Publications by authors named "Jean Michaud"

57 Publications

Histologic Correlates of Molecular Group 4 Pediatric Medulloblastoma: A Retrospective Canadian Review.

Pediatr Dev Pathol 2021 Mar 22:10935266211001986. Epub 2021 Mar 22.

Department of Pathology and Laboratory Medicine, Division of Anatomical Pathology, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

Introduction: The World Health Organization currently classifies medulloblastoma (MB) into four molecular groups (WNT, SHH, Group 3 and Group 4) and four histologic subtypes (classic, desmoplastic nodular, MB with extensive nodularity, and large cell/anaplastic). "Classic" MB is the most frequent histology, but unfortunately it does not predict molecular group or patient outcome. While MB may exhibit additional histologic features outside of the traditional WHO subtypes, the clinical significance of such features, in a molecular context, is unclear.

Methods: The clinicopathologic features of 120 pediatric MB were reviewed in the context of NanoString molecular grouping. Each case was evaluated for five ancillary histologic features, including: nodularity without desmoplasia (i.e., "biphasic", B-MB), rhythmic palisades, and focal anaplasia. Molecular and histological features were statistically correlated to clinical outcome using Chi-square, log-rank, and multivariate Cox regression analysis.

Results: While B-MB (N = 32) and rhythmic palisades (N = 12) were enriched amongst non-WNT/SHH MB (especially Group 4), they were not statistically associated with outcome. In contrast, focal anaplasia (N = 12) was not associated with any molecular group, but did predict unfavorable outcome.

Conclusion: These data nominate B-MB as a surrogate marker of Groups 3 and particularly 4 MB, which may earmark a clinically significant subset of cases.
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http://dx.doi.org/10.1177/10935266211001986DOI Listing
March 2021

SMN Depleted Mice Offer a Robust and Rapid Onset Model of Nonalcoholic Fatty Liver Disease.

Cell Mol Gastroenterol Hepatol 2021 Feb 2. Epub 2021 Feb 2.

Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada; Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada. Electronic address:

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of survival motor neuron (SMN) depletion (Smn mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. The rapid onset of fatty liver in Smn mice provides an opportunity to identify molecular markers of NAFLD. Here, we investigated whether Smn mice display typical features of NAFLD/nonalcoholic steatohepatitis (NASH).

Methods: Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used.

Results: The Smn mice develop microvesicular steatohepatitis within 2 weeks, a feature prevented by AAV9-SMN gene therapy. Although fibrosis is not overtly apparent in histologic sections of the liver, there is molecular evidence of fibrogenesis and presence of stellate cell activation. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in hepatic dysfunction in protein output, complement, coagulation, iron homeostasis, and insulin-like growth factor-1 metabolism. The NAFLD phenotype is likely due to non-esterified fatty acid overload from peripheral lipolysis subsequent to hyperglucagonemia compounded by reduced muscle use and insulin resistance. Despite the low hepatic mitochondrial content, isolated mitochondria show enhanced β-oxidation, likely as a compensatory response, resulting in the production of reactive oxygen species. In contrast to typical NAFLD/NASH, the Smn mice lose weight because of their associated neurological condition (spinal muscular atrophy) and develop hypoglycemia.

Conclusions: The Smn mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early-onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations.
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http://dx.doi.org/10.1016/j.jcmgh.2021.01.019DOI Listing
February 2021

Spinal muscular atrophy type III complicated by spinal superficial siderosis: a case report with molecular and neuropathological findings.

Acta Neuropathol Commun 2020 11 9;8(1):188. Epub 2020 Nov 9.

Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada.

