Publications by authors named "Elisabeth Tournier-Lasserve"

107 Publications

Hemiplegic Migraine Associated With Mutations: A Clinical and Genetic Study.

Neurology 2021 Oct 14. Epub 2021 Oct 14.

Neurology Department, Montpellier University Hospital, Montpellier, France.

Background And Objective: PRRT2 variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands.

Methods: was analyzed in 860 probands with hemiplegic migraine and mutations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with mutations whose clinical manifestations were detailed.

Results: mutations were found in 12 of 163 probands previously tested negative for , and mutations, and in 18 of 697 consecutive probands screened simultaneously on the four genes. In this second group, pathogenic variants were found in 105 subjects, mostly in (42%), followed by (26%), 17%) and (15%). The mutations included seven distinct variants, five of which already described in persons with paroxysmal kinesigenic dyskinesia, and two new variants. Eight probands had a deletion of the whole gene.Among the 49 mutated patients, 26 had pure hemiplegic migraine, 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4) or abnormal movement (3). Three patients had epilepsy without migraine, two had paroxysmal kinesigenic dyskinesia without migraine, and one was asymptomatic.

Conclusion: should be regarded as the fourth autosomal dominant gene for hemiplegic migraine, and screened in any affected patient, together with the three other main genes. Further studies are needed to understand how the same loss of function mutations can lead to a wide range of neurologic phenotypes including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder and hemiplegic migraine.
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http://dx.doi.org/10.1212/WNL.0000000000012947DOI Listing
October 2021

End-Truncated LAMB1 Causes a Hippocampal Memory Defect and a Leukoencephalopathy.

Ann Neurol 2021 12 20;90(6):962-975. Epub 2021 Oct 20.

Université de Paris, INSERM UMR 1141 NeuroDiderot, Paris, France.

Objective: The majority of patients with a familial cerebral small vessel disease (CSVD) referred for molecular screening do not show pathogenic variants in known genes. In this study, we aimed to identify novel CSVD causal genes.

Methods: We performed a gene-based collapsing test of rare protein-truncating variants identified in exome data of 258 unrelated CSVD patients of an ethnically matched control cohort and of 2 publicly available large-scale databases, gnomAD and TOPMed. Western blotting was used to investigate the functional consequences of variants. Clinical and magnetic resonance imaging features of mutated patients were characterized.

Results: We showed that LAMB1 truncating variants escaping nonsense-mediated messenger RNA decay are strongly overrepresented in CSVD patients, reaching genome-wide significance (p < 5 × 10 ). Using 2 antibodies recognizing the N- and C-terminal parts of LAMB1, we showed that truncated forms of LAMB1 are expressed in the endogenous fibroblasts of patients and trapped in the cytosol. These variants are associated with a novel phenotype characterized by the association of a hippocampal type episodic memory defect and a diffuse vascular leukoencephalopathy.

Interpretation: These findings are important for diagnosis and clinical care, to avoid unnecessary and sometimes invasive investigations, and also from a mechanistic point of view to understand the role of extracellular matrix proteins in neuronal homeostasis. ANN NEUROL 2021;90:962-975.
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http://dx.doi.org/10.1002/ana.26242DOI Listing
December 2021

Early-Onset Cerebral Amyloid Angiopathy and Alzheimer Disease Related to an APP Locus Triplication.

Neurol Genet 2021 Oct 8;7(5):e609. Epub 2021 Sep 8.

Department of Neurology and CNR-MAJ (L.G., D.W.), Normandie University, UNIROUEN, Inserm U1245, CHU Rouen, CIC-CRB1404, F 76000; Department of Genetics and CNR-MAJ (K.C., S.R., N.L.M., A.R.-L., D.C., G.N.), Normandie University, UNIROUEN, Inserm U1245 and CHU Rouen, F 76000; Department of Neurology (B.C., M.F.), Lyon University Hospital; Department of Neurology (O.M.), Grenoble University Hospital; Department of Histology (J.B.), Grenoble University Hospital; AP-HP (M.M., T.C., E.T.-L.), Groupe Hospitalier Saint-Louis Lariboisière-Fernand-Widal, Service de Génétique Moléculaire Neurovasculaire, INSERM UMR 1141, NeuroDiderot,Université de Paris; Department of Histology Embryology and Cytogenetics (E.P.), Jean Verdier Hospital; Paris 13 University (E.P.), Sorbonne Paris Cité, UFR SMBH Bobigny; and PROTECT (E.P.), INSERM, Paris Diderot University, Bondy, France.

Background And Objective: To report a triplication of the amyloid-β precursor protein () locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD).

Methods: Four copies of the gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. mRNA levels were assessed using reverse-transcription-digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 duplication carriers.

