Publications by authors named "Simone A Mandelstam"

20 Publications

  • Page 1 of 1

Somatic IDH1 variant (p.R132C) in an adult male with Maffucci syndrome.

Cold Spring Harb Mol Case Stud 2021 Sep 29. Epub 2021 Sep 29.

Epilepsy Research Centre, Department of Medicine (Austin Hospital), University of Melbourne, Heidelberg, Victoria, Australia.

Maffucci Syndrome is a rare, highly variable somatic mosaic condition and well-known cancer related gain-of-function variants in either the IDH1 or IDH2 genes have been found in the affected tissues of most reported patients. Features include benign enchondroma and spindle cell hemangioma, with a recognized increased risk of various malignancies. Fewer than 200 cases have been reported, therefore accurate estimates of malignancy risk are difficult to quantify and recommended surveillance guidelines are not available. The same gain-of-function IDH1 and IDH2 variants are also implicated in a variety of other benign and malignant tumors. An adult male presented with several soft palpable lesions on the right upper limb. Imaging and histopathology raised the possibility of Maffucci syndrome. DNA was extracted from peripheral blood lymphocytes and tissue surgically resected from a spindle-cell hemangioma. Sanger sequencing and Droplet-digital PCR analysis of the IDH1 gene was performed. We identified a somatic mosaic c.394C>T (p.R132C) variant in exon 5 of IDH1, in DNA derived from hemangioma tissue at ~ 17% mutant allele frequency. This variant was absent in DNA derived from blood. This variant has been identified in the affected tissue of most reported patients with Maffucci syndrome Although the patient has a potentially targetable variant, and there is a recognized risk of malignant transformation in this condition, a decision was made not to intervene with an IDH1 inhibitor. The reasons and prospects for therapy in this condition are discussed.
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http://dx.doi.org/10.1101/mcs.a006127DOI Listing
September 2021

One-Stage, Limited-Resection Epilepsy Surgery for Bottom-of-Sulcus Dysplasia.

Neurology 2021 07 4;97(2):e178-e190. Epub 2021 May 4.

From the Departments of Neurology (E.M.-L., C.A.B., S.M.B., R.J.L., J.L.F., A.S.H.), Neurosurgery (W.J.M., J.Y.-M.Y., A.E.L.W., A.W.), Medical Imaging (S.A.M., M.J.K., P.F.), Anatomical Pathology (D.M., C.D.), Psychology (J.A.W.), and Anaesthesia (A.D.), The Royal Children's Hospital; Murdoch Children's Research Institute (E.M.-L., W.J.M., S.M.B., S.A.M., J.Y.-M.Y., A.E.L.W., C.D., A.D., K.P., R.J.L., A.W., A.S.H.); University of Melbourne (E.M.-L., W.J.M, S.M.B., S.A.M., J.Y.-M.Y., A.E.L.W., M.J.K., C.D., A.D., R.J.L., A.S.H.); and Florey Institute of Neuroscience and Mental Health (A.E.L.W., G.D.J., A.S.H.), Parkville, Victoria, Australia.

Objective: To determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD).

Methods: We reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG.

Results: Thirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0-14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasia (FCD) type IIb in 29 patients and FCDIIa in 9. Dysmorphic neurons were present in the bottom of the sulcus but not the top or the gyral crown in 17 of 22 patients. Six (16%) patients required reoperation for postoperative seizures and residual dysplasia; reoperation was not correlated with ECoG, neuroimaging, or histologic abnormalities in the gyral crown. At a median 6.3 (IQR 4.8-9.9) years of follow-up, 33 (87%) patients are seizure-free, 31 off antiseizure medication.

Conclusion: BOSD can be safely and effectively resected with MRI and ECoG guidance, corticectomy potentially being limited to the dysplastic sulcus, without need for intracranial EEG monitoring and functional mapping.

Classification Of Evidence: This study provides Class IV evidence that 1-stage, limited corticectomy for BOSD is safe and effective for control of seizures.
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http://dx.doi.org/10.1212/WNL.0000000000012147DOI Listing
July 2021

Resection of tuber centers only for seizure control in tuberous sclerosis complex.