Spinal muscular atrophy (SMA) is largely linked to deletion or mutation of the Survival motor neuron 1 (SMN1) gene located on chromosome 5q13. Type III (Kugelberg-Welander disease) is the mildest childhood form and patients may become ambulatory and have a normal life expectancy. We report the clinical history and morphological findings of a 55-year-old woman who began to experience motor problems at the age of two. She was never fully ambulatory, and her severe scoliosis required the insertion of surgical rod at age 19. Unexpectedly, around 35 years of age, she began to experience sensory symptoms best characterized as a myelo-radiculo-neuropathy with pain as the dominant symptom. Investigations never clarified the etiology of these symptoms. Molecular confirmation of SMA type III was done post-mortem. Neuropathological examination showed classic changes of lower motor neuron neurodegeneration, in line with those reported in the single molecularly confirmed case published so far, and with findings in rare cases reported prior to the discovery of the gene defect. A key autopsy finding was the presence of a severe superficial siderosis of the lower half of the spinal cord. In recent years, the concept of duropathy was put forward, associating superficial siderosis of the spinal cord with various spinal abnormalities, some of which were present in our patient. The presence of significant hemosiderin deposits in the spinal cord and sensory nerve roots with associated tissue and axonal damage provide a plausible explanation for the unexpected sensory symptomatology in this mild lower motor neurodegeneration.
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http://dx.doi.org/10.1186/s40478-020-01063-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653749PMC
November 2020

Inhaled Solvent Abuse Mimicking Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

Child Neurol Open 2020 Jan-Dec;7:2329048X20934914. Epub 2020 Jun 19.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ontario, Canada.

Exposure to n-hexane or toluene-containing solvents such as glue or gasoline can produce clinical symptoms and neurophysiological findings that can mimic chronic inflammatory demyelinating polyneuropathy. The authors present a case of a boy with severe sensorimotor polyneuropathy with demyelinating features. Cerebrospinal fluid testing and magnetic resonance imaging spine did not show findings typical of chronic inflammatory demyelinating polyneuropathy. His lack of response to immunosuppressive therapy prompted a nerve biopsy which was instrumental in confirming a diagnosis of chronic organic solvent exposure, subsequently confirmed on history. This case highlights the importance of additional testing to ensure diagnostic certainty which allows appropriate treatment and/or disease management to be tailored appropriately including in this instance, the involvement of mental health counseling and avoidance of immunosuppressant medication.
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http://dx.doi.org/10.1177/2329048X20934914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307582PMC
June 2020

Motor transmission defects with sex differences in a new mouse model of mild spinal muscular atrophy.

EBioMedicine 2020 May 24;55:102750. Epub 2020 Apr 24.

Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Department of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada. Electronic address:

Background: Mouse models of mild spinal muscular atrophy (SMA) have been extremely challenging to generate. This paucity of model systems has limited our understanding of pathophysiological events in milder forms of the disease and of the effect of SMN depletion during aging.

Methods: A mild mouse model of SMA, termed Smn;SMN2, was generated by crossing Smn;SMN2 and Smn mice. This new model was characterized using behavioral testing, histology, western blot, muscle-nerve electrophysiology as well as ultrasonography to study classical SMA features and extra-neuronal involvement.

Findings: Smn;SMN2 mice have normal survival, mild but sustained motor weakness, denervation and neuronal/neuromuscular junction (NMJ) transmission defects, and neurogenic muscle atrophy that are more prominent in male mice. Increased centrally located nuclei, intrinsic contractile and relaxation muscle defects were also identified in both female and male mice, with some male predominance. There was an absence of extra-neuronal pathology.

Interpretation: The Smn;SMN2 mouse provides a model of mild SMA, displaying some hallmark features including reduced weight, sustained motor weakness, electrophysiological transmission deficit, NMJ defects, and muscle atrophy. Early and prominent increase central nucleation and intrinsic electrophysiological deficits demonstrate the potential role played by muscle in SMA disease. The use of this model will allow for the understanding of the most susceptible pathogenic molecular changes in motor neurons and muscles, investigation of the effects of SMN depletion in aging, sex differences and most importantly will provide guidance for the currently aging SMA patients treated with the recently approved genetic therapies.

