervention. Providing a helmet without the intervention was effective in 80% to 83% of cases with respect to parental report of helmet wearing compliance. [ABSTRACT FROM AUTHOR]

The neuronal ceroid lipofuscinoses, collectively the most common neurodegenerative disorders of childhood, are primarily caused by an autosomal recessive genetic mutation leading to a lysosomal storage disease. Clinically, these diseases manifest at varying ages of onset, and associated symptoms include cognitive decline, movement disorders, seizures, and retinopathy. The underlying cell biology and biochemistry that cause the clinical phenotypes of neuronal ceroid lipofuscinoses are still being elaborated. The 2012 Neurobiology of Disease in Children Symposium, held in conjunction with the 41st Annual Meeting of the Child Neurology Society, aimed to (1) provide a survey of the currently accepted forms of neuronal ceroid lipofuscinoses and their associated genetic mutations and clinical phenotypes; (2) highlight the specific pathology of Batten disease; (3) discuss the contemporary understanding of the molecular mechanisms that lead to pathology; and (4) introduce strategies that are being translated from bench to bedside as potential therapeutics. [ABSTRACT FROM AUTHOR]

Childhood ataxia is characterized by impaired balance and coordination primarily because of cerebellar dysfunction. Friedreich ataxia, a form of childhood ataxia, is the most common multisystem autosomal recessive disease. Most of these patients are homozygous for the GAA repeat expansion located on the first intron of the frataxin gene on chromosome 9. Mutations in the frataxin gene impair mitochondrial function, increase reactive oxygen species, and trigger redistribution of iron in the mitochondria and cytosol. Targeted therapies for Friedreich ataxia are undergoing testing. In addition, a centralized database, patient registry, and natural history study have been launched to support clinical trials in Friedreich ataxia. The 2011 Neurobiology of Disease in Children symposium, held in conjunction with the 40th annual Child Neurology Society meeting, aimed to (1) describe clinical features surrounding Friedreich ataxia, including cardiomyopathy and genetics; (2) discuss recent advances in the understanding of the pathogenesis of Friedreich ataxia and developments of clinical trials; (3) review new investigations of characteristic symptoms; and (4) establish clinical and biochemical overlaps in neurodegenerative diseases and possible directions for future basic, translational, and clinical studies. [ABSTRACT FROM AUTHOR]

The article focuses on the recent advances in the diagnosis and management of cerebrovascular disease (CVD) in children. It says that new diagnostic imaging techniques help practitioners do an accurate and quick identification of CVD in children. It presents insights from doctor Gabrielle deVeber on the initial treatment and diagnosis of pediatric stroke and how it differs with adult stroke. Furthermore, the role of hypothermia as a treatment method for pediatric stroke is discussed.

Background: Despite evidence linking obesity to impaired immune function, little is known about the specific mechanisms. Because of emerging evidence that immune responses are epigenetically regulated, we hypothesized that DNA methylation changes are involved in obesity induced immune dysfunction and aimed to identify these changes. Method: We conducted a genome wide methylation analysis on seven obese cases and seven lean controls aged 14 to 18 years from extreme ends of the obesity distribution and performed further validation of six CpG sites from six genes in 46 obese cases and 46 lean controls aged 14 to 30 years. Results: In comparison with the lean controls, we observed one CpG site in the UBASH3A gene showing higher methylation levels and one CpG site in the TRIM3 gene showing lower methylation levels in the obese cases in both the genome wide step (P = 5 × 10-6 and P = 2 × 10-5 for the UBASH3A and the TRIM3 gene respectively) and the validation step (P = 0.008 and P = 0.001 for the UBASH3A and the TRIM3 gene respectively). Conclusions: Our results provide evidence that obesity is associated with methylation changes in blood leukocyte DNA. Further studies are warranted to determine the causal direction of this relationship as well as whether such methylation changes can lead to immune dysfunction. See commentary: http://www.biomedcentral.com/1741-7015/8/XX/abstract [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is characterized by degenerating lower motor neurons and an increased incidence of congenital bone fractures. Survival motor neuron (SMN) levels are significantly reduced due to deletions/mutations in the telomeric SMN1 gene in these patients. We utilized the Smn−/− SMN2 mouse model of SMA to determine the functional role for SMN in bone remodelling. µCT analysis of lumber vertebrae, tibia and femur bones from SMA mice revealed an osteoporotic bone phenotype. Histological analysis demonstrated a thin porous cortex of cortical bone and thin trabeculae at the proximal end of the growth plate in the vertebrae of SMA mice compared to wild-type mice. Histochemical staining of the vertebrae showed the presence of abundant activated osteoclasts on the sparse trabeculae and on the endosteal surface of the thin cortex in SMA mice. Histomorphometric analysis of vertebrae from SMA mice showed an increased number of osteoclasts. Serum TRAcP5b and urinary NTx levels were elevated, consistent with increased bone resorption in these mice. SMA mice showed a significant decrease in the levels of osteoblast differentiation markers, osteocalcin, osteopontin and osterix mRNA expression; however, there were no change in the levels of alkaline phosphatase expression compared to WT mice. SMA mouse bone marrow cultures revealed an increased rate of osteoclast formation (54%) and bone resorption capacity (46%) compared to WT mice. Pre-osteoclast cells from SMA mice showed constitutive up-regulation of RANK receptor signalling molecules critical for osteoclast differentiation. Our results implicate SMN function in bone remodelling and skeletal pathogenesis in SMA. Understanding basic mechanisms of SMN action in bone remodelling may uncover new therapeutic targets for preventing bone loss/fracture risk in SMA. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Cerebral palsy will affect nearly 10% of the 60 000 very low-birth-weight infants born in the United States in the next year, and an even greater percentage will display some form of permanent neurological impairment resulting from injury to the preterm brain. The 2008 Neurobiology of Disease in Children Symposium, held in conjunction with the 37th annual meeting of the Child Neurology Society, aimed to define current knowledge and to develop specific aims for future clinical, translational, and fundamental science. A complex interplay of both destructive and developmental forces is responsible for injury to the preterm brain. Advances in imaging and histology have implicated a variety of cell types, though preoligodendrocyte injury remains the focus. Research into different mechanisms of injury is facilitating new neuroprotective and rehabilitative interventions. A cooperative effort is necessary to translate basic research findings into clinically effective therapies and better care for these children. [ABSTRACT FROM AUTHOR]

