James Barkovich

Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome

Objective: To define the clinical, radiologic, and genetic features of periventricular heterotopia (PH) with Ehlers-Danlos syndrome (EDS). Methods: Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region. Results: The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected. Conclusion: These results suggest that the Ehlers-Danlos variant of periventricular heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.

Radiologic Classification of Brain Stem Tumors: Correlation of Magnetic Resonance Imaging Appearance with Clinical Outcome

Although tumors of the brain stem have traditionally been classified as a single entity, these tumors are increasingly being recognized as a heterogeneous group, with some subgroups having better prognoses for long-term survival. Although several systems for classification of brain stem tumors have been proposed, none have been based on data derived from contrast-enhanced magnetic resonance (MR) imaging. In this review, we present a classification scheme based on our review of the literature and of the MR scans of 64 patients with brain stem tumors. In addition, we assess the contribution of gadolinium to the classification of brain stem tumors and correlate the various tumor subtypes, based on MR appearance, with prognosis. Our results suggest that the most important factor in determining prognosis based on MR characteristics is whether the tumor is diffuse or focal. Focal tumors have an excellent prognosis regardless of the site of tumor origin. Diffuse tumors of the mesencephalon and pons have a significantly poorer prognosis than focal tumors (p = 0.0013), with diffuse pontine tumors having the worst prognosis. Differentiation of diffuse and focal medullary tumors was difficult, possibly explaining the lack of significant difference in the survival of patients with diffuse versus focal medullary tumors. The presence or absence of enhancement after the administration of paramagnetic contrast has no significant relation with outcome, overall or within specific tumor subgroups.

Pulmonary, Gonadal, and Central Nervous System Status after Bone Marrow Transplantation for Sickle Cell Disease

We conducted a prospective, multicenter investigation of human-leukocyte antigen (HLA) identical sibling bone marrow transplantation (BMT) in children with severe sickle cell disease (SCD) between 1991 and 2000. To determine if children were protected from complications of SCD after successful BMT, we extended our initial study of BMT for SCD to conduct assessments of the central nervous system (CNS) and of pulmonary function 2 or more years after transplantation. In addition, the impact on gonadal function was studied. After BMT, patients with stroke who had stable engraftment of donor cells experienced no subsequent stroke events after BMT, and brain magnetic resonance imaging (MRI) exams demonstrated stable or improved appearance. However, 2 patients with graft rejection had a second stroke after BMT. After transplantation, most patients also had unchanged or improved pulmonary function. Among the 11 patients who had restrictive lung changes at baseline, 5 were improved and 6 had persistent restrictive disease after BMT. Of the 2 patients who had obstructive changes at baseline, 1 improved and 1 had worsened obstructive disease after BMT. There was, however, significant gonadal toxicity after BMT, particularly among female recipients. In summary, individuals who had stable donor engraftment did not experience sickle-related complications after BMT, and were protected from progressive CNS and pulmonary disease.

A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects

Abstract.TDGF1(CRIPTO) is an EGF-CFC family member and an obligate co-receptor involved in NODAL signaling, a developmental program implicated in midline, forebrain, and left-right axis development in model organisms. Previous studies of CFC1(CRYPTIC), another member of the EGF-CFC family, demonstrated that normal function of this protein is required for proper laterality development in humans. Here we identify a mutation in the conserved CFC domain of TDGF1 in a patient with midline anomalies of the forebrain. The mutant protein is inactive in a zebrafish rescue assay, indicating a role for TDGF1 in human midline and forebrain development.

Etiological heterogeneity of familial periventricular heterotopia and hydrocephalus.

Periventricular heterotopia (PH) represents a neuronal migration disorder that results in gray matter nodules along the lateral ventricles beneath an otherwise normal appearing cortex. While prior reports have shown that mutations in the filamin A (FLNA) gene can cause X-linked dominant PH, an increasing number of studies suggest the existence of additional PH syndromes. Further classification of these cortical malformation syndromes associated with PH allows for determination of the causal genes. Here we report three familial cases of PH with hydrocephalus. One pedigree has a known FLNA mutation with hydrocephalus occurring in the setting of valproic acid exposure. Another pedigree demonstrated possible linkage to the Xq28 locus including FLNA, although uncharacteristically a male was affected and sequencing of the FLNA gene in this individual revealed no mutation. However, in the third family with an autosomal mode of inheritance, microsatellite analysis ruled out linkage with the FLNA gene. Routine karyotyping and fluorescent in situ hybridization using BAC probes localized to FLNA also showed no evidence of genomic rearrangement. Western blot analysis of one of the affected individuals demonstrated normal expression of the FLNA protein. Lastly, sequencing of greater than 95% of the FLNA gene in an affected member failed to demonstrate a mutation. In conclusion, these findings demonstrate the etiological heterogeneity of PH with hydrocephalus. Furthermore, there likely exists an autosomal PH gene, distinct from the previously described X-linked and autosomal recessive forms. Affected individuals have severe developmental delay and may have radiographic findings of hydrocephalus.

De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome.

KBG syndrome is a rare, autosomal dominant disorder caused by mutations or deletions leading to haploinsufficiency for the Ankrin Repeating Domain‐Containing protein 11 (ANKRD11) at chromosome 16q24.3. Kabuki syndrome is caused by mutations or deletions of lysine (K)‐specific methyltransferase 2D (KMT2D) and lysine‐specific methylase 6A (KDM6A). We report on a male with developmental delays, cleft palate, craniofacial dysmorphism, hypotonia, and central nervous system anomalies including diminished white matter with thinning of the corpus callosum. Exome sequencing revealed a de novo mutation in ANKRD11, c.2606_2608delAGA, predicting p.Lys869del and an additional, de novo mutation, c.2353T>C, predicting p.Tyr785His in KDM1A, a gene not previously associated with a human phenotype. We describe this child as the first report of a deleterious sequence variant in KDM1A and hypothesize that his phenotype resulted from the combined effect of both mutations.