Funding: This work was supported by Cure SMA/Families of SMA Canada (grant numbers KOT-1819 and KOT-2021); Muscular Dystrophy Association (USA) (grant number 575466); and Canadian Institutes of Health Research (CIHR) (grant number PJT-156379).
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http://dx.doi.org/10.1016/j.ebiom.2020.102750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184161PMC
May 2020

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Nat Commun 2019 09 25;10(1):4343. Epub 2019 Sep 25.

Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.
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http://dx.doi.org/10.1038/s41467-019-12187-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761184PMC
September 2019

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy.

Ann Clin Transl Neurol 2019 08 26;6(8):1519-1532. Epub 2019 Jul 26.

Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Objective: Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra-neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease.

Methods: We analyzed clinical data collected from a large cohort of pediatric SMA type I-III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA.

Results: We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non-alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation.

Interpretation: This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.
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http://dx.doi.org/10.1002/acn3.50855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689695PMC
August 2019

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor.

Cancer Cell 2019 07;36(1):51-67.e7

Children's Brain Tumor Research Centre, Queen's Medical Centre University of Nottingham, Nottingham NG72UH, UK.

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death.
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http://dx.doi.org/10.1016/j.ccell.2019.06.002DOI Listing
July 2019

Fatal Second Impact Syndrome in Rowan Stringer, A 17-Year-Old Rugby Player.

Can J Neurol Sci 2019 05 4;46(3):351-354. Epub 2019 Apr 4.

Faculty of Medicine,University of Ottawa,Ottawa, Ontario,Canada.

Second impact syndrome (SIS) is associated with malignant brain swelling and usually occurs in young athletes with one or more prior, recent concussions. SIS is rare and some dispute its existence. We report a case of SIS in Rowan Stringer, age 17, a rugby player who sustained a fatal brain injury despite prompt medical therapy including decompression surgery. The cause of the massive brain swelling was initially unknown. An inquest revealed Rowan's text messages to friends describing symptoms from two prior, recent rugby brain injuries, likely concussions, within 5 days of the fatal blow and confirming the diagnosis of SIS.
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http://dx.doi.org/10.1017/cjn.2019.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536829PMC
May 2019

Rowan's Rugby Fatality Prompts Canada's First Concussion Legislation.

Can J Neurol Sci 2019 05 4;46(3):280-282. Epub 2019 Apr 4.

University of Ottawa Faculty of Medicine,Ottawa, Ontario,Canada.

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http://dx.doi.org/10.1017/cjn.2019.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536820PMC
May 2019

Neu-Laxova syndrome presenting prenatally with increased nuchal translucency and cystic hygroma: The utility of exome sequencing in deciphering the diagnosis.

Am J Med Genet A 2019 05 5;179(5):813-816. Epub 2019 Mar 5.

Regional Genetics Program, CHEO, University of Ottawa, Ottawa, Ontario, Canada.

Neu-Laxova syndrome (NLS) is a lethal autosomal recessive microcephaly syndrome associated with intrauterine growth restriction (IUGR) and multiple congenital anomalies. Clinical features include central nervous system malformations, joint contractures, ichthyosis, edema, and dysmorphic facial features. Biallelic pathogenic variants in either the PHGDH or PSAT1 genes have been shown to cause NLS. Using exome sequencing, we aimed to identify the underlying genetic diagnosis in three fetuses (from one family) with prenatal skin edema, severe IUGR, micrognathia, renal anomalies, and arthrogryposis and identified a homozygous c.1A>C (p.Met1?, NM_006623.3) variant in the PHGDH gene. Loss of the translation start codon is a novel genetic mechanism for the development of NLS. Prenatal diagnosis of NLS is challenging and few reports describe the fetal pathology. Fetal neuropathologic examination revealed: delayed brain development, congenital agenesis of the corticospinal tracts, and hypoplasia of the hippocampus, cerebellum and brainstem. Each pregnancy also showed increased nuchal translucency (NT) or cystic hygroma. While NLS is rare, it may be a cause of recurrent increased NT/cystic hygroma. This finding provides further support that cystic hygroma has many different genetic causes and that exome sequencing may shed light on the underlying genetic diagnoses in this group of prenatal patients.
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http://dx.doi.org/10.1002/ajmg.a.61076DOI Listing
May 2019

Self-antigen MASH2 combined with the AS15 immunostimulant induces tumor protection in colorectal cancer mouse models.