Results: Beginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an locus triplication, which was consistent with the presence of 2 copies in the healthy mother and with the paternal medical history. Analysis of the mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in duplication carriers compared with controls.

Discussion: Increased copy number of is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.
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http://dx.doi.org/10.1212/NXG.0000000000000609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439959PMC
October 2021

Hereditary Cerebral Small Vessel Diseases and Stroke: A Guide for Diagnosis and Management.

Stroke 2021 Aug 17;52(9):3025-3032. Epub 2021 Aug 17.

CERVCO, FHU NeuroVasc, Assistance Publique des Hôpitaux de Paris and Paris University, France (S.G., E.T.-L., H.C.).

Cerebral small vessel diseases represent a frequent cause of stroke and cognitive or motor disability in adults. A small proportion of cerebral small vessel diseases is attributable to monogenic conditions. Since the characterization in the late 1990s of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, several other monogenic conditions leading to adult-onset ischemic or hemorrhagic stroke have been described. In this practical guide, we summarize the key features that should elicit the differential diagnosis of a hereditary cerebral small vessel diseases in adult stroke patients, describe the main clinical and imaging characteristics of the major hereditary cerebral small vessel diseases that can manifest as stroke, and provide general recommendations for the clinical management of affected patients and their relatives.
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http://dx.doi.org/10.1161/STROKEAHA.121.032620DOI Listing
August 2021

Heterozygous HTRA1 nonsense or frameshift mutations are pathogenic.

Brain 2021 Oct;144(9):2616-2624

AP-HP, Service de Génétique Moléculaire Neurovasculaire, Hôpital Saint-Louis, France.

Heterozygous missense HTRA1 mutations have been associated with an autosomal dominant cerebral small vessel disease (CSVD) whereas the pathogenicity of heterozygous HTRA1 stop codon variants is unclear. We performed a targeted high throughput sequencing of all known CSVD genes, including HTRA1, in 3853 unrelated consecutive CSVD patients referred for molecular diagnosis. The frequency of heterozygous HTRA1 mutations leading to a premature stop codon in this patient cohort was compared with their frequency in large control databases. An analysis of HTRA1 mRNA was performed in several stop codon carrier patients. Clinical and neuroimaging features were characterized in all probands. Twenty unrelated patients carrying a heterozygous HTRA1 variant leading to a premature stop codon were identified. A highly significant difference was observed when comparing our patient cohort with control databases: gnomAD v3.1.1 [P = 3.12 × 10-17, odds ratio (OR) = 21.9], TOPMed freeze 5 (P = 7.6 × 10-18, OR = 27.1) and 1000 Genomes (P = 1.5 × 10-5). Messenger RNA analysis performed in eight patients showed a degradation of the mutated allele strongly suggesting a haploinsufficiency. Clinical and neuroimaging features are similar to those previously reported in heterozygous missense mutation carriers, except for penetrance, which seems lower. Altogether, our findings strongly suggest that heterozygous HTRA1 stop codons are pathogenic through a haploinsufficiency mechanism. Future work will help to estimate their penetrance, an important information for genetic counselling.
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http://dx.doi.org/10.1093/brain/awab271DOI Listing
October 2021

Extension of SKAT to multi-category phenotypes through a geometrical interpretation.

Eur J Hum Genet 2021 05 14;29(5):736-744. Epub 2021 Jan 14.

CESP Inserm, U1018, UFR Médecine, Univ Paris-Sud, Université Paris-Saclay, Villejuif, France.

Rare genetic variants are expected to play an important role in disease and several statistical methods have been developed to test for disease association with rare variants, including variance-component tests. These tests however deal only with binary or continuous phenotypes and it is not possible to take advantage of a suspected heterogeneity between subgroups of patients. To address this issue, we extended the popular rare-variant association test SKAT to compare more than two groups of individuals. Simulations under different scenarios were performed that showed gain in power in presence of genetic heterogeneity and minor lack of power in absence of heterogeneity. An application on whole-exome sequencing data from patients with early- or late-onset moyamoya disease also illustrated the advantage of our SKAT extension. Genetic simulations and SKAT extension are implemented in the R package Ravages available on GitHub ( https://github.com/genostats/Ravages ).
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http://dx.doi.org/10.1038/s41431-020-00792-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110546PMC
May 2021

Vascular Remodeling in Moyamoya Angiopathy: From Peripheral Blood Mononuclear Cells to Endothelial Cells.

Int J Mol Sci 2020 Aug 11;21(16). Epub 2020 Aug 11.

Laboratory of Cellular Neurobiology, Neurology IX Unit, UCV, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45CD34CD133 mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.
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http://dx.doi.org/10.3390/ijms21165763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460840PMC
August 2020

Blocking Signalopathic Events to Treat Cerebral Cavernous Malformations.