Developmental progress and creatine restoration upon long-term creatine supplementation of a patient with arginine:glycine amidinotransferase deficiency

BACKGROUND Arginine:glycineamidinotransferase (AGAT/GATM) deficiency has been described in 9 patients across 4 families. Here we describe the clinical outcome and response to creatine supplementation in a patient of the second family affected with AGAT deficiency-a 9-year-old girl. PATIENT AND METHODS Delayed motor milestones were noticed from 4 months of age and at 14 months moderate hypotonia, developmental delay and failure to thrive. Laboratory studies revealed low plasma creatine as well as extremely low levels of guanidinoacetic acid in urine and plasma. Proton magnetic resonance spectroscopy (MRS) of the brain showed absence of creatine. DNA sequence analysis revealed a homozygous mutation (c.484+1G>T) in the AGAT/GATM gene. AGAT activity was not detectable in lymphoblasts and RNA analysis revealed a truncated mRNA (r.289_484del196) that is degraded via Nonsense Mediated Decay. At 16 months, Bayleys Infant Development Scale (BIDS) showed functioning at 43% of chronologic age. Oral creatine supplementation (up to 800 mg/kg/day) was begun. RESULTS At age 9 years she demonstrated advanced academic performance. Partial recovery of cerebral creatine levels was demonstrated on MRS at 25 months of age. Brain MRS at 40 months of age revealed a creatine/NAA ratio of about 80% of that in age-matched controls. CONCLUSIONS 8 years post initiation of oral creatine supplementation, patient demonstrates superior nonverbal and academic abilities, with average verbal skills. We emphasize that early diagnosis combined with early treatment onset of AGAT deficiency may lead to improvement of developmental outcome.

Selected Indications for and Applications of Magnetic Resonance Angiography in Children

The purpose of this study was to investigate the efficacy and practicality of magnetic resonance angiography (MRA) in evaluating pediatric cerebrovascular disorders. A retrospective evaluation was performed of MR angiograms in 20 pediatric patients with cerebrovascular pathology. When appropriate, comparisons were made with duplex ultrasonography or conventional catheter angiography. MRA accurately assessed the patency of carotid reanastomoses in 8 babies who had previously undergone extracorporeal membrane oxygenation (ECMO). In 6 patients with moyamoya syndrome, MRA accurately evaluated stenotic intracranial carotid and circle of Willis arteries and progressive enlargement of the superficial temporal and middle cerebral arteries after revascularization procedures, and thus obviated the need for sequential angiograms. Thrombi and emboli were identified in 4 of 5 patients with symptoms and imaging evidence of an acute stroke. Two-dimensional time-of-flight MR venograms, acquired in both axial and coronal planes, were useful for preoperative venous mapping in a patient with an occipital encephalocele and detecting venoocclusive disease. MRA provided diagnostically useful information in a spectrum of pediatric cerebrovascular disorders. It can be used as the initial vascular imaging modality for patients with imaging evidence of acute cerebrovascular event, to evaluate progression of chronic vasoocclusive disease, to evaluate vessel patency following intracranial revascularization surgery, and for visualization of the venous circulation.

Periventricular heterotopia with white matter abnormalities associated with 6p25 deletion

Periventricular Heterotopia With White Matter Abnormalities Associated With 6p25 Deletion Elena Cellini, Vittoria Disciglio, Francesca Novara, James A. Barkovich, Maria Antonietta Mencarelli, Joussef Hayek, Alessandra Renieri, Orsetta Zuffardi, and Renzo Guerrini* Child Neurology Unit, Children’s Hospital A. Meyer—University of Florence, Florence, Italy Medical Genetics, University of Siena, Siena, Italy Department of Molecular Medicine, University of Pavia, Pavia, Italy Department of Radiology, University of California, San Francisco, California Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy Child Neurology Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy Neurological Clinic C. Mondino, Pavia, Italy IRCCS Stella Maris, Pisa, Italy

Maldevelopment of the cerebral cortex in the surgically induced model of myelomeningocele: implications for fetal neurosurgery.

PURPOSE The purpose of this study is to describe the malformations of cortical development detected in a model of cerebrospinal fluid (CSF) leakage and the influence of surgical closure technique on developmental outcome. METHODS Using a surgically induced model of myelomeningocele (MMC) in sheep, we studied the effects of different repair methods upon the development of hydrocephalus, the presence of the Arnold-Chiari II (AC-II) hindbrain malformation, and cerebral cortex developmental anomalies using gross and histologic (hematoxylin and eosin and Nissl staining) study techniques. RESULTS A malformed cerebral cortex, including 2 anomalous cortical folding patterns, and lower brain weights were observed in the untreated animals. Hydrocephalus and AC-II malformations were also found in this group. These malformations were mostly prevented with prenatal 2-layer closure. CONCLUSIONS Cerebral cortical malformations and hydrocephalus, in addition to the AC-II hindbrain malformation, are disorders caused by fetal CSF leakage. These malformations were prevented with the technique of MMC closure currently used in humans. Both observations magnify the importance of the second hit associated with chronic CSF leakage, in addition to the primary defect causing the MMC, in the development of the malformation complex.