Although significant advances have been made in treating malignant pediatric central nervous system tumors such as medulloblastoma, no effective therapy exists for diffuse pontine glioma or intramedullary spinal astrocytoma. Biology of these 2 tumors is poorly understood, in part because diffuse pontine gliomas are not treated surgically, and tumor specimens from intramedullary spinal astrocytomas are rare and minuscule. At the 2007 Neurobiology of Disease in Children Symposium, we presented evidence that malignant glioma behaviors, including antiapoptosis, invasiveness, and treatment resistance, are enhanced by hyaluronan, an extracellular glycosaminoglycan. We review the clinical course of pediatric intramedullary spinal astrocytoma and diffuse pontine glioma, and show expression of membrane proteins that interact with hyaluronan: CD44, extracellular matrix metalloproteinase inducer, and breast cancer resistance protein (BCRP/ABCG2). Furthermore, we describe novel animal models of these tumors for preclinical studies. These findings suggest that hyaluronan antagonism has potential therapeutic value in malignant central nervous system tumors. [ABSTRACT FROM AUTHOR]

Central nervous system tumors are the most common solid tumors in children. Many histological subtypes and biological variants exist. The 2007 Neurobiology of Disease in Children Symposium, held in conjunction with the 36th annual meeting of the Child Neurology Society, aimed to define current knowledge in the field and to develop specific aims for future clinical, translational, and fundamental science. Because of advances in structural and metabolic imaging, surgical technique, and combination therapies, the life expectancy of children with some of the most common tumors, such as cerebellar astrocytomas and medulloblastomas, has improved. Other common tumor types, including diffuse pontine gliomas and malignant embryonal tumors, still have a dismal prognosis. As novel therapies are identified for pediatric central nervous system tumors, long-term survival may be associated with considerable disability. A cooperative effort is crucial to early diagnosis and to translating basic research findings into safe, effective new treatments. [ABSTRACT FROM AUTHOR]

Ceruloplasmin (glycosylphosphatidylinositol-linked ferroxidase associated with normal astrocytes) can also be secreted by glioma cells, where its function is unknown. Ceruloplasmin is not only present in glioma cells and in human glioma specimens but also is enriched in highly malignant glioma stem-like cells. Hyaluronan is a large extracellular glycosaminoglycan that enhances malignant glioma behaviors by interacting with CD44 receptors and by downstream activation of signaling proteins and transporters associated with malignancy. We examined the relationship between hyaluronan and ceruloplasmin expression in glioma stem-like cells. Antagonism of hyaluronan interactions with short-fragment hyaluronan oligomers decreased ceruloplasmin expression in parental and stem-like glioma cells in vivo and in cell culture, implying thathyaluronan regulates ceruloplasmin expression. Further gain and loss-of-function studies are needed to fully define the relationship between hyaluronan and ceruloplasmin, and ceruloplasmin's effect on malignant behaviors. [ABSTRACT FROM AUTHOR]

