Publications by authors named "Richard J Leventer"

122 Publications

Large-scale functional network dynamics in human callosal agenesis: Increased subcortical involvement and preserved laterality.

Neuroimage 2021 Nov 27;243:118471. Epub 2021 Aug 27.

Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Switzerland; Department of Radiology and Medical Informatics, University of Geneva, Geneva, Switzerland.

In the human brain, the corpus callosum is the major white-matter commissural tract enabling the transmission of sensory-motor, and higher level cognitive information between homotopic regions of the two cerebral hemispheres. Despite developmental absence (i.e., agenesis) of the corpus callosum (AgCC), functional connectivity is preserved, including interhemispheric connectivity. Subcortical structures have been hypothesised to provide alternative pathways to enable this preservation. To test this hypothesis, we used functional Magnetic Resonance Imaging (fMRI) recordings in children with AgCC and typically developing children, and a time-resolved approach to retrieve temporal characteristics of whole-brain functional networks. We observed an increased engagement of the cerebellum and amygdala/hippocampus networks in children with AgCC compared to typically developing children. There was little evidence that laterality of activation networks was affected in AgCC. Our findings support the hypothesis that subcortical structures play an essential role in the functional reconfiguration of the brain in the absence of a corpus callosum.
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http://dx.doi.org/10.1016/j.neuroimage.2021.118471DOI Listing
November 2021

A systematic review of brain MRI findings in monogenic disorders strongly associated with autism spectrum disorder.

J Child Psychol Psychiatry 2021 Aug 23. Epub 2021 Aug 23.

Murdoch Children's Research Institute, Parkville, Vic., Australia.

Background: Research on monogenic forms of autism spectrum disorder (autism) can inform our understanding of genetic contributions to the autism phenotype; yet, there is much to be learned about the pathways from gene to brain structure to behavior. This systematic review summarizes and evaluates research on brain magnetic resonance imaging (MRI) findings in monogenic conditions that have strong association with autism. This will improve understanding of the impact of genetic variability on brain structure and related behavioral traits in autism.

Methods: The search strategy for this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Risk of bias (ROB) assessment was completed on included studies using the Newcastle-Ottawa Scales.

Results: Of 4,287 studies screened, 69 were included pertaining to 13 of the top 20 genes with the strongest association with autism. The greatest number of studies related to individuals with PTEN variants and autism. Brain MRI abnormalities were reported for 12 of the 13 genes studied, and in 51.7% of participants across all 13 genes, including 100% of participants with ARID1B variants. Specific MRI findings were highly variable, with no clear patterns emerging within or between the 13 genes, although white matter abnormalities were the most common. Few studies reported specific details about methods for acquisition and processing of brain MRI, and descriptors for brain abnormalities were variable. ROB assessment indicated high ROB for all studies, largely due to small sample sizes and lack of comparison groups.

Conclusions: Brain abnormalities are common in this population of individuals, in particular, children; however, a range of different brain abnormalities were reported within and between genes. Directions for future neuroimaging research in monogenic autism are suggested.
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http://dx.doi.org/10.1111/jcpp.13510DOI Listing
August 2021

Guillain-Barré syndrome with optic neuritis.

J Paediatr Child Health 2021 Jul 31. Epub 2021 Jul 31.

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

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http://dx.doi.org/10.1111/jpc.15656DOI Listing
July 2021

Intra- and inter-hemispheric structural connectome in agenesis of the corpus callosum.

Neuroimage Clin 2021 5;31:102709. Epub 2021 Jun 5.

Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Switzerland; Department of Radiology and Medical Informatics, University of Geneva, Geneva, Switzerland; Brain and Mind Research, Clinical Sciences, Murdoch Children's Research Institute, Melbourne, Australia; Division of Development and Growth, Department of Paediatrics, Faculty of Medicine, University of Geneva, Switzerland. Electronic address:

Agenesis of the corpus callosum (AgCC) is a congenital brain malformation characterized by the complete or partial failure to develop the corpus callosum. Despite missing the largest white matter bundle connecting the left and right hemispheres of the brain, studies have shown preserved inter-hemispheric communication in individuals with AgCC. It is likely that plasticity provides mechanisms for the brain to adjust in the context of AgCC, as the malformation disrupts programmed developmental brain processes very early on. A proposed candidate for neuroplastic response in individuals with AgCC is strengthening of intra-hemispheric structural connections. In the present study, we explore this hypothesis using a graph-based approach of the structural connectome, which enables intra- and inter-hemispheric analyses at multiple resolutions and quantification of structural characteristics through graph metrics. Structural graph metrics of 19 children with AgCC (13 with complete, 6 with partial AgCC) were compared to those of 29 typically developing controls (TDC). Associations between structural graph metrics and a wide range of neurobehavioral outcomes were examined using a multivariate data-driven approach (Partial Least Squares Correlation, PLSC). Our results provide new evidence suggesting structural strengthening of intra-hemispheric pathways as a neuroplastic response in the acallosal brain, and highlight regional variability in structural connectivity in children with AgCC compared to TDC. There was little evidence that structural graph properties in children with AgCC were associated with neurobehavioral outcomes. To our knowledge, this is the first report leveraging graph theory tools to explicitly characterize whole-brain intra- and inter-hemispheric structural connectivity in AgCC, opening avenues for future research on neuroplastic responses in AgCC.
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http://dx.doi.org/10.1016/j.nicl.2021.102709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209843PMC
September 2021

Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations.

Am J Med Genet A 2021 10 4;185(10):2941-2950. Epub 2021 Jun 4.

Murdoch Children's Research Institute, Parkville, Australia.

Pathogenic heterozygous variants in HMBS encoding the enzyme hydroxymethylbilane synthase (HMBS), also known as porphobilinogen deaminase, cause acute intermittent porphyria (AIP). Biallelic variants in HMBS have been reported in a small number of children with severe progressive neurological disease and in three adult siblings with a more slowly, progressive neurological disease and distinct leukoencephalopathy. We report three further adult individuals who share a distinct pattern of white matter abnormality on brain MRI in association with biallelic variants in HMBS, two individuals with homozygous variants, and one with compound-heterozygous variants. We present their clinical and radiological features and compare these with the three adult siblings previously described with leukoencephalopathy and biallelic HMBS variants. All six affected individuals presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. This recognizable pattern of MRI abnormalities is seen in all six adults described here. Biallelic variants in HMBS cause a phenotype that is distinct from AIP. It is not known whether AIP treatments benefit individuals with HMBS-related leukoencephalopathy. One individual reported here had improved neurological function for 12 months following liver transplantation followed by decline and progression of disease.
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http://dx.doi.org/10.1002/ajmg.a.62377DOI Listing
October 2021

Revisiting brain rewiring and plasticity in children born without corpus callosum.

Dev Sci 2021 Jun 1. Epub 2021 Jun 1.

Medical Image Processing Lab, Institute of Bioengineering, Center for Neuroprosthetics, Ecole Polytechnique Fédérale de Lausanne, Lausanne, VD, Switzerland.

The corpus callosum is the largest white matter pathway connecting homologous structures of the two cerebral hemispheres. Remarkably, children and adults with developmental absence of the corpus callosum (callosal dysgenesis, CD) show typical interhemispheric integration, which is classically impaired in adult split-brain patients, for whom the corpus callosum is surgically severed. Tovar-Moll and colleagues (2014) proposed alternative neural pathways involved in the preservation of interhemispheric transfer. In a sample of six adults with CD, they revealed two homotopic bundles crossing the midline via the anterior and posterior commissures and connecting parietal cortices, and the microstructural properties of these aberrant bundles were associated with functional connectivity of these regions. The aberrant bundles were specific to CD and not visualised in healthy brains. We extended this study in a developmental cohort of 20 children with CD and 29 typically developing controls (TDC). The two anomalous white-matter bundles were visualised using tractography. Associations between structural properties of these bundles and their regional functional connectivity were explored. The proposed atypical bundles were observed in 30% of our CD cohort crossing via the anterior commissure, and in 30% crossing via the posterior commissure (also observed in 6.9% of TDC). However, the structural property measures of these bundles were not associated with parietal functional connectivity, bringing into question their role and implication for interhemispheric functional connectivity in CD. It is possible that very early disruption of embryological callosal development enhances neuroplasticity and facilitates the formation of these proposed alternative neural pathways, but further evidence is needed.
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http://dx.doi.org/10.1111/desc.13126DOI Listing
June 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

Clonally Focused Public and Private T Cells in Resected Brain Tissue From Surgeries to Treat Children With Intractable Seizures.

Front Immunol 2021 6;12:664344. Epub 2021 Apr 6.

Department of Neurosurgery, David Geffen School of Medicine at the University of California, Los Angeles, CA, United States.