Epilepsy Res 2021 Mar 8;171:106572. Epub 2021 Feb 8.

Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia; Clinical Sciences, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Neurology, The Royal Children's Hospital, Parkville, Victoria, Australia. Electronic address:

Our previous studies suggest the tuber center is the seizure focus in tuberous sclerosis complex (TSC). We report findings from 5 epilepsy surgeries in 4 children with TSC and focal motor seizures from single tubers in primary sensorimotor cortex in which resection was limited to the cortex in the tuber center. Intraoperative electrocorticography showed epileptiform activity in the tuber center, with or without propagation to the tuber rim and surrounding perituberal cortex. Histopathology showed an abundance of dysmorphic neurons in the tuber center compared to the rim in four paired specimens, dysmorphic neurons being the reported epileptogenic cell line in TSC. Associated focal motor seizures were eliminated in all children (mean follow up 6.3 years) without postoperative deficits. Tuber center resections are a potential alternative to complete tuberectomy in patients with epileptogenic tubers in eloquent cortex and potentially also in children with a high tuber load and multifocal seizures.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106572DOI Listing
March 2021

Second-hit DEPDC5 mutation is limited to dysmorphic neurons in cortical dysplasia type IIA.

Ann Clin Transl Neurol 2019 07 17;6(7):1338-1344. Epub 2019 Jun 17.

Murdoch Children's Research Institute, Melbourne, Victoria, Australia.

Focal cortical dysplasia (FCD) causes drug-resistant epilepsy and is associated with pathogenic variants in mTOR pathway genes. How germline variants cause these focal lesions is unclear, however a germline + somatic "2-hit" model is hypothesized. In a boy with drug-resistant epilepsy, FCD, and a germline DEPDC5 pathogenic variant, we show that a second-hit DEPDC5 variant is limited to dysmorphic neurons, and the somatic mutation load correlates with both dysmorphic neuron density and the epileptogenic zone. These findings provide new insights into the molecular and cellular correlates of FCD determining drug-resistant epilepsy and refine conceptualization of the epileptogenic zone.
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http://dx.doi.org/10.1002/acn3.50815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649645PMC
July 2019

Abnormal Cell Sorting Underlies the Unique X-Linked Inheritance of PCDH19 Epilepsy.

Neuron 2018 01;97(1):59-66.e5

School of Biological Sciences and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5005, Australia; School of Medicine and Robinson Research Institute, The University of Adelaide, Adelaide, SA 5005, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia. Electronic address:

X-linked diseases typically exhibit more severe phenotypes in males than females. In contrast, protocadherin 19 (PCDH19) mutations cause epilepsy in heterozygous females but spare hemizygous males. The cellular mechanism responsible for this unique pattern of X-linked inheritance is unknown. We show that PCDH19 contributes to adhesion specificity in a combinatorial manner such that mosaic expression of Pcdh19 in heterozygous female mice leads to striking sorting between cells expressing wild-type (WT) PCDH19 and null PCDH19 in the developing cortex, correlating with altered network activity. Complete deletion of PCDH19 in heterozygous mice abolishes abnormal cell sorting and restores normal network activity. Furthermore, we identify variable cortical malformations in PCDH19 epilepsy patients. Our results highlight the role of PCDH19 in determining cell adhesion affinities during cortical development and the way segregation of WT and null PCDH19 cells is associated with the unique X-linked inheritance of PCDH19 epilepsy.
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http://dx.doi.org/10.1016/j.neuron.2017.12.005DOI Listing
January 2018

Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay.

Am J Med Genet A 2018 01 21;176(1):230-234. Epub 2017 Nov 21.

Department of Medicine, Epilepsy Research Centre, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.

Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next-generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in β-galactosidase deficiency. A 10-year-old girl had progressive neurologic deterioration, macular cherry-red spot, and cornea verticillata. She had marked clinical improvement with initiation of the ketogenic diet. Comparative genomic hybridization microarray showed mosaic chromosome 3 paternal uniparental disomy (UPD). GM1 gangliosidosis was suspected, however β-galactosidase assay was normal. Trio WES identified a paternally-inherited pathogenic splice-site GLB1 mutation (c.75+2dupT). The girl had GM1 gangliosidosis; however, enzymatic testing in blood was normal, presumably compensated for by non-UPD cells. Severe neurologic dysfunction occurred due to disruptive effects of UPD brain cells.
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http://dx.doi.org/10.1002/ajmg.a.38549DOI Listing
January 2018

The epileptology of Koolen-de Vries syndrome: Electro-clinico-radiologic findings in 31 patients.

Epilepsia 2017 06 25;58(6):1085-1094. Epub 2017 Apr 25.

Department of Medicine, Epilepsy Research Centre, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.

Objective: This study was designed to describe the spectrum of epilepsy phenotypes in Koolen-de Vries syndrome (KdVS), a genetic syndrome involving dysmorphic features, intellectual disability, hypotonia, and congenital malformations, that occurs secondary to 17q21.31 microdeletions and heterozygous mutations in KANSL1.

Methods: We were invited to attend a large gathering of individuals with KdVS and their families. While there, we recruited individuals with KdVS and seizures, and performed thorough phenotyping. Additional subjects were included who approached us after the family support group brought attention to our research via social media. Inclusion criteria were genetic testing results demonstrating 17q21.31 deletion or KANSL1 mutation, and at least one seizure.

Results: Thirty-one individuals were studied, aged 2-35 years. Median age at seizure onset was 3.5 years, and 9 of 22 had refractory seizures 2 years after onset. Focal impaired awareness seizures were the most frequent seizure type occurring in 20 of 31, usually with prominent autonomic features. Twenty-one patients had prolonged seizures and, at times, refractory status epilepticus. Electroencephalography (EEG) showed focal/multifocal epileptiform discharges in 20 of 26. MRI studies of 13 patients were reviewed, and all had structural anomalies. Corpus callosum dysgenesis, abnormal hippocampi, and dilated ventricles were the most common, although periventricular nodular heterotopia, focal cortical dysplasia, abnormal sulcation, and brainstem and cerebellum abnormalities were also observed. One patient underwent epilepsy surgery for a lesion that proved to be an angiocentric glioma.

Significance: The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features. Multifocal epileptiform discharges are the typical EEG pattern. Structural brain abnormalities may be universal, including signs of abnormal neuroblast migration and abnormal axonal guidance. Epilepsy surgery should be undertaken with care given the widespread neuroanatomic abnormalities; however, tumors are a rare, yet important, occurrence.
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http://dx.doi.org/10.1111/epi.13746DOI Listing
June 2017

Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K channel properties.

Ann Neurol 2017 May;81(5):677-689

Department of Neurology and Epileptology, Epilepsy Center Hamburg-Alsterdorf, Hamburg, Germany.

Objective: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever.

Methods: We analyzed clinical, electroclinical, and neuroimaging data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch-clamp to explore biophysical properties of wild-type and mutant K 3.1 channels.

Results: Symptoms began at between 3 and 15 years of age (median = 9.5), with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus; 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed generalized spike and polyspike wave discharges, with documented photosensitivity in most. Polygraphic EEG-electromyographic studies demonstrated a cortical origin for myoclonus and striking coactivation of agonist and antagonist muscles. Magnetic resonance imaging revealed symmetrical cerebellar atrophy, which appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in 6 patients. To explore this, we performed high-temperature in vitro recordings. At elevated temperatures, there was a robust leftward shift in activation of wild-type K 3.1, increasing channel availability.

Interpretation: MEAK has a relatively homogeneous presentation, resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent leftward shift in activation of wild-type K 3.1 subunit-containing channels, which would counter the loss of function observed for mutant channels, highlighting KCNC1 as a potential target for precision therapeutics. Ann Neurol 2017;81:677-689.
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http://dx.doi.org/10.1002/ana.24929DOI Listing
May 2017

Fatal Cerebral Edema With Status Epilepticus in Children With Dravet Syndrome: Report of 5 Cases.