PLoS One 2019 25;14(1):e0210261. Epub 2019 Jan 25.

GSK, Rixensart, Belgium.

Human achaete scute homolog 2 (HASH2) and its murine ortholog MASH2 are potential targets for colorectal cancer immunotherapy. We assessed immunogenicity and antitumor potential of recombinant MASH2 protein combined with AS15 immunostimulant (recMASH2+AS15) in CB6F1 and Apc+/Min-FCCC mice. CB6F1 mice received 4 injections of recMASH2+AS15 or AS15 alone before challenge with TC1-MASH2 tumor cells (Tumor Challenge). Apc+/Min-FCCC mice received 9 injections of recMASH2+AS15 or vehicle (phosphate buffer saline [PBS] or AS15 alone), before (two independent Prophylactic Studies) or after (Immunotherapy) colon adenomas were detectable by colonoscopy. CB6F1 mice immunized with recMASH2+AS15 had a significantly smaller mean tumor size and improved survival rate compared to controls (104 mm2 vs. 197 mm2 [p = 0.009] and 67% vs. 7% [p = 0.001], respectively). In Prophylactic Study 1, the mean number of colon adenomas was significantly lower in Apc+/Min-FCCC mice receiving recMASH2+AS15 compared to PBS (1.8 [95% confidence interval 1.0-3.3] vs. 5.2 [3.7-7.4], p = 0.003). Fewer microadenomas were observed in recMASH2+AS15 groups compared to PBS in both Prophylactic Studies (Study 1: mean 0.4 [0.2-1.0] vs. 1.5 [0.9-2.4], p = 0.009; Study 2: 0.4 [0.2-0.6] vs. 1.1 [0.8-1.5], p = 0.001). In the Immunotherapy Study, fewer colon adenomas tended to be observed in recMASH2+AS15-treated mice (4.1 [2.9-6.0]) compared to controls (AS15 4.7 [3.3-6.6]; PBS 4.9 [3.5-6.9]; no significant difference). recMASH2+AS15 induced MASH2-specific antibody and CD4+ responses in both mouse models. recMASH2+AS15 partially protected mice against MASH2-expressing tumors and reduced spontaneous colorectal adenomas in Apc+/Min-FCCC mice, indicating that MASH2/HASH2 antigens are targets for colorectal cancer immunotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210261PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347180PMC
October 2019

Severe TUBB4A-Related Hypomyelination With Atrophy of the Basal Ganglia and Cerebellum: Novel Neuropathological Findings.

J Neuropathol Exp Neurol 2019 01;78(1):3-9

Division of Pediatric Neurology, Children's Hospital of Eastern Ontario, Ottawa, Ontario Canada.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare hypomyelinating leukodystrophy characterized by infantile or childhood onset of motor developmental delay, progressive rigidity and spasticity, with hypomyelination and progressive atrophy of the basal ganglia and cerebellum due to a genetic mutation of the TUBB4A gene. It has only been recognized since 2002 and the full spectrum of the disorder is still being delineated. Here, we review a case report of a severely affected girl with a thorough neuropathological evaluation demonstrating novel clinical and pathological findings. Clinically, our patient demonstrated visual dysfunction and hypodontia in addition to the typical phenotype. Morphologically, more severe and widespread changes in the white matter were observed, including to the optic tracts; in gray structures such as the caudate nucleus, thalamus, globus pallidus, and substantia nigra; as well as an area of focal cortical dysplasia. Overall this case offers further insight into the broad range of clinical and neuropathological findings that may be associated with H-ABC and related TUBB4A gene mutations.
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http://dx.doi.org/10.1093/jnen/nly105DOI Listing
January 2019

Infantile Myofibromatosis With Intracranial Extradural Involvement and PDGFRB Mutation: A Case Report and Review of the Literature.

