Glenda Hendson

Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants.

The major form of magnetic resonance imaging–defined white matter injury (WMI) comprises diffuse lesions where the burden of small necrotic foci (microscopic necrosis) is poorly defined. We hypothesized that myelination failure associated with diffuse WMI involves an aberrant injury response linked to arrested preoligodendrocyte (preOL) maturation in reactive astrocyte‐rich lesions.

Hemispheric Surgery in Children with Refractory Epilepsy: Seizure Outcome, Complications, and Adaptive Function

Summary:  Purpose: To describe seizure control, complications, adaptive function and language skills following hemispheric surgery for epilepsy.

Murine MPS I: insights into the pathogenesis of Hurler syndrome

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease resulting from deficiency of the lysosomal enzyme α‐L‐iduronidase. A murine model which shows complete deficiency in α‐L‐iduronidase activity has been developed and shows phenotypic features similar to severe MPS I in humans. Here we report on the long‐term clinical, biochemical, and pathological course of MPS I in mice with emphasis on the skeletal and central nervous system (CNS) manifestations. Affected mice show a progressive clinical course with the development of coarse features, altered growth characteristics and a shortened life span. Progressive lysosomal accumulation is seen in all tissues. Skeletal manifestations represent the earliest clinical finding in MPS I mice with histologic analysis of growth plate and cortical bone revealing evidence that significant early pathology is present. Analysis of the CNS has revealed the novel finding of progressive neuronal loss within the cerebellum. In addition, brain tissue from MPS I mice shows increased levels of GM2 and GM3 gangliosides. This murine model clearly shows phenotypic and pathologic features which mimic those seen in severe human MPS I and should be an invaluable tool for the study of the pathogenesis of generalized storage disorders.

Intracystic bleomycin therapy for craniopharyngioma in children: the Canadian experience.

Surgical removal and radiation therapy are associated with significant risk for morbidity in the pediatric population with craniopharyngioma. Intracystic therapies have been utilized in some centers to potentially decrease morbidity associated with cystic craniopharyngioma. The aim of the study was to review the Canadian experience with intracystic bleomycin therapy (ICB).

Tuberous sclerosis complex: a review of the management of epilepsy with emphasis on surgical aspects

ObjectiveTo review the management of epilepsy in patients with tuberous sclerosis complex (TSC) with an emphasis on surgical aspects, neuropathology, and pathogenesis.MethodsReview of the literature and presentation of the authors’ experience of surgery for refractory epilepsy in patients with TSC.ResultsTSC is a multisystem genetic disorder with variable phenotypic expression. TSC results from a mutation in the TSC1 gene on chromosome 9, which codes for hamartin, or in the TSC 2 gene on chromosome 16 which codes for tuberin. The majority of the patients have TSC as a result of spontaneous genetic mutations while in one-third of the patients, the disorder is inherited in an autosomal dominant manner. Epilepsy is the most common neurological complication, and up to 80–90% of individuals with TSC develop epilepsy at some point in their lifetime. The onset of epilepsy is typically in early childhood. Infantile spasms are a very common early seizure type although partial seizures may occur. Developmental delay, intellectual impairment, autism, behavioral problems, and neuropsychiatric disorders occur commonly in individuals with TSC and may be associated with poorly controlled epilepsy. Antiepileptic drugs are the first-line management for epilepsy but the ketogenic diet, resection of one or more tubers, corpus callosotomy, and vagus nerve stimulation are other therapeutic options for individuals with poorly controlled epilepsy.

Postvaricella angiopathy: report of a case with pathologic correlation

Varicella is a common childhood illness, and central nervous system complications occur frequently. Delayed angiopathy has been described, although there are few reports of clinicopathologic correlation. A previously well 4-year-old male is presented. He suffered varicella 2 months before presentation with extensive right middle cerebral artery (MCA) territory infarction. Cerebral angiography demonstrated an isolated 89% stenosis of the right proximal MCA. He developed cerebral edema refractory to medical treatment and progressed to transtentorial herniation. Right frontal temporoparietal craniotomies were performed with evacuation of infarcted brain tissue. Pathologic studies revealed small vessel vasculitis with lymphocytic infiltration of the vessel wall. Areas of demyelination were present within the white matter. Polymerase chain reaction for varicella was negative on brain tissue. Postvaricella angiopathy, although an uncommon complication, may affect both small and large blood vessels, with catastrophic results.