Using a targeted transcriptomics approach, we have analyzed resected brain tissue from a cohort of 53 pediatric epilepsy surgery cases, and have found that there is a spectrum of involvement of both the innate and adaptive immune systems as evidenced by the differential expression of immune-specific genes in the affected brain tissue. The specimens with the highest expression of immune-specific genes were from two Rasmussen encephalitis cases, which is known to be a neuro-immunological disease, but also from tuberous sclerosis complex (TSC), focal cortical dysplasia, and hemimegalencephaly surgery cases. We obtained T cell receptor (TCR) Vβ chain sequence data from brain tissue and blood from patients with the highest levels of T cell transcripts. The clonality indices and the frequency of the top 50 Vβ clonotypes indicated that T cells in the brain were clonally restricted. The top 50 Vβ clonotypes comprised both public and private (patient specific) clonotypes, and the TCR Vβ chain third complementarity region (CDR3) of the most abundant public Vβ clonotype in each brain sample was strikingly similar to a CDR3 that recognizes an immunodominant epitope in either human cytomegalovirus or Epstein Barr virus, or influenza virus A. We found that the frequency of 14 of the top 50 brain Vβ clonotypes from a TSC surgery case had significantly increased in brain tissue removed to control recurrent seizures 11 months after the first surgery. Conversely, we found that the frequency in the blood of 18 of the top 50 brain clonotypes from a second TSC patient, who was seizure free, had significantly decreased 5 months after surgery indicating that T cell clones found in the brain had contracted in the periphery after removal of the brain area associated with seizure activity and inflammation. However, the frequency of a public and a private clonotype significantly increased in the brain after seizures recurred and the patient underwent a second surgery. Combined single cell gene expression and TCR sequencing of brain-infiltrating leukocytes from the second surgery showed that the two clones were CD8 effector T cells, indicating that they are likely to be pathologically relevant.
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http://dx.doi.org/10.3389/fimmu.2021.664344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056262PMC
April 2021

DCC regulates astroglial development essential for telencephalic morphogenesis and corpus callosum formation.

Elife 2021 04 19;10. Epub 2021 Apr 19.

The University of Queensland, Queensland Brain Institute, Brisbane, Australia.

The forebrain hemispheres are predominantly separated during embryogenesis by the interhemispheric fissure (IHF). Radial astroglia remodel the IHF to form a continuous substrate between the hemispheres for midline crossing of the corpus callosum (CC) and hippocampal commissure (HC). Deleted in colorectal carcinoma (DCC) and netrin 1 (NTN1) are molecules that have an evolutionarily conserved function in commissural axon guidance. The CC and HC are absent in and knockout mice, while other commissures are only partially affected, suggesting an additional aetiology in forebrain commissure formation. Here, we find that these molecules play a critical role in regulating astroglial development and IHF remodelling during CC and HC formation. Human subjects with mutations display disrupted IHF remodelling associated with CC and HC malformations. Thus, axon guidance molecules such as DCC and NTN1 first regulate the formation of a midline substrate for dorsal commissures prior to their role in regulating axonal growth and guidance across it.
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http://dx.doi.org/10.7554/eLife.61769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116049PMC
April 2021

Cerebrospinal fluid liquid biopsy for detecting somatic mosaicism in brain.

Brain Commun 2021 21;3(1):fcaa235. Epub 2021 Jan 21.

Department of Medicine (Austin Health), University of Melbourne, Melbourne, Victoria 3084, Australia.

Brain somatic mutations are an increasingly recognized cause of epilepsy, brain malformations and autism spectrum disorders and may be a hidden cause of other neurodevelopmental and neurodegenerative disorders. At present, brain mosaicism can be detected only in the rare situations of autopsy or brain biopsy. Liquid biopsy using cell-free DNA derived from cerebrospinal fluid has detected somatic mutations in malignant brain tumours. Here, we asked if cerebrospinal fluid liquid biopsy can be used to detect somatic mosaicism in non-malignant brain diseases. First, we reliably quantified cerebrospinal fluid cell-free DNA in 28 patients with focal epilepsy and 28 controls using droplet digital PCR. Then, in three patients we identified somatic mutations in cerebrospinal fluid: in one patient with subcortical band heterotopia the p. Lys64* variant at 9.4% frequency; in a second patient with focal cortical dysplasia the p. Phe581His*6 variant at 7.8% frequency; and in a third patient with ganglioglioma the p. Val600Glu variant at 3.2% frequency. To determine if cerebrospinal fluid cell-free DNA was brain-derived, whole-genome bisulphite sequencing was performed and brain-specific DNA methylation patterns were found to be significantly enriched ( = 0.03). Our proof of principle study shows that cerebrospinal fluid liquid biopsy is valuable in investigating mosaic neurological disorders where brain tissue is unavailable.
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http://dx.doi.org/10.1093/braincomms/fcaa235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954394PMC
January 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

Clinical seizure manifestations in the absence of synaptic connections.