Pediatrics 2017 Apr 22;139(4). Epub 2017 Mar 22.

Epilepsy Research Centre, Department of Medicine and

Dravet syndrome (DS) is a well-recognized developmental and epileptic encephalopathy associated with mutations and 15% mortality by 20 years. Although over half of cases succumb to sudden unexpected death in epilepsy, the cause of death in the remainder is poorly defined. We describe the clinical, radiologic, and pathologic characteristics of a cohort of children with DS and mutations who developed fatal cerebral edema causing mass effect after fever-associated status epilepticus. Cases were identified from a review of children with DS enrolled in the Epilepsy Genetics Research Program at The University of Melbourne, Austin Health, who died after fever-associated status epilepticus. Five children were identified, all of whom presented with fever-associated convulsive status epilepticus, developed severe brain swelling, and died. All had de novo mutations. Fever of 40°C or greater was measured in all cases. Signs of brainstem dysfunction, indicating cerebral herniation, were first noted 3 to 5 days after initial presentation in 4 patients, though were apparent as early as 24 hours in 1 case. When MRI was performed early in a patient's course, focal regions of cortical diffusion restriction were noted. Later MRI studies demonstrated diffuse cytotoxic edema, with severe cerebral herniation. Postmortem studies revealed diffuse brain edema and widespread neuronal damage. Laminar necrosis was seen in 1 case. Cerebral edema leading to fatal brain herniation is an important, previously unreported sequela of status epilepticus in children with DS. This potentially remediable complication may be a significant contributor to the early mortality of DS.
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http://dx.doi.org/10.1542/peds.2016-1933DOI Listing
April 2017

Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance.

Nat Genet 2017 Apr 27;49(4):511-514. Epub 2017 Feb 27.

AP-HP, Groupe Hospitalier Saint-Louis -La Riboisière -Fernand Vidal, Laboratoire de Génétique, Paris, France.

Brain malformations involving the corpus callosum are common in children with developmental disabilities. We identified DCC mutations in four families and five sporadic individuals with isolated agenesis of the corpus callosum (ACC) without intellectual disability. DCC mutations result in variable dominant phenotypes with decreased penetrance, including mirror movements and ACC associated with a favorable developmental prognosis. Possible phenotypic modifiers include the type and location of mutation and the sex of the individual.
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http://dx.doi.org/10.1038/ng.3794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894478PMC
April 2017

A mutation in COL4A2 causes autosomal dominant porencephaly with cataracts.

Am J Med Genet A 2016 Apr 28;170A(4):1059-63. Epub 2015 Dec 28.

School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.

Mutations in COL4A1 are well described and result in brain abnormalities manifesting with severe neurological deficits including cerebral palsy, intellectual disability, and focal epilepsy. Families with mutations in COL4A2 are now emerging with a similar phenotype. We describe a family with an autosomal dominant disorder comprising porencephaly, focal epilepsy, and lens opacities, which was negative for mutations in COL4A1. Using whole exome sequencing of three affected individuals from three generations, we identified a rare variant in COL4A2. This COL4A2 (c.2399G>A, p.G800E, CCDS41907.1) variant was predicted to be damaging by multiple bioinformatics tools and affects an invariable glycine residue that is essential for the formation of collagen IV heterotrimers. The cataracts identified in this family expand the phenotypic spectrum associated with mutations in COL4A2 and highlight the increasing overlap with phenotypes associated with COL4A1 mutations.
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http://dx.doi.org/10.1002/ajmg.a.37527DOI Listing
April 2016

Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3.

Ann Neurol 2016 Jan 12;79(1):132-7. Epub 2015 Dec 12.

Department of Neurology, Royal Children's Hospital, Melbourne, Australia.