Pediatr Dev Pathol 2019 May-Jun;22(3):258-264. Epub 2018 Aug 13.

1 Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.

Infantile myofibroma is a rare benign mesenchymal tumor that presents as solitary or multiple lesions (myofibromatosis) in the skin, soft tissue, bone, or internal organs. It most commonly affects the head and neck of infants and young children, but it can also affect adults. Intracranial involvement is reported to be extremely rare, and its clinical picture has been poorly characterized. Recently, it has been demonstrated that germline and somatic mutations in the platelet-derived growth factor receptor beta (PDGFRB) are associated with familial infantile myofibromatosis. We report a case of infantile myofibromatosis with predominant posterior fossa extradural involvement in a 14-year-old adolescent girl with a confirmed mutation in the PDGFRB gene.
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http://dx.doi.org/10.1177/1093526618787736DOI Listing
September 2019

Fatal Entrapment of the Basilar Artery in a Longitudinal Fracture of the Clivus Due to Head Injury: A Case Report and Review of the Literature.

Acad Forensic Pathol 2017 Sep 1;7(3):453-468. Epub 2017 Sep 1.

Ottawa Hospital - Department of Pathology and Laboratory Medicine.

Infarction of the posterior cerebral artery circulation arising from entrapment of the basilar artery in a fracture of the clivus has been reported in the medical literature, predominantly in the radiology and emergency medicine journals. Review of the medical literature on the topic revealed 14 published cases of entrapment of the basilar and/or vertebral artery within a longitudinal fracture of the clivus. These were all reported between 1964 and 2016 and postmortem examination had been conducted on seven cases. To date, no case of entrapment of the basilar and/or vertebral artery in a fracture of the clivus has been reported in the forensic pathology literature, and the published literature on the entity is reviewed.
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http://dx.doi.org/10.23907/2017.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474569PMC
September 2017

Yunis-Varón syndrome caused by biallelic VAC14 mutations.

Eur J Hum Genet 2017 09 21;25(9):1049-1054. Epub 2017 Jun 21.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.

Yunis-Varón syndrome (YVS) is an autosomal recessive disorder comprising skeletal anomalies, dysmorphism, global developmental delay and intracytoplasmic vacuolation in brain and other tissues. All hitherto-reported pathogenic variants affect FIG4, a lipid phosphatase involved in phosphatidylinositol (3,5)-bisphosphate [PtdIns(3,5)P] metabolism. FIG4 interacts with PIKfyve, a lipid kinase, via the adapter protein VAC14; all subunits of the resulting complex are essential for PtdIns(3,5)P synthesis in the endolysosomal membrane compartment. Here, we present the case of a female neonate with clinical features of YVS and normal FIG4 sequencing; exome sequencing identified biallelic rare coding variants in VAC14. Cultured patient fibroblasts exhibited a YVS-like vacuolation phenotype ameliorated in a dose-dependent fashion by ML-SA1, a pharmacological activator of the lysosomal PtdIns(3,5)P effector TRPML1. The patient developed a diffuse leukoencephalopathy with loss of the normal N-acetylaspartate spectrographic peak and presence of a large abnormal peak consistent with myoinositol. We report that VAC14 is a second gene for Yunis-Varón syndrome.
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http://dx.doi.org/10.1038/ejhg.2017.99DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558182PMC
September 2017

Novel Roles for Staufen1 in Embryonal and Alveolar Rhabdomyosarcoma via c-myc-dependent and -independent events.

Sci Rep 2017 02 17;7:42342. Epub 2017 Feb 17.