Epileptic Disord 2021 Feb;23(1):167-172

Department of Neurology, The Royal Children's Hospital, Parkville, Victoria, Australia, The University of Melbourne, Parkville, Victoria, Australia, Murdoch Children's Research Institute, Parkville, Victoria, Australia.

We report a child with a history of temporal-parietal-occipital disconnection for epilepsy secondary to posterior quadrantic dysplasia who developed recurrent and prolonged bouts of distress and autonomic disturbance associated with EEG and PET evidence of status epilepticus confined to his disconnected cortex. These bouts were refractory to antiseizure medications but resolved following resection of the disconnected cortex. In the absence of synaptic connections, we hypothesise that his seizure-related symptoms were mediated either by neurochemical transmission in preserved vascular and lymphatic channels or by ephaptic transmission to trigeminal nerve fibres in overlying dura, producing symptoms akin to migraine. The case highlights potential means by which seizures may manifest clinically, without synaptic connections, and adds to the differential for symptoms post-disconnection surgery.
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http://dx.doi.org/10.1684/epd.2021.1252DOI Listing
February 2021

Genetic heterogeneity of polymicrogyria: study of 123 patients using deep sequencing.

Brain Commun 2021 26;3(1):fcaa221. Epub 2020 Dec 26.

Murdoch Children's Research Institute, Melbourne, 3052, Australia.

Polymicrogyria is a malformation of cortical development characterized by overfolding and abnormal lamination of the cerebral cortex. Manifestations include epilepsy, speech disturbance and motor and cognitive disability. Causes include acquired prenatal insults and inherited and genetic variants. The proportion of patients with polymicrogyria and a causative germline or mosaic variant is not known. The aim of this study was to identify the monogenic causes of polymicrogyria in a heterogeneous cohort of patients reflective of specialized referral services. Patients with polymicrogyria were recruited from two clinical centres in Australia and Belgium. Patients with evidence of congenital cytomegalovirus infection or causative chromosomal copy number variants were excluded. One hundred and twenty-three patients were tested using deep sequencing gene panels including known and candidate genes for malformations of cortical development. Causative and potentially causative variants were identified and correlated with phenotypic features. Pathogenic or likely pathogenic variants were identified in 25/123 (20.3%) patients. A candidate variant was identified for an additional patient but could not be confirmed as , and therefore it was classified as being of uncertain significance with high clinical relevance. Of the 22 dominant variants identified, 5 were mosaic with allele fractions less than 0.33 and the lowest allele fraction 0.09. The most common causative genes were and . The other eleven causative genes were , , and . A genetic cause was more likely to be identified in the presence of an abnormal head size or additional brain malformations suggestive of a tubulinopathy, such as dysmorphic basal ganglia. A gene panel test provides greater sequencing depth and sensitivity for mosaic variants than whole exome or genome sequencing but is limited to the genes included, potentially missing variants in newly discovered genes. The diagnostic yield of 20.3% indicates that polymicrogyria may be associated with genes not yet known to be associated with brain malformations, brain-specific somatic mutations or non-genetic causes.
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http://dx.doi.org/10.1093/braincomms/fcaa221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878248PMC
December 2020

Speech, Language, and Oromotor Skills in Patients With Polymicrogyria.

Neurology 2021 04 15;96(14):e1898-e1912. Epub 2021 Feb 15.

From Murdoch Children's Research Institute (R.O.B., J.O.B., C.A.S., K.P., R.J.L., I.E.S., A.T.M.); Departments of Audiology and Speech Pathology (R.O.B., J.O.B., A.T.M.) and Paediatrics (C.A.S., R.J.L., I.E.S.), University of Melbourne; The Royal Children's Hospital (C.A.S., K.P., R.J.L., I.E.S., A.T.M.); Victorian Clinical Genetics Service (C.A.S., K.P.), Parkville, Victoria; Hunter Genetics (H.G.), John Hunter Hospital, New Lambton Heights, New South Wales; Austin Health (I.E.S.), Heidelberg, Victoria; and Florey Institute of Neuroscience and Mental Health (I.E.S.), Parkville, Victoria, Australia.

Objective: To determine whether specific speech, language, and oromotor profiles are associated with different patterns of polymicrogyria, we assessed 52 patients with polymicrogyria using a battery of standardized tests and correlated findings with topography and severity of polymicrogyria.

Methods: Patients were identified via clinical research databases and invited to participate, irrespective of cognitive and verbal language abilities. We conducted standardized assessments of speech, oromotor structure and function, language, and nonverbal IQ. Data were analyzed according to normative assessment data and descriptive statistics. We conducted a correlation analysis between topographic pattern and speech and language findings.