We describe first cousin sibling pairs with focal epilepsy, one of each pair having focal cortical dysplasia (FCD) IIa. Linkage analysis and whole-exome sequencing identified a heterozygous germline frameshift mutation in the gene encoding nitrogen permease regulator-like 3 (NPRL3). NPRL3 is a component of GAP Activity Towards Rags 1, a negative regulator of the mammalian target of rapamycin complex 1 signaling pathway. Immunostaining of resected brain tissue demonstrated mammalian target of rapamycin activation. Screening of 52 unrelated individuals with FCD identified 2 additional patients with FCDIIa and germline NPRL3 mutations. Similar to DEPDC5, NPRL3 mutations may be considered as causal variants in patients with FCD or magnetic resonance imaging-negative focal epilepsy.
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http://dx.doi.org/10.1002/ana.24502DOI Listing
January 2016

Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5.

Ann Clin Transl Neurol 2015 May 12;2(5):575-80. Epub 2015 Mar 12.

Department of Pediatrics, University of Melbourne Melbourne, Australia ; Murdoch Childrens Research Institute Melbourne, Australia ; Department of Neurology, Royal Children's Hospital Melbourne, Australia.

Whole-exome sequencing of two brothers with drug-resistant, early-onset, focal epilepsy secondary to extensive type IIA focal cortical dysplasia identified a paternally inherited, nonsense variant of DEPDC5 (c.C1663T, p.Arg555*). This variant has previously been reported to cause familial focal epilepsy with variable foci in patients with normal brain imaging. Immunostaining of resected brain tissue from both brothers demonstrated mammalian target of rapamycin (mTOR) activation. This report shows the histopathological features of cortical dysplasia associated with a DEPDC5 mutation, confirms mTOR dysregulation in the malformed tissue and expands the spectrum of neurological manifestations of DEPDC5 mutations to include severe phenotypes with large areas of cortical malformation.
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http://dx.doi.org/10.1002/acn3.191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435711PMC
May 2015

The surgically remediable syndrome of epilepsy associated with bottom-of-sulcus dysplasia.

Neurology 2015 May 17;84(20):2021-8. Epub 2015 Apr 17.

From the Departments of Neurology (A.S.H., R.J.L., G.D.J.), Medical Imaging (S.A.M., M.J.K.), Neurosurgery (W.J.M.), and Anatomical Pathology (D.M.), The Royal Children's Hospital, Parkville; Departments of Neurology (G.D.J.), Radiology (Y.P., G.J.F.), Neurosurgery (G.C.A.F.), and Anatomical Pathology (R.M.K.), Austin Health, Heidelberg; Departments of Paediatrics (A.S.H., S.A.M., R.J.L.), Medicine (G.D.J.), Surgery (G.C.A.F.), Pathology (D.M., R.M.K.), and Radiology (S.A.M., Y.P., G.J.F.), The University of Melbourne; Florey Institute of Neuroscience and Mental Health (A.S.H., S.A.M., M.S., G.D.J.), Heidelberg; Neurosciences (A.S.H., W.J.M., R.J.L.) and Developmental Imaging (S.B., M.J.K.) Groups, Murdoch Children's Research Institute, Parkville, Australia.

Objective: To determine clinical and EEG features that might help identify patients with epilepsy harboring small, intrinsically epileptogenic, surgically treatable, bottom-of-sulcus dysplasias (BOSDs).

Methods: Retrospective review of clinical records, EEG, MRI, and histopathology in 32 patients with drug-resistant epilepsy and MRI-positive (72% 3.0 tesla), pathologically proven (type 2B cortical dysplasia) BOSDs operated at our centers during 2005-2013.

Results: Localization of BOSDs was frontal in 19, insula in 5, parietal in 5, and temporal in 3, on the convexity or interhemispheric surfaces. BOSDs were missed on initial MRI at our centers in 22% of patients. Patients presented with focal seizures during infancy in 9, preschool years in 15, and school years in 8 (median age 5 years). Seizures were stereotyped, predominantly nocturnal, and typically nonconvulsive, with semiology referable to the fronto-central or perisylvian regions. Seizures occurred at high frequency during active periods, but often went into prolonged remission with carbamazepine or phenytoin. Intellect was normal or borderline, except in patients with seizure onset during infancy. Scalp EEG frequently revealed localized interictal epileptiform discharges and ictal rhythms. Patients underwent lesionectomy (median age 14 years) guided by electrocorticography and MRI, with prior intracranial EEG monitoring in only one patient. Twenty-eight patients (88%) became seizure-free, and 20 discontinued antiepileptic medication (median follow-up 4.1 years).