A15 year-old girl presented to our emergency department with diziness, anorexia, nausea, and malaise. Clinical examination and magnetic resonance imaging studies showed characteristic features of multiple sclerosis. Surprisingly, a diagnostic lumbar puncture showed significant intracranial hypertension in addition to numerous oligoclonal bands, elevated immunoglobolin G index and immunoglobulin G/albumin ratio in the cerebrospinal fluid. It is proposed that a large burden of active demyelinating disease may cause increased intracranial pressure, thus providing an additional sound rationale for prompt therapeutic administration of intravenous high-dose steroids. [ABSTRACT FROM AUTHOR]

Evidence-based medicine practices are widely touted in medicine, although their adoption by busy practitioners is problematic and cumbersome. In this study, we examined published evidence underpinning 2 relevant clinical management questions in pediatric epilepsy: when to initiate an antiepileptic drug and when to prescribe the ketogenic diet. We surveyed practicing child neurologists who were attending their national meeting to determine whether their current practices aligned with the evidence. Clinical studies were evaluated using the Oxford Scale, which was adopted by the American Academy of Neurology. In addition, using a novel rating approach, we examined the impact on overall recommendations by scoring results from studies refuting a given practice. The data show that child neurologists' attitudes firmly adhere to evidence-based practice on when to initiate treatment with an antiepileptic drug, but not on when to prescribe the ketogenic diet. It seems clear that important differences in attitudes of practitioners toward different management strategies for epilepsy cannot be explained only by differences in the evidence. Safety and efficacy data suggest that the ketogenic diet should be more widely adopted as a management strategy in pediatric epilepsy. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy is the second most common fatal childhood disorder. Core clinical features include muscle weakness caused by degenerating lower motor neurons and a high incidence of bone fractures and hypercalcemia. Fractures further compromise quality of life by progression of joint contractures or additional loss of motor function. Recent observations suggest that bone disease in spinal muscular atrophy may not be attributed entirely to lower motor neuron degeneration. The presence of the spinal muscular atrophy disease-determining survival motor neuron gene (SMN), SMN expression, and differential splicing in bone-resorbing osteoclasts was recently discovered. Its ubiquitous expression and the differential expression of splice variants suggest that SMN has specific roles in hone cell function. SMN protein also interacts with osteoclast stimulatory factor. Mouse models of human spinal muscular atrophy disease suggest a potential role of SMN protein in skeletal development. Dual energy x-ray absorptiometry analysis demonstrated a substantial decrease in total bone area and poorly developed caudal vertebra in the mouse model. These mice also had pelvic bone fractures. Studies delineating SMN signaling mechanisms and gene transcription in a cell- specific manner will provide important molecular insights into the pathogenesis of bone disease in children with spinal muscular atrophy Moreover, understanding bone remodeling in spinal muscular atrophy may lead to novel therapeutic approaches to enhance skeletal health and quality of life. This article reviews the skeletal complications associated with spinal muscular atrophy and describes a functional role for SMN protein in osteoclast development and bone resorption activity. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder that affects the motor neurons responsible for movement of the proximal muscles of the trunk and body. To date, the disease can be classified into 3 main categories based on severity and age of onset. During the October 18th symposium held in Pittsburgh, Pennsylvania, researchers met to (1) describe current diagnostic strategies, (2) discuss recent thoughts on pathogenesis, (3) review current therapies and clinical trials, and (4) define future research directions. In her opening remarks, Dr Story Landis, director of the National Institute of Neurological Disorders and Stroke, emphasized the degree to which the Neurobiology of Disease in Children conference series has broadened awareness of the many rare diseases affecting children, not only through the advancement of research but also by educating practitioners about diagnostic strategies. Dr Landis also discussed the role this conference may play in fostering research that seeks to develop a single mechanism of therapy for spinal muscular atrophy. She also discussed the current funding situation at the National Institutes of Health and addressed the crucial function of volunteer research organizations that sponsor research in further improving management of this condition. This article summarizes the presentations and includes the verbatim edited transcript of question-and-answer sessions. [ABSTRACT FROM AUTHOR]