Results: Fifty-two patients (33 male, 63%) were studied at an average age of 12.7 years (range 2.5-36 years). All patients had dysarthria, which ranged from mild impairment to anarthria. Developmental speech errors (articulation and phonology), oral motor structure and function deficits, and language disorder were frequent. A total of 23/29 (79%) had cognitive abilities in the low average to extremely low range. In the perisylvian polymicrogyria group (36/52), speech, everyday language, and oral motor impairments were more severe, compared to generalized (1 patient), frontal (3), polymicrogyria with periventricular nodular heterotopia (3), parasagittal parieto-occipital (1), mesial occipital (1), and other (7) patterns.

Conclusions: Dysarthria is a core feature of polymicrogyria, often accompanied by receptive and expressive language impairments. These features are associated with all polymicrogyria distribution patterns and more severe in individuals with bilateral polymicrogyria, particularly in the perisylvian region.
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http://dx.doi.org/10.1212/WNL.0000000000011698DOI Listing
April 2021

The severe epilepsy syndromes of infancy: A population-based study.

Epilepsia 2021 02 21;62(2):358-370. Epub 2021 Jan 21.

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

Objective: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes.

Methods: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined.

Results: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased.

Significance: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.
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http://dx.doi.org/10.1111/epi.16810DOI Listing
February 2021

Gradient of brain mosaic RHEB variants causes a continuum of cortical dysplasia.

Ann Clin Transl Neurol 2021 02 12;8(2):485-490. Epub 2021 Jan 12.

Department of Paediatrics, The University of Melbourne, Parkville, 3052, Australia.

Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are related malformations with shared etiologies. We report three patients with a spectrum of cortical malformations associated with pathogenic brain-specific somatic Ras homolog enriched in brain (RHEB) variants. The somatic variant load directly correlated with the size of the malformation, with upregulated mTOR activity confirmed in dysplastic tissues. Laser capture microdissection showed enrichment of RHEB variants in dysmorphic neurons and balloon cells. Our findings support the role of RHEB in a spectrum of cortical malformations confirming that FCD and HME represent a disease continuum, with the extent of dysplastic brain directly correlated with the somatic variant load.
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http://dx.doi.org/10.1002/acn3.51286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886042PMC
February 2021

The spectrum of brain malformations and disruptions in twins.

Am J Med Genet A 2021 09 18;185(9):2690-2718. Epub 2020 Nov 18.

Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA.

Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband twins and 7 less affected co-twins with abnormal brain imaging and compared them to population-based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11). The MCD group included 37/39 (95%) with polymicrogyria (PMG), 8/39 (21%) with pia-ependymal clefts (schizencephaly), and 15/39 (38%) with periventricular nodular heterotopia (PNH) including 2 with PNH but not PMG. Cerebellar malformations were found in 19 individuals including 13 with a cerebellar malformation only and another 6 with cerebellar malformation and MCD. The pattern varied from diffuse cerebellar hypoplasia to classic Dandy-Walker malformation. Brain disruptions were seen in 11 individuals with hydranencephaly, porencephaly, or white matter loss without cysts. Our series included an expected statistically significant excess of monozygotic (MZ) twin pairs (22/41 MZ, 54%) compared to population data (482/1448 MZ, 33.3%; p = .0110), and an unexpected statistically significant excess of dizygotic (DZ) twins (19/41, 46%) compared to the literature cohort (1/46 DZ, 2%; p < .0001. Recurrent association with twin-twin transfusion syndrome, intrauterine growth retardation, and other prenatal factors support disruption of vascular perfusion as the most likely unifying cause.
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http://dx.doi.org/10.1002/ajmg.a.61972DOI Listing
September 2021

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns.

Genet Med 2021 02 4;23(2):363-373. Epub 2020 Nov 4.

Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy.

Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy.

Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism.

Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
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http://dx.doi.org/10.1038/s41436-020-00988-9DOI Listing
February 2021

Structural Neuroplastic Responses Preserve Functional Connectivity and Neurobehavioural Outcomes in Children Born Without Corpus Callosum.

Cereb Cortex 2021 01;31(2):1227-1239

Institute of Bioengineering, Center for Neuroprosthetics, Ecole Polytechnique Fédérale de Lausanne, Geneva, Geneva 1202, Switzerland.