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Rhabdomyosarcoma is the most common soft tissue sarcoma in children and young adults. Rhabdomyosarcomas are skeletal muscle-like tumours that typically arise in muscle beds, and express key myogenic regulatory factors. However, their developmental program remains blocked in the proliferative phase with cells unable to exit the cell cycle to fuse into myotubes. Recently, we uncovered a key role for the RNA-binding protein Staufen1 during myogenic differentiation through the regulation of c-myc translation. Given the known implication of c-myc in rhabdomyosarcoma, we hypothesized in the current work that Staufen1 controls rhabdomyosarcoma tumorigenesis. Here, we report for the first time the novel role of Staufen1 in cancer, specifically in rhabdomyosarcoma. We demonstrate that Staufen1 is markedly upregulated in human rhabdomyosarcoma tumours and cell lines as compared to normal skeletal muscle. Moreover, we show that Staufen1 promotes the tumorigenesis of embryonal and alveolar rhabdomyosarcoma subtypes both in cell culture and in animal models. Finally, our data demonstrate that Staufen1 has differential roles in embryonal versus alveolar rhabdomyosarcoma through the control of proliferative and apoptotic pathways, respectively. Together, these results provide the first evidence for Staufen1's direct implication in cancer biology. Accordingly, Staufen1 thus represents a novel target for the development of future therapeutic strategies for rhabdomyosarcoma.
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http://dx.doi.org/10.1038/srep42342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314364PMC
February 2017

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors.

Cancer Cell 2016 Dec;30(6):891-908

Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.
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http://dx.doi.org/10.1016/j.ccell.2016.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5500911PMC
December 2016

11-Year-Old Male with Spinal Mass.

Brain Pathol 2016 09;26(5):681-2

Anatomical Pathology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada.

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http://dx.doi.org/10.1111/bpa.12418DOI Listing
September 2016

Impaired activity of CCA-adding enzyme TRNT1 impacts OXPHOS complexes and cellular respiration in SIFD patient-derived fibroblasts.

Orphanet J Rare Dis 2016 06 18;11(1):79. Epub 2016 Jun 18.

Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.

Background: SIFD (Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay) is a novel form of congenital sideroblastic anemia associated with B-cell immunodeficiency, periodic fevers, and developmental delay caused by mutations in the CCA-adding enzyme TRNT1, but the precise molecular pathophysiology is not known.

Results: We show that the disease causing mutations in patient-derived fibroblasts do not affect subcellular localization of TRNT1 and show no gross morphological differences when compared to control cells. Analysis of cellular respiration and oxidative phosphorylation (OXPHOS) complexes demonstrates that both basal and maximal respiration rates are decreased in patient cells, which may be attributed to an observed decrease in the abundance of select proteins of the OXPHOS complexes.

Conclusions: Our data provides further insight into cellular pathophysiology of SIFD.
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http://dx.doi.org/10.1186/s13023-016-0466-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912790PMC
June 2016

Severe Neonatal Presentation of Mitochondrial Citrate Carrier (SLC25A1) Deficiency.

JIMD Rep 2016 16;30:73-79. Epub 2016 Jun 16.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.

Mutations of the mitochondrial citrate carrier (CIC) SLC25A1 cause combined D-2- and L-2-hydroxyglutaric aciduria (DL-2HGA; OMIM #615182), a neurometabolic disorder characterized by developmental delay, hypotonia, and seizures. Here, we describe the female child of consanguineous parents who presented neonatally with lactic acidosis, periventricular frontal lobe cysts, facial dysmorphism, recurrent apneic episodes, and deficient complex IV (cytochrome c oxidase) activity in skeletal muscle. Exome sequencing revealed a homozygous SLC25A1 missense mutation [NM_005984.4: c.593G>A; p.(Arg198His)] of a ubiquitously conserved arginine residue putatively situated within the substrate-binding site I of CIC. Retrospective review of the patient's organic acids confirmed the D- and L-2-hydroxyglutaric aciduria typical of DL-2HGA to be present, although this was not appreciated on initial presentation. Cultured patient skin fibroblasts showed reduced survival in culture, diminished mitochondrial spare respiratory capacity, increased glycolytic flux, and normal mitochondrial bulk, inner membrane potential, and network morphology. Neither cell survival nor cellular respiratory parameters were improved by citrate supplementation, although oral citrate supplementation did coincide with amelioration of lactic acidosis and apneic attacks in the patient. This is the fifth clinical report of CIC deficiency to date. The clinical features in our patient suggest that this disorder, which can potentially be recognized either by molecular means or based on its characteristic organic aciduria, should be considered in the differential diagnosis of pyruvate dehydrogenase deficiency and respiratory chain disorders. One-Sentence Summary A novel homozygous missense substitution in SLC25A1 was identified in a neonate presenting with lactic acidosis, intracerebral cysts, and an apparent mitochondrial complex IV defect in muscle.
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http://dx.doi.org/10.1007/8904_2016_536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110450PMC
June 2016