Trends Mol Med 2020 09 3;26(9):874-887. Epub 2020 Apr 3.

Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8; Developmental and Cell Biology Program, The Hospital for Sick Children, 686 Bay Street, Toronto, Ontario, Canada M5G 0A4.

Cerebral cavernous malformations (CCMs) are pathologies of the brain vasculature characterized by capillary-venous angiomas that result in recurrent cerebral hemorrhages. Familial forms are caused by a clonal loss of any of three CCM genes in endothelial cells, which causes the activation of a novel pathophysiological pathway involving mitogen-activated protein kinase and Krüppel-like transcription factor KLF2/4 signaling. Recent work has shown that cavernomas can undergo strong growth when CCM-deficient endothelial cells recruit wild-type neighbors through the secretion of cytokines. This suggests a treatment strategy based on targeting signalopathic events between CCM-deficient endothelial cells and their environment. Such approaches will have to consider recent evidence implicating 'third hits' from hypoxia-induced angiogenesis signaling or the microbiome in modulating the development of cerebral hemorrhages.
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http://dx.doi.org/10.1016/j.molmed.2020.03.003DOI Listing
September 2020

Molecular Genetic Screening of CCM Patients: An Overview.

Methods Mol Biol 2020 ;2152:49-57

INSERM U1141, Assistance Publique Hôpitaux de Paris, Paris University, Paris, France.

Cerebral Cavernous Malformations (CCMs) are vascular lesions which can occur as a sporadic (80% of the cases) or a familial autosomal dominant disease (20%), the latter being characterized by the presence of multiple lesions. Three CCM genes have been identified in the last 10 years. More than 95% of familial cases and 60% of sporadic cases with multiple lesions harbor a germline heterozygous loss of function mutation in one of these 3 genes. Most mutations lead to a premature stop codon whatever the mechanism, including nonsense mutations, deletions, insertions and intronic mutations leading to abnormal splicing and frameshift. A combination of analyses, including sequencing and copy number analysis of germline DNA extracted from blood and cDNA analysis, are therefore required to ensure the best diagnostic sensitivity. Additional causative rare structural CCM gene anomalies have been identified in a research context, as well as rare causative missense mutations. These mutations are rarely searched for in a diagnostic context and explain part of the negative cases, in addition to germline mosaicism which occurs in some sporadic cases with multiple lesions. On top of germline mutations, somatic mutations occur on the wild-type allele in endothelial cells lining CCM lesions. These data established both the role of a double hit in the pathophysiology of CCM lesions and the heterogeneity of endothelial cells lining these lesions.
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http://dx.doi.org/10.1007/978-1-0716-0640-7_4DOI Listing
March 2021

Novel Chronic Mouse Model of Cerebral Cavernous Malformations.

Stroke 2020 04 29;51(4):1272-1278. Epub 2020 Jan 29.

From the Université de Paris, NeuroDiderot, Inserm, Paris, France (C.C., M.A., C.D.L., A.-L.L., E.T.-L., G.B.).

Background and Purpose- Cerebral cavernous malformations (CCMs) are vascular malformations of the brain that lead to cerebral hemorrhages. A pharmacological treatment is needed especially for patients with nonoperable deep-seated lesions. We and others obtained CCM mouse models that were useful for mechanistic studies and rapid trials testing the preventive effects of candidate drugs. The shortened lifespan of acute mouse models hampered evaluation of compounds that would not only prevent lesion appearance but also cure preexisting lesions. Indirubin-3'-monoxime previously demonstrated its efficacy to reverse the cardiac phenotype of zebrafish mutants and to prevent lesion development in an acute CCM2 mouse model. In the present article, we developed and characterized a novel chronic CCM2 mouse model and evaluated the curative therapeutic effect of indirubin-3'-monoxime after CCM lesion development. Methods- The chronic mouse model was obtained by a postnatal induction of brain-endothelial-cell-specific ablation of the gene using the inducible -CreER mouse line. Results- We obtained a fully penetrant novel CCM chronic mouse model without any obvious off-target phenotypes and compatible with long-term survival. By 3 months of age, CCM lesions ranging in size from small isolated lesions to multiple caverns developed throughout the brain. Lesion burden was quantified in animals from 1 week to 5 months of age. Clear signs of intracerebral hemorrhages were noticed in brain-endothelial-cell-specific ablation of the gene. In contrast with its preventive effect in the acute CCM2 mouse model, a 20 mg/kg indirubin-3'-monoxime treatment for 3 weeks in 3-month old animals neither had any beneficial effect on the lesion burden nor alleviated cerebral hemorrhages. Conclusions- The brain-endothelial-cell-specific ablation of the gene chronic model is a strongly improved disease model for the CCM community whose challenge today is to decipher which candidate drugs might have a curative effect on patients' preexisting lesions. Visual Overview- An online visual overview is available for this article.
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http://dx.doi.org/10.1161/STROKEAHA.119.027207DOI Listing
April 2020

Novel CCM2 missense variants abrogating the CCM1-CCM2 interaction cause cerebral cavernous malformations.