The corpus callosum is the largest white matter pathway in the brain connecting the two hemispheres. In the context of developmental absence (agenesis) of the corpus callosum (AgCC), a proposed candidate for neuroplastic response is strengthening of intrahemispheric pathways. To test this hypothesis, we assessed structural and functional connectivity in a uniquely large cohort of children with AgCC (n = 20) compared with typically developing controls (TDC, n = 29), and then examined associations with neurobehavioral outcomes using a multivariate data-driven approach (partial least squares correlation, PLSC). For structural connectivity, children with AgCC showed a significant increase in intrahemispheric connectivity in addition to a significant decrease in interhemispheric connectivity compared with TDC, in line with the aforementioned hypothesis. In contrast, for functional connectivity, children with AgCC and TDC showed a similar pattern of intrahemispheric and interhemispheric connectivity. In conclusion, we observed structural strengthening of intrahemispheric pathways in children born without corpus callosum, which seems to allow for functional connectivity comparable to a typically developing brain, and were relevant to explain neurobehavioral outcomes in this population. This neuroplasticity might be relevant to other disorders of axonal guidance, and developmental disorders in which corpus callosum alteration is observed.
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http://dx.doi.org/10.1093/cercor/bhaa289DOI Listing
January 2021

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Am J Med Genet A 2021 01 7;185(1):15-25. Epub 2020 Oct 7.

Department of Paediatric Neurology, University Hospital of Wales, Cardiff, UK.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.
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http://dx.doi.org/10.1002/ajmg.a.61907DOI Listing
January 2021

Chudley-McCullough Syndrome: A Recognizable Clinical Entity Characterized by Deafness and Typical Brain Malformations.

J Child Neurol 2021 02 4;36(2):152-158. Epub 2020 Oct 4.

Neurogenetics Research Group, Reproduction-Genetics & Regenerative Medicine Research Cluster, Vrije Universiteit Brussel, Brussels, Belgium.

Chudley-McCullough syndrome, a rare autosomal recessive disorder due to pathogenic variants in the (G-protein signaling modulator 2) gene, is characterized by early-onset sensorineural deafness and a typical combination of brain malformations, including ventriculomegaly, (partial) agenesis of the corpus callosum, cerebellar dysplasia, arachnoid cysts, frontal subcortical heterotopia, and midline polymicrogyria. When hearing loss is managed early, most patients have minor or no impairment of motor and cognitive development, despite the presence of brain malformations. We report 2 cases of Chudley-McCullough syndrome, one presenting with congenital deafness and normal development except for speech delay and one presenting prenatally with ventriculomegaly and an atypical postnatal course characterized by epileptic spasms, deafness, and moderate intellectual disability. These highlight the challenges faced by clinicians when predicting prognosis based on pre- or postnatal imaging of brain malformations. We have also reviewed the phenotype and genotype of previous published cases to better understand Chudley-McCullough syndrome.
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http://dx.doi.org/10.1177/0883073820960314DOI Listing
February 2021

Bilateral polymicrogyria associated with dystonia: A new neurogenetic syndrome?

Am J Med Genet A 2020 10 17;182(10):2207-2213. Epub 2020 Aug 17.

Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and pyramidal signs. Extrapyramidal features are extremely rare. We present four apparently unrelated patients with a unique association of PMG with dystonia. The clinical, genetic, and radiologic features are described and possible mechanisms of dystonia are discussed. All patients were female and two were born to consanguineous families. All presented with early childhood onset dystonia. Other neurologic symptoms and signs classically seen in bilateral perisylvian PMG were observed, including oromotor dysfunction and speech abnormalities ranging from dysarthria to anarthria (4/4), pyramidal signs (3/4), hypotonia (3/4), postnatal microcephaly (1/4), and seizures (1/4). Neuroimaging showed a unique pattern of bilateral PMG with an infolded cortex originating primarily from the perisylvian region in three out of four patients. Whole exome sequencing was performed in two out of four patients and did not reveal pathogenic variants in known genes for cortical malformations or movement disorders. The dystonia seen in our patients is not described in bilateral PMG and suggests an underlying mechanism of impaired connectivity within the motor network or compromised cortical inhibition. The association of bilateral PMG with dystonia in our patients may represent a new neurogenetic disorder.
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http://dx.doi.org/10.1002/ajmg.a.61795DOI Listing
October 2020

International consensus recommendations on the diagnostic work-up for malformations of cortical development.

Nat Rev Neurol 2020 Nov 7;16(11):618-635. Epub 2020 Sep 7.

Institute for Clinical Genetics, TU Dresden, Dresden, Germany.

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk.
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http://dx.doi.org/10.1038/s41582-020-0395-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790753PMC
November 2020

Genetic characterization identifies bottom-of-sulcus dysplasia as an mTORopathy.

Neurology 2020 11 26;95(18):e2542-e2551. Epub 2020 Aug 26.