Conclusions: In patients with cryptogenic focal epilepsy, this clinical presentation and course should prompt review of or repeat MRI, looking for a BOSD in the frontal, parietal, or insula cortex. If a BOSD is identified, the patient might be considered for single-stage lesionectomy.
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http://dx.doi.org/10.1212/WNL.0000000000001591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442099PMC
May 2015

CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures.

Neurology 2015 Mar 11;84(9):951-8. Epub 2015 Feb 11.

From the Epilepsy Research Centre (R.H.T., L.M.Z., J.S.A., S.B.H., S.A.M., S.F.B., I.E.S.), University of Melbourne, Austin Health, Heidelberg, Australia; MRC Centre for Neuropsychiatric Genetics & Genomics (R.H.T.), Hadyn Ellis Building, Cathays, Cardiff University, UK; Department of Neurology (L.M.Z.), Children's Hospital of Fudan University, Shanghai, China; Department of Pediatrics (G.L.C., H.C.M.), Division of Genetic Medicine, University of Washington, Seattle; Florey Institute of Neuroscience and Mental Health (S.A.M., I.E.S.), Melbourne, Australia; Departments of Radiology and Paediatrics (S.A.M., I.E.S.), Royal Children's Hospital, and University of Melbourne, Australia; Carol Davila University of Medicine (D.C.), Pediatric Neurology Clinic, Al Obregia Hospital, Bucharest, Romania; and TY Nelson Department of Neurology (D.S.G.), The Children's Hospital at Westmead, Sydney, Australia.

Objective: To delineate the phenotype of early childhood epileptic encephalopathy due to de novo mutations of CHD2, which encodes the chromodomain helicase DNA binding protein 2.

Methods: We analyzed the medical history, MRI, and video-EEG recordings of 9 individuals with de novo CHD2 mutations and one with a de novo 15q26 deletion encompassing CHD2.

Results: Seizures began at a mean of 26 months (12-42) with myoclonic seizures in all 10 cases. Seven exhibited exquisite clinical photosensitivity; 6 self-induced with the television. Absence seizures occurred in 9 patients including typical (4), atypical (2), and absence seizures with eyelid myoclonias (4). Generalized tonic-clonic seizures occurred in 9 of 10 cases with a mean onset of 5.8 years. Convulsive and nonconvulsive status epilepticus were later features (6/10, mean onset 9 years). Tonic (40%) and atonic (30%) seizures also occurred. In 3 cases, an unusual seizure type, the atonic-myoclonic-absence was captured on video. A phenotypic spectrum was identified with 7 cases having moderate to severe intellectual disability and refractory seizures including tonic attacks. Their mean age at onset was 23 months. Three cases had a later age at onset (34 months) with relative preservation of intellect and an initial response to antiepileptic medication.

Conclusion: The phenotypic spectrum of CHD2 encephalopathy has distinctive features of myoclonic epilepsy, marked clinical photosensitivity, atonic-myoclonic-absence, and intellectual disability ranging from mild to severe. Recognition of this genetic entity will permit earlier diagnosis and enable the development of targeted therapies.
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http://dx.doi.org/10.1212/WNL.0000000000001305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351660PMC
March 2015

GRIN2A: an aptly named gene for speech dysfunction.

Neurology 2015 Feb 16;84(6):586-93. Epub 2015 Jan 16.

From the Department of Paediatrics (S.J.T., S.A.M., A.T.M., I.E.S.), The University of Melbourne, The Royal Children's Hospital, Parkville; Language and Literacy Group (A.K.M., A.T.M.), Population Health Theme, Murdoch Childrens Research Institute, Parkville; Speech Pathology Department (A.V.), The Royal Children's Hospital, Parkville; Department of Radiology (S.A.M.), The University of Melbourne, Parkville; Epilepsy Research Centre (I.E.S.), Department of Medicine, The University of Melbourne, Austin Health, Melbourne; and Florey Institute of Neuroscience and Mental Health (S.A.M., I.E.S.), Melbourne, Australia.