Congenital Trismus From Brainstem Dysgenesis: Case Report and Review of Literature.

Pediatrics 2016 07 2;138(1). Epub 2016 Jun 2.

Otolaryngology-Head and Neck Surgery, University of Ottawa, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada

Trismus refers to any condition inducing limited mouth opening and may present as a result of acquired or congenital pathology. We present the case of a newborn who presented with severe, congenital trismus due to brainstem dysgenesis. We describe the course of his investigations, and a multidisciplinary approach to the management of his care and follow-up. To our knowledge, this is one of the earliest reported cases of congenital trismus attributable to brainstem dysgenesis. A literature review was conducted to provide an overview of the differential pathogenesis as it presents in congenital cases and discuss the complexity of managing congenital trismus due to brainstem dysgenesis in a neonate and infant.
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http://dx.doi.org/10.1542/peds.2015-4605DOI Listing
July 2016

Fetal segmental spinal dysgenesis and unusual segmental agenesis of the anterior spinal artery.

Childs Nerv Syst 2016 Aug 11;32(8):1537-41. Epub 2016 Mar 11.

Department of Medical Imaging, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario, K1H 8L1, Canada.

Segmental spinal dysgenesis (SSD) is a rare congenital spinal abnormality characterized by segmental dysgenesis or agenesis of the thoracolumbar or lumbar spine, congenital kyphosis, and abnormal configuration of the underlying spinal cord. A unique feature of SSD is that the vertebrae are present above and below the defect, and there is often a lower cord segment in the caudal spinal canal. We report a fetal MRI case of SSD with postmortem and neuropathological correlations. Our report confirms already published findings including the presence of a neurenteric cyst but is the first to document anterior spinal artery segmental agenesis in SSD.
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http://dx.doi.org/10.1007/s00381-016-3054-xDOI Listing
August 2016

DNM1L-related mitochondrial fission defect presenting as refractory epilepsy.

Eur J Hum Genet 2016 07 25;24(7):1084-8. Epub 2015 Nov 25.

Children's Hospital of Eastern Ontario Research Institute and University of Ottawa, Ottawa, Ontario, Canada.

Mitochondrial fission and fusion are dynamic processes vital to mitochondrial quality control and the maintenance of cellular respiration. In dividing mitochondria, membrane scission is accomplished by a dynamin-related GTPase, DNM1L, that oligomerizes at the site of fission and constricts in a GTP-dependent manner. There is only a single previous report of DNM1L-related clinical disease: a female neonate with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF; OMIM #614388), a lethal disorder characterized by cerebral dysgenesis, seizures, lactic acidosis, elevated very long chain fatty acids, and abnormally elongated mitochondria and peroxisomes. Here, we describe a second individual, diagnosed via whole-exome sequencing, who presented with developmental delay, refractory epilepsy, prolonged survival, and no evidence of mitochondrial or peroxisomal dysfunction on standard screening investigations in blood and urine. EEG was nonspecific, showing background slowing with frequent epileptiform activity at the frontal and central head regions. Electron microscopy of skeletal muscle showed subtle, nonspecific abnormalities of cristal organization, and confocal microscopy of patient fibroblasts showed striking hyperfusion of the mitochondrial network. A panel of further bioenergetic studies in patient fibroblasts showed no significant differences versus controls. The proband's de novo DNM1L variant, NM_012062.4:c.1085G>A; NP_036192.2:p.(Gly362Asp), falls within the middle (oligomerization) domain of DNM1L, implying a likely dominant-negative mechanism. This disorder, which presents nonspecifically and affords few diagnostic clues, can be diagnosed by means of DNM1L sequencing and/or confocal microscopy.
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http://dx.doi.org/10.1038/ejhg.2015.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5070894PMC
July 2016

Detailed Biochemical and Bioenergetic Characterization of FBXL4-Related Encephalomyopathic Mitochondrial DNA Depletion.