J Med Genet 2020 06 14;57(6):400-404. Epub 2020 Jan 14.

UMR-S1141, INSERM, Paris, Île-de-France, France

Background: Cerebral cavernous malformations (CCMs) are vascular malformations mostly located within the central nervous system. Most deleterious variants are loss of function mutations in one of the three genes. These genes code for proteins that form a ternary cytosolic complex with CCM2 as a hub. Very few missense variants have been shown to be deleterious by modifying the ternary CCM complex stability.

Objectives: To investigate the causality of novel missense variants detected in patients with CCM.

Methods: The three CCM genes were screened in 984 patients referred for molecular screening. Interaction between CCM1 and CCM2 proteins was tested using co-immunoprecipitation experiments for the missense variants located in the phosphotyrosine binding (PTB) domain.

Results: 11 distinct rare missense variants were found. Six variants predicted to be damaging were located in the PTB domain, four of them were novel. When co-transfected with CCM1 in HEK293T cells, a loss of interaction between CCM1 and CCM2 was observed for all six variants.

Conclusion: We showed, using co-immunoprecipitation experiments, that CCM2 missense variants located in the PTB domain were actually damaging by preventing the normal interaction between CCM1 and CCM2. These data are important for diagnosis and genetic counselling, which are challenging in patients harbouring such variants.
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http://dx.doi.org/10.1136/jmedgenet-2019-106401DOI Listing
June 2020

Xq28 copy number gain causing moyamoya disease and a novel moyamoya syndrome.

J Med Genet 2020 05 10;57(5):339-346. Epub 2020 Jan 10.

Université de Paris, NeuroDiderot, Inserm UMR1141, Paris, France

Background: The molecular anomalies causing moyamoya disease (MMD) and moyamoya syndromes (MMS) are unknown in most patients.

Objective: This study aimed to identify de novo candidate copy number variants (CNVs) in patients with moyamoya.

Methods: Rare de novo CNVs screening was performed in 13 moyamoya angiopathy trios using whole exome sequencing (WES) reads depth data and whole genome high density SNP array data. WES and SNP array data from an additional cohort of 115 unrelated moyamoya probands were used to search for recurrence of these rare de novo CNVs.

Results: Two de novo CNVs were identified in two unrelated probands by both methods and confirmed by qPCR. One of these CNVs, located on Xq28, was detected in two additional families. This interstitial Xq28 CNV gain is absent from curated gold standard database of control genomic variants and gnomAD databases. The critical region contains five genes, including MAMLD1, a major NOTCH coactivator. Typical MMD was observed in the two families with a duplication, whereas in the triplicated patients of the third family, a novel MMS associating moyamoya and various systemic venous anomalies was evidenced.

Conclusion: The recurrence of this novel Xq28 CNV, its de novo occurrence in one patient and its familial segregation with the affected phenotype in two additional families strongly suggest that it is pathogenic. In addition to genetic counselling application, its association with pulmonary hypertension is of major importance for clinical care. These data also provide new insights into the genomic architecture of this emblematic, non-atherosclerotic, large vessel disease.
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http://dx.doi.org/10.1136/jmedgenet-2019-106525DOI Listing
May 2020

Nontraumatic Pediatric Intracerebral Hemorrhage.

Stroke 2019 12 22;50(12):3654-3661. Epub 2019 Oct 22.

From the Pediatric Radiology Department, Necker Enfants Malades (NEM), INSERM UMR1266, Sainte-Anne (G.B., J.F.H., O.N.).

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http://dx.doi.org/10.1161/STROKEAHA.119.025783DOI Listing
December 2019

The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.

Genet Med 2020 02 2;22(2):427-431. Epub 2019 Sep 2.

Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Purpose: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger.

Methods: Exome sequencing from 39 trios were analyzed.

Results: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease.

Conclusion: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.
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http://dx.doi.org/10.1038/s41436-019-0639-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673309PMC
February 2020

Predictors of clinical or cerebral lesion progression in adult moyamoya angiopathy.

Neurology 2019 07 25;93(4):e388-e397. Epub 2019 Jun 25.