From the Bruce Lefroy Centre (W.S.L., S.E.M.S., K.P., G.G., P.J.L.), Murdoch Children's Research Institute (W.M., A.S.H., R.J.L.); Department of Paediatrics (W.S.L., S.E.M.S., W.M., E.M.-L., A.S.H., R.J.L., P.J.L.), The University of Melbourne; Departments of Neurosurgery (W.M.), Neurology (E.M.-L., A.S.H., R.J.L.), and Anatomical Pathology (D.M., C.D.), The Royal Children's Hospital, Parkville; and Melbourne Brain Centre (G.J.), The Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia.

Objective: To determine the genetic basis of bottom-of-sulcus dysplasia (BOSD), which is a highly focal and epileptogenic cortical malformation in which the imaging, electrophysiologic, and pathologic abnormalities are maximal at the bottom of sulcus, tapering to a normal gyral crown.

Methods: Targeted panel deep sequencing (>500×) was performed on paired blood and brain-derived genomic DNA from 20 operated patients with drug-resistant focal epilepsy and BOSD. Histopathology was assessed using immunohistochemistry.

Results: Brain-specific pathogenic somatic variants were found in 6 patients and heterozygous pathogenic germline variants were found in 2. Somatic variants were identified in and germline variants were identified in and . Two patients with somatic variants showed a mutation gradient, with higher mutation load at the bottom of sulcus compared to the gyral crown. Immunohistochemistry revealed an abundance of dysmorphic neurons and balloon cells in the bottom of sulcus but not in the gyral crown or adjacent gyri.

Conclusions: BOSD is associated with mTOR pathway dysregulation and shares common genetic etiologies and pathogenic mechanisms with other forms of focal and hemispheric cortical dysplasia, suggesting these disorders are on a genetic continuum.
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http://dx.doi.org/10.1212/WNL.0000000000010670DOI Listing
November 2020

Definitions and classification of malformations of cortical development: practical guidelines.

Brain 2020 10;143(10):2874-2894

Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Malformations of cortical development are a group of rare disorders commonly manifesting with developmental delay, cerebral palsy or seizures. The neurological outcome is extremely variable depending on the type, extent and severity of the malformation and the involved genetic pathways of brain development. Neuroimaging plays an essential role in the diagnosis of these malformations, but several issues regarding malformations of cortical development definitions and classification remain unclear. The purpose of this consensus statement is to provide standardized malformations of cortical development terminology and classification for neuroradiological pattern interpretation. A committee of international experts in paediatric neuroradiology prepared systematic literature reviews and formulated neuroimaging recommendations in collaboration with geneticists, paediatric neurologists and pathologists during consensus meetings in the context of the European Network Neuro-MIG initiative on Brain Malformations (https://www.neuro-mig.org/). Malformations of cortical development neuroimaging features and practical recommendations are provided to aid both expert and non-expert radiologists and neurologists who may encounter patients with malformations of cortical development in their practice, with the aim of improving malformations of cortical development diagnosis and imaging interpretation worldwide.
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http://dx.doi.org/10.1093/brain/awaa174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586092PMC
October 2020

Defining the phenotypical spectrum associated with variants in .

J Med Genet 2021 01 22;58(1):33-40. Epub 2020 Jun 22.

Neurogenetics Research Group, Reproduction Genetics and Regenerative Medicine Research Cluster, Vrije Universiteit Brussel, Brussels, Belgium.

Background: Variants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis.

Methods: In order to further refine the phenotypical spectrum associated with , clinical and imaging features of 12 patients with pathogenic variants, recruited via the international network of the authors, were reviewed.

Results: We report 12 patients with eight novel and one recurrent variants spread throughout the gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy.

Conclusion: The imaging phenotype associated with pathogenic variants in is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype-phenotype correlations could be established, suggesting the role of additional modifiers.
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http://dx.doi.org/10.1136/jmedgenet-2019-106740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803914PMC
January 2021

Parental health spillover effects of paediatric rare genetic conditions.

Qual Life Res 2020 Sep 7;29(9):2445-2454. Epub 2020 Apr 7.

Centre for Health Policy, University of Melbourne, Melbourne, VIC, Australia.

Purpose: The complexity and severity of rare genetic conditions pose substantial burden to families. While the importance of spillovers on carers' health in resource allocation decisions is increasingly recognised, there is significant lack of empirical evidence in the context of rare diseases. The objective of this study was to estimate the health spillovers of paediatric rare genetic conditions on parents.