Two months following an Epstein-Barr virus infection, a 17-year-old white female presented with seizures, intermit- tent visual changes, and altered mental status. Magnetic resonance imaging showed white matter changes of acute disseminated encephalomyelitis with a predilection for posterior cerebral artery distributions but without radiological evidence of arteritis. Epstein-Barr virus titers and polymerase chain reaction analysis results for the virus were consistent with postinfectious acute disseminated encephalomyelitis. The symptoms and signs improved following treatment with high-dose corticosteroids and intravenous immunoglobulin. Although Epstein-Barr virus can cause acute viral encephalomyelitis, the authors report a case of acute disseminated encephalomyelitis months after acute Epstein-Barr virus infection. [ABSTRACT FROM AUTHOR]

Tourette syndrome is a neuropsychiatric condition characterized by multiple motor tics and at least one vocal tic that persist for more than 1 year. On September 28, 2005, a symposium was held to (1) describe current diagnostic strategies, (2) discuss recent thoughts on pathogenesis, (3) review current therapies and clinical trials, and (4) define future research directions in Tourette syndrome. In her opening remarks, Dr Story Landis, director of the National Institute of Neurological Disorders and Stroke, emphasized the influence that this conference series has not only on the advancement of research but also on the education of practicing clinicians. Dr Landis also discussed the role of the Institute and the crucial function of volunteer research organizations in funding research to further improve the management of this condition. This article summarizes the presentations and includes the verbatim edited transcript of question and answer sessions. [ABSTRACT FROM AUTHOR]

This study provides descriptive information in the areas of oromotor abilities and communication to better understand the spectrum of disability in individuals with Joubert syndrome. Participants included 21 individuals with the diagnosis of Joubert syndrome (mean age 10.45 years). Participants completed oromotor and receptive language measures. In addition, all of the participants' speech and gesture communication from a narrative task was coded and analyzed from videotape. Caregivers reported the participants' level of fine and gross motor function. The results show that individuals with Joubert syndrome exhibit a distinct oromotor pattern consistent with verbal and lingual apraxias. Despite significant motor skills deficits and oculomotor apraxia, persons with Joubert syndrome produced gestures when communicating, and those whose speech was less intelligible used a higher rate of gesture compared with those with greater verbal output. These findings suggest a new form of apraxia not previously described in the condition and are consistent with previous research that suggests that persons with Joubert syndrome typically do not exhibit classic symptoms of autism spectrum disorder. [ABSTRACT FROM AUTHOR]

Background: Pluripotent mouse embryonic stem (ES) cells can be induced in vitro to become neural progenitors. Upon transplantation, neural progenitors migrate toward areas of damage and inflammation in the CNS. We tested whether undifferentiated and neuralized mouse ES cells migrate toward media conditioned by glioma cell lines (C6, U87 & N1321) or Stem Cell Factor (SCF). Results: Cell migration assays revealed selective migration by neuralized ES cells to conditioned media as well as to synthetic SCF. Migration of undifferentiated ES cells was extensive, but not significantly different from that of controls (Unconditioned Medium). RT-PCR analysis revealed that all the three tumor cell lines tested synthesized SCF and that both undifferentiated and neuralized ES cells expressed c-kit, the receptor for SCF. Conclusion: Our results demonstrate that undifferentiated ES cells are highly mobile and that neural progenitors derived from ES cells are selectively attracted toward factors produced by gliomas. Given that the glioma cell lines synthesize SCF, SCF may be one of several factors that contribute to the selective migration observed. [ABSTRACT FROM AUTHOR]

Desmoplastic infantile ganglioglioma is a rare World Health Organization (WHO) grade I tumor commonly arising in early infancy and usually presenting with both solid and cystic components. We report a case of a large midline-enhancing desmoplastic infantile ganglioglioma in which newly formed cysts in communication with lateral ventricles contained highly proteinaceous fluid. Proteomic analysis of the fluid showed three proteins not normally found in cerebrospinal fluid. Immunohistochernical analysis of the tumor sample showed that the desmoplastic infantile ganglioglioma produced a high concentration of ceruloplasmin, which probably accounts for most of the 30- to 40-fold increase in protein compared with normal cerebrospinal fluid. To our knowledge, this is the first report of ceruloplasmin secretion by a brain tumor, and ongoing studies on the mechanism might yield novel approaches to reducing cyst production and protein content in an otherwise stable solid tumor. [ABSTRACT FROM AUTHOR]

This article reports that on October 13, 2004, a symposium was held to determine how research findings enhance clinical practice for practitioners working with persons who have Rett syndrome and to identify the research needed to improve diagnostic accuracy and develop safe, effective therapies. Participants described diagnostic strategies, pathogenesis, therapies, and clinical trials and defined future research directions. Rett syndrome is a progressive neuro developmental disorder characterized by cognitive impairment, deficits in communication, stereotypic movements, and growth failure.