From the Referral Center for Rare Vascular Diseases of the Brain and Retina (CERVCO), Department of Neurology and DHU NeuroVasc (D.H., N.I.-A., C.R., O.G., H.C.), Department of Neuroradiology (M.A.L., J.P.G.), and Laboratoire de Génétique Moléculaire (E.T.L.), Hopital Lariboisiére, Department of Nuclear Medicine, Hopital Salpêtrière (M.O.H.), and Service de Biostatistique et Information Médicale, Hôpital Saint Louis (S.C.), Assistance Publique des Hôpitaux de Paris; INSERM U 1161 (D.H., E.T.L., H.C.) and UMR 1153 INSERM (S.C.), Université Paris 7 Diderot (E.T.L., H.C.), Sorbonne Paris Cité; Unité Neurovasculaire (L.C.), Hôpital Pierre-Paul-Riquet, Toulouse; Centre National de Référence de l'AVC de l'Enfant, Hôpital Universitaire Necker-Enfants Malades (M.K.), AP-HP; Sorbonne Paris Cité, Paris; and ECSTRA Team (Épidémiologie Clinique et Statistiques pour la Recherche en Santé) (S.C.), Paris, France.

Objective: To identify independent predictors of clinical or cerebral lesion progression in a large sample of adult patients with moyamoya angiopathy (MMA) prior to decisions regarding revascularization surgery.

Methods: Ninety participants (median age, 37.5 years) were assessed at baseline and followed for a median time of 42.8 months. Incident ischemic and hemorrhagic strokes, death, as well as any incident ischemic and hemorrhagic lesions on MRI were recorded. Multiple demographic, clinical, and cerebral imaging measures at baseline were considered as potential predictors of clinical or cerebral tissue change at follow-up. Data were analyzed based on the Andersen-Gill counting process model, followed by internal validation of the prediction model.

Results: Among multiple potential predictive measures considered in the analysis, Asian origin, a history of TIAs, and a reduction in hemodynamic reserve, as detected by imaging, were found to be significantly associated with an increased risk of combined clinical and imaging events. While the model estimated the risk of clinical or cerebral lesion progression to be approximately 0.5% per year when none of these factors was present, this risk exceeded 20% per year when all factors were present.

Conclusion: A simple combination of demographic, clinical, and cerebral perfusion imaging measures may aid in predicting the risk of incident stroke and cerebral lesion progression in adult patients with MMA. These results may help to improve therapeutic decisions and aid in the design of future trials in adults with this rare condition.
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http://dx.doi.org/10.1212/WNL.0000000000007819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669931PMC
July 2019

Cognitive impairment in children with CACNA1A mutations.

Dev Med Child Neurol 2020 03 21;62(3):330-337. Epub 2019 May 21.

Département de Neuropédiatrie, CHU Gui de Chauliac, Montpellier, France.

Aim: To describe the clinico-radiological phenotype of children with a CACNA1A mutation and to precisely evaluate their learning ability and cognitive status.

Method: Children between the ages of 3 and 18 years harboring a pathogenic CACNA1A mutation associated with episodic ataxia, hemiplegic migraine, benign paroxysmal torticollis, benign paroxysmal vertigo, or benign paroxysmal tonic upgaze, were enrolled in this cross-sectional study. Data concerning psychomotor development, academic performance, educational management, clinical examination at inclusion, and brain imaging were collected. Cognitive assessment was performed using age-standardized scales.

Results: Eighteen patients (nine males, nine females; mean age at inclusion: 11y 7mo [SD 4y 5mo; range 3y-17y 11mo]) from 14 families were enrolled. Eleven patients displayed the coexistence or consecutive occurrence of more than one type of episodic event. Nine patients exhibited abnormal neurological examination at inclusion. Brain magnetic resonance imaging (MRI) showed cerebellar atrophy in five patients. Psychomotor development was delayed in nine patients and academic difficulties were reported by the parents in 15 patients; nine patients were in special education. Impairment of intellectual function was assessed in six of the 12 patients with interpretable Full-scale IQ scores and was more frequent when cerebellar atrophy was present on MRI.

Interpretation: Cognitive impairment is commonly associated with CACNA1A mutations. We suggest that CACNA1A-associated phenotype should be considered a neurodevelopmental disorder.

What This Paper Adds: Cognitive disabilities and academic difficulties are common in children with CACNA1A mutations associated with episodic syndromes. Cognitive function ranges from normal to moderate intellectual disorder in wheelchair-dependent children. Patients with vermian atrophy are at a higher risk of cognitive impairment.
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http://dx.doi.org/10.1111/dmcn.14261DOI Listing
March 2020

Rare variant association testing for multicategory phenotype.

Genet Epidemiol 2019 09 13;43(6):646-656. Epub 2019 May 13.

Univ Brest, Inserm, EFS, UMR 1078, GGB, Brest, France.