Methods: Health-related quality-of-life (HRQoL) data from children with rare genetic conditions (genetic kidney diseases, mitochondrial diseases, epileptic encephalopathies, brain malformations) and their parents were collected using the CHU9D and SF-12 measures, respectively. We used two approaches to estimate parental health spillovers. To quantify the 'absolute health spillover', we matched our parent cohort to the Australian general population. To quantify the 'relative health spillover', regression models were applied using the cohort data.

Results: Parents of affected children had significantly lower HRQoL compared to matched parents in the general public (- 0.06; 95% CIs - 0.08, - 0.04). Multivariable regression demonstrated a positive association between parental and child health. The mean magnitude of HRQoL loss in parents was estimated to be 33% of the HRQoL loss observed in children (95% CIs 21%, 46%).

Conclusion: Paediatric rare genetic conditions appear to be associated with substantial parental health spillovers. This highlights the importance of including health effects on family members and caregivers into economic evaluation of genomic technologies and personalised medicine. Overlooking spillover effects may undervalue the benefits of diagnosis and management in this context. This study also expands the knowledge of family spillover to the rare disease spectrum.
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http://dx.doi.org/10.1007/s11136-020-02497-3DOI Listing
September 2020

Autosomal dominant TUBB3-related syndrome: Fetal, radiologic, clinical and morphological features.

Eur J Paediatr Neurol 2020 May 4;26:46-60. Epub 2020 Mar 4.

Metabolic Neurogenetic Service, Wolfson Medical Center, Holon, Israel; Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Objective: To describe fetal, clinical, radiological, morphological features of TUBB3 related syndrome.

Methods: We report two families each of two generations harboring a novel and a previously described heterozygous TUBB3 pathogenic variants. We compared these patients with other published TUBB3-related cases. We describe the pathological features of dysgyria in the two aborted fetuses.

Results: The mother and son from family 1 had a history of mild developmental delay in motor and language skills and demonstrated mild cerebellar signs and mirror movements. Neuroimaging findings included: hypoplastic corpus callosum (CC), asymmetric ventriculomegaly and cerebellar vermis hypoplasia in all patients and frontal dysgyria in three. Autopsy of the fetal brain showed an unusual shape and orientation of the frontal sulci and gyri with normal cortical layering and no abnormal cell types. The mother of family 2 had congenital strabismus, mild muscle weakness on the right and a past history of developmental delay. Fetal brain MRI showed abnormal cerebral sulcation, hemispheric asymmetry, asymmetric ventriculomegaly, dysmorphic short CC and frontal cortical interdigitation. Autopsy demonstrated fronto-parietal predominant dysgyria, bilateral ventriculomegaly, hippocampal and CC hypoplasia, abnormal Sylvian fissure. Lamination and neuron morphology in the areas of dysgyria were normal.

Conclusions: TUBB3 related cortical malformations can be mild, consistent with dysgyria rather than typical pachygyria or polymicrogyria. The autopsy findings in fetal TUBB3 related dysgyria are abnormal orientation of sulci and gyri, but normal neuron morphology and layering. We suggest that TUBB3 - associated brain malformations can be suspected in-utero which in turn can aid in prognostic counselling and interpretation of genetic testing.
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http://dx.doi.org/10.1016/j.ejpn.2020.03.001DOI Listing
May 2020

Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.

Neuron 2020 04 24;106(2):237-245.e8. Epub 2020 Feb 24.

Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052, VIC, Australia; Departments of Paediatrics and Neurology, The Royal Children's Hospital, The University of Melbourne, Melbourne 3052, VIC, Australia; Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne 3084, VIC, Australia; The Florey Institute of Neuroscience and Mental Health, Melbourne 3052, VIC, Australia.

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.
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http://dx.doi.org/10.1016/j.neuron.2020.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357395PMC
April 2020

Hyperinsulinaemic hypoglycaemia: A rare association of vanishing white matter disease.

JIMD Rep 2020 Jan 12;51(1):11-16. Epub 2019 Nov 12.

Department of Metabolic Medicine Royal Children's Hospital Melbourne Australia.

We report two unrelated patients with infantile onset leukoencephalopathy with vanishing white matter (VWM) and hyperinsulinaemic hypoglycaemia. To our knowledge, this association has not been described previously. Both patients had compound heterozygous pathogenic variants in detected on exome sequencing and absence of other variants which might explain the hyperinsulinism. Hypoglycaemia became apparent at 6 and 8 months, respectively, although in one patient, transient neonatal hypoglycaemia was also documented. One patient responded to diazoxide and the other was managed with continuous nasogastric feeding. We hypothesise that the pathophysiology of hyperinsulinism in VWM may involve dysregulation of transcription of genes related to insulin secretion.
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http://dx.doi.org/10.1002/jmd2.12081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012737PMC
January 2020
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