The article reports on the symposium on tuberous sclerosis complex, which was the third in a series of five symposia titled "Neurobiology of Disease in Children." The conference was supported by the National Institute of Neurological Disorders and Stroke (NINDS), the Tuberous Sclerosis Alliance, and the Child Neurology Society. Dr Maria outlined the goals for the series. Two of them were to identify research findings that have the potential to enhance clinical practice in child neurology and to identify future research needed to improve diagnostic accuracy and to develop safe and effective therapies.

Joubert syndrome is an autosomal recessive disorder characterized by hypotonia, ataxia, developmental delay, and a distinctive hindbrain malformation involving the cerebellum and brain stem, visualized radiographically on magnetic resonance imaging (MRI) as the "molar tooth sign." In postmortem brains from subjects with Joubert syndrome, there is an apparent absence of decussation of both corticospinal and superior cerebellar tracts, although the functional significance has not been elucidated. We sought to explore the cerebral and cerebellar activation pattern elicited by finger topping in an adolescent with Joubert syndrome and in a normal control subject using functional MRI. In contrast to the typical highly lateralized activation seen in our control subject, the subject with Joubert syndrome demonstrated striking bilateral activation of the sensorimotor and cerebellar cortex. Although our functional MRI data do not indicate a clear absence of decussation, the abnormal activation pattern observed suggests altered brain functional organization in relation to anatomic differences. Malformation of the hindbrain could result in recruitment of alternative pathways, similar to what has been observed following ischémie injury to the developing or mature central nervous system. (J Child Neural 2004;19:214-218). [ABSTRACT FROM AUTHOR]

Leukodystrophies comprise a heterogeneous group of disorders characterized by destruction or failed development, of central white matter. On October 9, 2002, a symposium was held to determine how research findings enhance clinical practice and to identify research needed to improve diagnostic accuracy and develop safe, effective therapies. Several gross neuropathologic features are common to all leukodystrophies, including reduced brain weight, optic atrophy, ventriculomegaly, and atrophy of the corpus callosum. Common light microscopic features include reduced myelin signing, loss of oligodendrocytes, relative sparing of axons despite marked axonal loss, macrophages with myelin debris, reactive astrocytosis in the early stagesand fibrillary astrogliosis and sclerosis in the late stages. An absence of inflammatory cells is associated with all leukodystrophies except adrenoleukodystrophy.

Key features of Joubert syndrome include development delay, hypotonia, hyperpnea and apnea, oculomotor apraxia, and the presence of the molar tooth sign on axial imaging through the brainstem isthmus—the junction of the pons and mesencephalon. Interestingly, 1 in 10 patients with Joubert syndrome has abnormal cerebrospinal fluid collections misdiagnosed as Dandy-Walker variants. Because of important differences in patient management, genetic counseling, and prognosis between these conditions, we undertook a study to determine if the brainstem isthmus is normal in Dandy-Walker syndrome. Using standard landmarks, we evaluated development of the isthmus in normal subjects and in subjects with Joubert syndrome and Dandy-Walker syndrome. Four of five brainstem measures increased with age in normal subjects. In subjects with Joubert syndrome, the depth and length of the interpenduncular fossa were increased, and the width of the isthmus was decreased. In subjects with Dandy-Walker syndrome, the width of the brainstem isthmus was normal, and the molar tooth sign was absent. Although the pons can be hypoplastic in Dandy-Walker syndrome, we conclude that the pontomesencephalic junction is normal. Thus, the molar tooth sign can effectively distinguish between Joubert and Dandy-Walker syndromes. Genetic heterogeneity or epigenetic factors may account for abnormal cerebrospinal fluid collections in some cases of Joubert syndrome. [ABSTRACT FROM AUTHOR]

We report the case of a right-handed adolescent male with a history of a pituitary germinoma. Developmental history was reportedly unremarkable and a conservative estimate of the level of cognitive function before his illness, based on reported academic performance, places this individual in the low average range of intellectual ability. Subsequent resection of the tumor resulted in a lesion in the right mesial basal orbitofrontal region involving the tuber cinereum, lamina terminalis, gyrus rectus, olfactory gyrus and diagonal band of Broca. Initial evaluation revealed profoundly impaired memory for both verbal and visual–spatial information. Follow-up evaluations at 4, 24 and 42 months further substantiated profound impairments in memory for both verbal and visual–spatial information, as well as behavioral problems involving emotional lability and disinhibition. Given the location of this lesion, it is suggested that this patient’s profound deficits in memory are due to disruption of both the Papez circuit and the lateral limbic circuit, which are known to be involved in the memory system. [ABSTRACT FROM AUTHOR]