Genetic association studies have provided new insights into the genetic variability of human complex traits with a focus mainly on continuous or binary traits. Methods have been proposed to take into account disease heterogeneity between subgroups of patients when studying common variants but none was specifically designed for rare variants. Because rare variants are expected to have stronger effects and to be more heterogeneously distributed among cases than common ones, subgroup analyses might be particularly attractive in this context. To address this issue, we propose an extension of burden tests by using a multinomial regression model, which enables association tests between rare variants and multicategory phenotypes. We evaluated the type I error and the power of two burden tests, CAST and WSS, by simulating data under different scenarios. In the case of genetic heterogeneity between case subgroups, we showed an advantage of multinomial regression over logistic regression, which considers all the cases against the controls. We replicated these results on real data from Moyamoya disease where the burden tests performed better when cases were stratified according to age-of-onset. We implemented the functions for association tests in the R package "Ravages" available on Github.
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http://dx.doi.org/10.1002/gepi.22210DOI Listing
September 2019

Clinical and Molecular Features of 5 European Multigenerational Families With Moyamoya Angiopathy.

Stroke 2019 04;50(4):789-796

Department of Neurology, Alfried Krupp Hospital Essen, Germany (J.C.S., M.K.).

Background and Purpose Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy outside of Asia. In Japanese patients, a vast majority of patients carry the founder p.R4810K variant in the RNF213 gene, and familial cases are around 10%. In European patients, data about familial occurrence are limited. The aim of this study was to characterize the clinical and molecular features of several European families with a parent-to-child transmission of MMA. Methods Out of 126 MMA probands referred, we identified 113 sporadic probands and 13 familial probands. Segregation analysis showed a vertical parent-to-child pattern of inheritance in the families of 5 of these probands. All 5 families were of German or Dutch ancestry. We investigated the clinical features of affected members and used whole-exome sequencing to screen RNF213 and 13 genes involved in Mendelian MMA and to identify genes recurrently mutated in these families. Results Twelve affected MMA patients were identified, including 9 females and 3 males. Age at clinical onset ranged from 11 to 65 years. In 3 of 5 families, associated livedo racemosa was found. We did not detect any deleterious variants in the 13 known MMA genes. RNF213 rare missense variants predicted to be pathogenic were detected in all affected members of 2 of these families, as well as 2 candidate variants of the PALD1 gene. Conclusions Nonsyndromic MMA was identified in 5 European families, including 2 to 3 clinically affected cases segregating with a parent-to-child pattern of inheritance in each family. Molecular screening detected rare deleterious variants within RNF213 and PALD1 in all affected members of 2 of these 5 families, as well as in some clinically unaffected members. Altogether these data raise the difficult and, to date unanswered, question of the medical indication of presymptomatic screening.
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http://dx.doi.org/10.1161/STROKEAHA.118.023972DOI Listing
April 2019

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease-study protocol and preliminary results.

Neurol Sci 2019 Mar 3;40(3):561-570. Epub 2019 Jan 3.

Stroke Unit, Nuovo Ospedale Civile S Agostino Estense, University Hospital of Modena, Modena, Italy.

Background: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results.

Methods: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies.

Results: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed.

Conclusion: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy.
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http://dx.doi.org/10.1007/s10072-018-3664-zDOI Listing
March 2019

Acute-Onset Ataxia and Transient Cerebellar Diffusion Restriction Associated with a PRRT2 Mutation.

J Stroke Cerebrovasc Dis 2019 Feb 28;28(2):e3-e4. Epub 2018 Nov 28.

Neurology Department, Bicêtre Hospital, Assistance Publique des Hôpitaux de Paris, (AP-HP), Paris, France.

PRRT2 gene mutations cause paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions, hemiplegic migraine, and episodic ataxia. A 21-year-old woman reported an episode of dizziness and ataxic gait occurring after swimming. Brain MRI showed a hyperintense cerebellar lesion on diffusion-weighted imaging (DWI) with decreased apparent diffusion coefficient. The clinical course was favorable. Both clinical and MRI abnormalities regressed. Her brother had presented PKD since adulthood. A C.649dupC PRRT2 truncating mutation was identified in both patients. To our knowledge, this is the first case of an acute cerebellar ataxia associated with heterozygous PRRT2 mutation and transient cerebellar hyperintensity on DWI. Among the clinical and genetic heterogeneities of familial paroxysmal disorders, PRRT2 mutation may be considered in patients with episodic cerebellar ataxia and diffusion restriction on neuroimaging.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2018.10.021DOI Listing
February 2019

Further refinement of COL4A1 and COL4A2 related cortical malformations.

Eur J Med Genet 2018 Dec 11;61(12):765-772. Epub 2018 Oct 11.