Objective: To delineate the specific speech deficits in individuals with epilepsy-aphasia syndromes associated with mutations in the glutamate receptor subunit gene GRIN2A.

Methods: We analyzed the speech phenotype associated with GRIN2A mutations in 11 individuals, aged 16 to 64 years, from 3 families. Standardized clinical speech assessments and perceptual analyses of conversational samples were conducted.

Results: Individuals showed a characteristic phenotype of dysarthria and dyspraxia with lifelong impact on speech intelligibility in some. Speech was typified by imprecise articulation (11/11, 100%), impaired pitch (monopitch 10/11, 91%) and prosody (stress errors 7/11, 64%), and hypernasality (7/11, 64%). Oral motor impairments and poor performance on maximum vowel duration (8/11, 73%) and repetition of monosyllables (10/11, 91%) and trisyllables (7/11, 64%) supported conversational speech findings. The speech phenotype was present in one individual who did not have seizures.

Conclusions: Distinctive features of dysarthria and dyspraxia are found in individuals with GRIN2A mutations, often in the setting of epilepsy-aphasia syndromes; dysarthria has not been previously recognized in these disorders. Of note, the speech phenotype may occur in the absence of a seizure disorder, reinforcing an important role for GRIN2A in motor speech function. Our findings highlight the need for precise clinical speech assessment and intervention in this group. By understanding the mechanisms involved in GRIN2A disorders, targeted therapy may be designed to improve chronic lifelong deficits in intelligibility.
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http://dx.doi.org/10.1212/WNL.0000000000001228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335991PMC
February 2015

Quantitative assessment of corpus callosum morphology in periventricular nodular heterotopia.

Epilepsy Res 2015 Jan 30;109:40-7. Epub 2014 Oct 30.

Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.

We investigated systematic differences in corpus callosum morphology in periventricular nodular heterotopia (PVNH). Differences in corpus callosum mid-sagittal area and subregional area changes were measured using an automated software-based method. Heterotopic gray matter deposits were automatically labeled and compared with corpus callosum changes. The spatial pattern of corpus callosum changes were interpreted in the context of the characteristic anterior-posterior development of the corpus callosum in healthy individuals. Individuals with periventricular nodular heterotopia were imaged at the Melbourne Brain Center or as part of the multi-site Epilepsy Phenome Genome project. Whole brain T1 weighted MRI was acquired in cases (n=48) and controls (n=663). The corpus callosum was segmented on the mid-sagittal plane using the software "yuki". Heterotopic gray matter and intracranial brain volume was measured using Freesurfer. Differences in corpus callosum area and subregional areas were assessed, as well as the relationship between corpus callosum area and heterotopic GM volume. The anterior-posterior distribution of corpus callosum changes and heterotopic GM nodules were quantified using a novel metric and compared with each other. Corpus callosum area was reduced by 14% in PVNH (p=1.59×10(-9)). The magnitude of the effect was least in the genu (7% reduction) and greatest in the isthmus and splenium (26% reduction). Individuals with higher heterotopic GM volume had a smaller corpus callosum. Heterotopic GM volume was highest in posterior brain regions, however there was no linear relationship between the anterior-posterior position of corpus callosum changes and PVNH nodules. Reduced corpus callosum area is strongly associated with PVNH, and is probably associated with abnormal brain development in this neurological disorder. The primarily posterior corpus callosum changes may inform our understanding of the etiology of PVNH. Our results suggest that interhemispheric pathways are affected in PVNH.
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http://dx.doi.org/10.1016/j.eplepsyres.2014.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272571PMC
January 2015

Is focal cortical dysplasia sporadic? Family evidence for genetic susceptibility.

Epilepsia 2014 Mar 6;55(3):e22-6. Epub 2014 Feb 6.

Department of Neurology, Royal Children's Hospital, Melbourne, Victoria, Australia; Murdoch Childrens Research Institute, Melbourne, Victoria, Australia; Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.