JIMD Rep 2016 25;27:1-9. Epub 2015 Sep 25.

Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.

Mutations of FBXL4, which encodes an orphan mitochondrial F-box protein, are a recently identified cause of encephalomyopathic mtDNA depletion. Here, we describe the detailed clinical and biochemical phenotype of a neonate presenting with hyperlactatemia, leukoencephalopathy, arrhythmias, pulmonary hypertension, dysmorphic features, and lymphopenia. Next-generation sequencing in the proband identified a homozygous frameshift, c.1641_1642delTG, in FBXL4, with a surrounding block of SNP marker homozygosity identified by microarray. Muscle biopsy showed a paucity of mitochondria with ultrastructural abnormalities, mitochondrial DNA depletion, and profound deficiency of all respiratory chain complexes. Cell-based mitochondrial phenotyping in fibroblasts showed mitochondrial fragmentation, decreased basal and maximal respiration, absence of ATP-linked respiratory and leak capacity, impaired survival under obligate aerobic respiration, and reduced mitochondrial inner membrane potential, with relative sparing of mitochondrial mass. Cultured fibroblasts from the patient exhibited a more oxidized glutathione ratio, consistent with altered cellular redox poise. High-resolution respirometry of permeabilized muscle fibers showed marked deficiency of oxidative phosphorylation using a variety of mitochondrial energy substrates and inhibitors. This constitutes the fourth and most detailed report of FBXL4 deficiency to date. In light of our patient's clinical findings and genotype (homozygous frameshift), this phenotype likely represents the severe end of the FBXL4 clinical spectrum.
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http://dx.doi.org/10.1007/8904_2015_491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5580732PMC
May 2016

Congenital Nemaline Myopathy: The Value of Magnetic Resonance Imaging of Muscle.

Can J Neurol Sci 2015 Sep;42(5):338-40

2Division of Neurology,University of Ottawa,Children's Hospital of Eastern Ontario,Ottawa,Ontario,Canada.

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http://dx.doi.org/10.1017/cjn.2015.59DOI Listing
September 2015

Neurogenic Ovarian Cyst--A Rare, Monodermal Teratoma.

Pediatr Dev Pathol 2015 Jul-Aug;18(4):341-2

Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON, Canada.

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http://dx.doi.org/10.2350/14-11-1576-LET.1DOI Listing
September 2015

Primary cutaneous adenoid cystic carcinoma with brain metastases: case report and literature review.

J Cutan Pathol 2016 Feb 11;43(2):137-41. Epub 2015 Sep 11.

Division of Anatomical Pathology, The Ottawa Hospital, Ottawa, Canada.

Primary cutaneous adenoid cystic carcinoma (ACC) is a rare skin tumor that is unlikely to metastasize. We present a case of primary cutaneous ACC in a 67-year-old male with axillary lymph node, pulmonary and brain metastases. To the best of our knowledge, this is the first reported case of cutaneous ACC with distant metastases to the brain.
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http://dx.doi.org/10.1111/cup.12563DOI Listing
February 2016

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis.

Lancet Oncol 2015 May 14;16(5):569-82. Epub 2015 Apr 14.

Department of Neurosurgery, University of Debrecen, Debrecen, Hungary.

Background: Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours.

Methods: We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling.

Findings: Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes.

Interpretation: An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours.

Funding: C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.
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http://dx.doi.org/10.1016/S1470-2045(15)70114-2DOI Listing
May 2015