Paris Descartes - Sorbonne Paris Cité University, Imagine Institute, Paris, France; Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Imagine Institute, Paris, France; Pediatric Neurology, APHP- Necker Enfants Malades Hospital, Paris, France; National Rare Disease Center- Centre de Référence "Déficiences Intellectuelles de Causes Rares", AP-HP, Necker Enfants Malades, 75015, Paris, France. Electronic address:

Mutations in COL4A1 have been reported in schizencephaly and porencephaly combined with microbleeds or calcifications, often associated with ocular and renal abnormalities, myopathy, elevated creatine kinase levels and haemolytic anaemia. In this study, we aimed to clarify the phenotypic spectrum of COL4A1/A2 mutations in the context of cortical malformations that include schizencephaly, polymicrogyria and/or heterotopia.

Methods: We screened for COL4A1/A2 mutations in 9 patients with schizencephaly and/or polymicrogyria suspected to be caused by vascular disruption and leading to a cerebral haemorrhagic ischaemic event. These included 6 cases with asymmetrical or unilateral schizencephaly and/or polymicrogyria and 3 cases with bilateral schizencephaly.

Results: One de novo missense COL4A1 mutation (c.3715 G > A, p.(Gly1239Arg)) and two COL4A2 mutations were found, respectively in one familial case (c.4129G > A, p.(Gly1377Arg)) and one sporadic patient (c.1776+1G > A). In three other cases, COL4A1 variants of unknown significance were identified. None of our patients demonstrated neuromuscular or hematological anomalies. Brain malformations included a combination of schizencephaly, mainly asymmetrical, with porencephaly or ventriculomegaly (3/3 mutated patients). We did not observe microbleeds or microcalcifications in any of our cases, hence we do not believe that they represent a distinctive feature of COL4A1/A2 mutations.

Conclusions: Our study further emphasizes the need to search for both COL4A1 and COL4A2 mutations in children presenting with uni- or bilateral polymicrogyria with schizencephaly, even in the absence of intracranial microbleeds, calcification or associated systemic features.
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http://dx.doi.org/10.1016/j.ejmg.2018.10.004DOI Listing
December 2018

Systematic pharmacological screens uncover novel pathways involved in cerebral cavernous malformations.

EMBO Mol Med 2018 10;10(10)

Institute of Biochemistry and Biology, Potsdam University, Potsdam, Germany

Cerebral cavernous malformations (CCMs) are vascular lesions in the central nervous system causing strokes and seizures which currently can only be treated through neurosurgery. The disease arises through changes in the regulatory networks of endothelial cells that must be comprehensively understood to develop alternative, non-invasive pharmacological therapies. Here, we present the results of several unbiased small-molecule suppression screens in which we applied a total of 5,268 unique substances to mutant worm, zebrafish, mouse, or human endothelial cells. We used a systems biology-based target prediction tool to integrate the results with the whole-transcriptome profile of zebrafish mutants, revealing signaling pathways relevant to the disease and potential targets for small-molecule-based therapies. We found indirubin-3-monoxime to alleviate the lesion burden in murine preclinical models of and and suppress the loss-of-CCM phenotypes in human endothelial cells. Our multi-organism-based approach reveals new components of the CCM regulatory network and foreshadows novel small-molecule-based therapeutic applications for suppressing this devastating disease in patients.
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http://dx.doi.org/10.15252/emmm.201809155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180302PMC
October 2018

Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant.

Eur J Med Genet 2019 Jun 22;62(6):103530. Epub 2018 Aug 22.

Service de Génétique Médicale, CHU de Bordeaux and Laboratoire MRGM, INSERM U1211, Univ. Bordeaux, Bordeaux, France; Centre de Référence Neurogénétique, Service de Génétique Médicale, CHU de Bordeaux, France.

The CACNA1A gene encodes a calcium-dependent voltage channel, localized in neuronal cells. Pathogenic variants in this gene are known to lead to a broad clinical spectrum including episodic ataxia type 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, and more recently epileptic encephalopathy. We report a large family revealing a wide variability of neurological manifestations associated with a CACNA1A missense pathogenic variant. The index case had early-onset epileptic encephalopathy with progressive cerebellar atrophy, although his mother and his great-grandmother suffered from paroxystic episodic ataxia. His grandfather and great grand-aunt reported no symptoms, but two of her sons displayed early-onset ataxia with intellectual disability. Two of her little daughters suffered from gait disorders, and also from epilepsy for one of them. All these relatives were carriers of the previously described heterozygous variant in CACNA1A gene. We report here the first family leading to major clinical variability and incomplete penetrance. Our family highlights the difficulties to provide accurate genetic counselling concerning prenatal diagnosis regarding highly variable severity of the clinical presentation.
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http://dx.doi.org/10.1016/j.ejmg.2018.08.011DOI Listing
June 2019

The CCM1-CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity.

J Cell Sci 2018 08 13;131(15). Epub 2018 Aug 13.