Focal cortical dysplasia is a common cortical malformation and an important cause of epilepsy. There is evidence for shared molecular mechanisms underlying cortical dysplasia, ganglioglioma, hemimegalencephaly, and dysembryoplastic neuroepithelial tumor. However, there are no familial reports of typical cortical dysplasia or co-occurrence of cortical dysplasia and related lesions within the same pedigree. We report the clinical, imaging, and histologic features of six pedigrees with familial cortical dysplasia and related lesions. Twelve patients from six pedigrees were ascertained from pediatric and adult epilepsy centers, eleven of whom underwent epilepsy surgery. Pedigree data, clinical information, neuroimaging findings, and histopathologic features are presented. The families comprise brothers with focal cortical dysplasia, a male and his sister with focal cortical dysplasia, a female with focal cortical dysplasia and her brother with hemimegalencephaly, a female with focal cortical dysplasia and her female first cousin with ganglioglioma, a female with focal cortical dysplasia and her male cousin with dysembryoplastic neuroepithelial tumor, and a female and her nephew with focal cortical dysplasia. This series shows that focal cortical dysplasia can be familial and provides clinical evidence suggesting that cortical dysplasia, hemimegalencephaly, ganglioglioma, and dysembryoplastic neuroepithelial tumors may share common genetic determinants.
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http://dx.doi.org/10.1111/epi.12533DOI Listing
March 2014

Pulmonary capillary haemangiomatosis in a premature infant.

Pediatr Radiol 2005 Jun 16;35(6):635-40. Epub 2005 Feb 16.

Royal Children's Hospital, University of Melbourne, Flemington Road, Parkville, VIC 3052, Australia.

Pulmonary capillary haemangiomatosis (PCH) is a rare disorder characterized by widespread capillary proliferation in the lung, infiltrating the interstitium and the alveolar walls. We present the HRCT features of PCH in a surviving ex-premature infant. To our knowledge, this is a unique case of the radiological features of PCH in a young living infant.
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http://dx.doi.org/10.1007/s00247-004-1374-6DOI Listing
June 2005

Anterior temporal changes on MR images of children with hippocampal sclerosis: an effect of seizures on the immature brain?

AJNR Am J Neuroradiol 2003 Sep;24(8):1670-7

Department of Radiology, Royal Children's Hospital, Melbourne, Australia.

Background And Purpose: Ipsilateral loss of anterior temporal gray-white matter definition, due mainly to white matter signal intensity abnormality, is frequently seen on MR images of patients with hippocampal sclerosis. Our aim was to determine the prevalence and clinical correlations of these anterior temporal changes in pediatric cases of hippocampal sclerosis and to determine whether cumulative damage from seizures is important for their development.

Methods: We reviewed the MR images and clinical details of 54 children (age range, 1.5-19 years) with typical hippocampal sclerosis. Specific imaging features noted included hippocampal sclerosis, anterior temporal changes, anterior temporal atrophy, and extra-hippocampal abnormality.

Results: Thirty-one (57%) of 54 children with hippocampal sclerosis had associated ipsilateral anterior temporal changes. Ipsilateral anterior temporal atrophy was associated with anterior temporal changes (P <.03). Children whose images showed anterior temporal changes were younger at onset of epilepsy (P <.01) and younger at antecedent cerebral insult (P <.03) than those with normal anterior temporal lobes. Most (84%) children whose images showed anterior temporal changes had experienced the onset of epilepsy or antecedent cerebral insult before the age of 2 years (P <.0009). Eighty-one percent of children with anterior temporal changes shown on their images experienced seizures at the time of antecedent insult.

Conclusion: Ipsilateral anterior temporal changes identical to those observed in adult cases are seen on the MR images of young children with hippocampal sclerosis, with a similar prevalence, and are associated with either epilepsy onset or seizure-related cerebral insult before the age of 2 years. We suggest that the loss of gray-white matter definition may represent a persistent immature appearance, including an abnormality of myelin or myelination, possibly a result of seizures occurring during maturation of the temporal pole.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973983PMC
September 2003
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