Hypomorphic Temperature-Sensitive Alleles of NSDHL Cause CK Syndrome

CK syndrome (CKS) is an X-linked recessive intellectual disability syndrome characterized by dysmorphism, cortical brain malformations, and an asthenic build. Through an X chromosome single-nucleotide variant scan in the first reported family, we identified linkage to a 5 Mb region on Xq28. Sequencing of this region detected a segregating 3 bp deletion (c.696_698del [p.Lys232del]) in exon 7 of NAD(P) dependent steroid dehydrogenase-like (NSDHL), a gene that encodes an enzyme in the cholesterol biosynthesis pathway. We also found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS. These two mutations, which alter protein folding, show temperature-sensitive protein stability and complementation in Erg26-deficient yeast. As described for the allelic disorder CHILD syndrome, cells and cerebrospinal fluid from CKS patients have increased methyl sterol levels. We hypothesize that methyl sterol accumulation, not only cholesterol deficiency, causes CKS, given that cerebrospinal fluid cholesterol, plasma cholesterol, and plasma 24S-hydroxycholesterol levels are normal in males with CKS. In summary, CKS expands the spectrum of cholesterol-related disorders and insight into the role of cholesterol in human development.

Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?

BackgroundArteriosclerosis and emphysema develop in individuals with Schimke immuno-osseous dysplasia (SIOD), a multisystem disorder caused by biallelic mutations in SMARCAL1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1). However, the mechanism by which the vascular and pulmonary disease arises in SIOD remains unknown.MethodsWe reviewed the records of 65 patients with SMARCAL1 mutations. Molecular and immunohistochemical analyses were conducted on autopsy tissue from 4 SIOD patients.ResultsThirty-two of 63 patients had signs of arteriosclerosis and 3 of 51 had signs of emphysema. The arteriosclerosis was characterized by intimal and medial hyperplasia, smooth muscle cell hyperplasia and fragmented and disorganized elastin fibers, and the pulmonary disease was characterized by panlobular enlargement of air spaces. Consistent with a cell autonomous disorder, SMARCAL1 was expressed in arterial and lung tissue, and both the aorta and lung of SIOD patients had reduced expression of elastin and alterations in the expression of regulators of elastin gene expression.ConclusionsThis first comprehensive study of the vascular and pulmonary complications of SIOD shows that these commonly cause morbidity and mortality and might arise from impaired elastogenesis. Additionally, the effect of SMARCAL1 deficiency on elastin expression provides a model for understanding other features of SIOD.

Spontaneous regression of septum pellucidum/forniceal pilocytic astrocytomas—possible role of Cannabis inhalation

IntroductionSpontaneous regression of pilocytic astrocytoma after incomplete resection is well recognized, especially for cerebellar and optic pathway tumors, and tumors associated with Neurofibromatosis type-1 (NF1). The purpose of this report is to document spontaneous regression of pilocytic astrocytomas of the septum pellucidum and to discuss the possible role of cannabis in promoting regression.Case reportWe report two children with septum pellucidum/forniceal pilocytic astrocytoma (PA) tumors in the absence of NF-1, who underwent craniotomy and subtotal excision, leaving behind a small residual in each case. During Magnetic Resonance Imaging (MRI) surveillance in the first three years, one case was dormant and the other showed slight increase in size, followed by clear regression of both residual tumors over the following 3-year period. Neither patient received any conventional adjuvant treatment. The tumors regressed over the same period of time that cannabis was consumed via inhalation, raising the possibility that the cannabis played a role in the tumor regression.ConclusionWe advise caution against instituting adjuvant therapy or further aggressive surgery for small residual PAs, especially in eloquent locations, even if there appears to be slight progression, since regression may occur later. Further research may be appropriate to elucidate the increasingly recognized effect of cannabis/cannabinoids on gliomas.

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.