INSERM U1209, Institute for Advanced Biosciences, F-38700 La Tronche, France

Endothelial integrity relies on a mechanical crosstalk between intercellular and cell-matrix interactions. This crosstalk is compromised in hemorrhagic vascular lesions of patients carrying loss-of-function mutations in cerebral cavernous malformation (CCM) genes. RhoA/ROCK-dependent cytoskeletal remodeling is central to the disease, as it causes unbalanced cell adhesion towards increased cell-extracellular matrix adhesions and destabilized cell-cell junctions. This study reveals that CCM proteins directly orchestrate ROCK1 and ROCK2 complementary roles on the mechanics of the endothelium. CCM proteins act as a scaffold, promoting ROCK2 interactions with VE-cadherin and limiting ROCK1 kinase activity. Loss of CCM1 (also known as KRIT1) produces excessive ROCK1-dependent actin stress fibers and destabilizes intercellular junctions. Silencing of ROCK1 but not ROCK2 restores the adhesive and mechanical homeostasis of CCM1 and CCM2-depleted endothelial monolayers, and rescues the cardiovascular defects of mutant zebrafish embryos. Conversely, knocking down Rock2 but not Rock1 in wild-type zebrafish embryos generates defects reminiscent of the mutant phenotypes. Our study uncovers the role of the CCM1-CCM2 complex in controlling ROCK1 and ROCK2 to preserve endothelial integrity and drive heart morphogenesis. Moreover, it solely identifies the ROCK1 isoform as a potential therapeutic target for the CCM disease.
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http://dx.doi.org/10.1242/jcs.216093DOI Listing
August 2018

Optical Coherence Tomography Angiography of Familial Retinal Arteriolar Tortuosity.

Ophthalmic Surg Lasers Imaging Retina 2018 06;49(6):397-401

Background And Objective: To analyze the location of familial retinal arterial tortuosity (fRAT) in the three-dimensional structure of retinal capillaries.

Patients And Methods: Retrospective observational study. Twelve eyes of six patients (two of whom were brothers) were imaged by optical coherence tomography angiography (OCTA). The data from their ocular and systemic examinations were recorded.

Results: OCTA imaging clearly showed increased tortuosity of second- and third-order retinal arteries in all cases, visible in the superficial vascular plexus (SVP) up to the arteriole termination in the capillaries. No change was visible in the deep capillary plexus (DCP).

Conclusions: OCTA shows that fRAT affects all the course of the arterioles up to the capillaries in the SVP. The DCP does not show arteriolar tortuosity because it does not contain arterioles. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:397-401.].
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http://dx.doi.org/10.3928/23258160-20180601-03DOI Listing
June 2018

Benign paroxysmal torticollis, benign paroxysmal vertigo, and benign tonic upward gaze are not benign disorders.

Dev Med Child Neurol 2018 12 21;60(12):1256-1263. Epub 2018 Jun 21.

Département de Neuropédiatrie, CHU Gui de Chauliac, Montpellier, France.

Aim: Benign paroxysmal torticollis (BPT), benign paroxysmal vertigo (BPV), and benign tonic upward gaze (BTU) are characterized by transient and recurrent episodes of neurological manifestations. The purpose of this study was to analyse the clinical relationships between these syndromes, associated comorbidities, and genetic bases.

Method: In this cross-sectional study, clinical data of patients with BPT, BPV, or BTU were collected with a focus on developmental achievements, learning abilities, and rehabilitation. Neuropsychological assessment and genetic testing were performed.

Results: Fifty patients (median age at inclusion 6y) were enrolled. Psychomotor delay, abnormal neurological examination, and low or borderline IQ were found in 19%, 32%, and 26% of the patients respectively. Cognitive dysfunction was present in 27% of the patients. CACNA1A gene mutation was identified in eight families, and KCNA1 and FGF14 mutation in one family respectively. The identification of a CACNA1A mutation was significantly associated with BTU (p=0.03) and with cognitive dysfunction (p=0.01). Patients with BPV were less likely to have cognitive dysfunction.

Interpretation: Children with BPT, BPV, or BTU are at high risk of impaired psychomotor and cognitive development. These syndromes should not be regarded as benign and should be considered as part of the spectrum of a neurodevelopmental disorder.

What This Paper Adds Ok: Patients with benign paroxysmal torticollis (BPT), benign paroxysmal vertigo (BPV), and benign tonic upward gaze (BTU) have an increased risk of psychomotor delay. These patients also have an increased risk of abnormal neurological examination and cognitive dysfunction. Gene mutations, especially in CACNA1A, were identified in 21% of the families. BPT, BTU, and BPV should not be regarded as benign. BPT, BTU, and BPV should be considered as part of the spectrum of a neurodevelopmental disorder.
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http://dx.doi.org/10.1111/dmcn.13935DOI Listing
December 2018

Fatal Aβ cerebral amyloid angiopathy 4 decades after a dural graft at the age of 2 years.

Acta Neuropathol 2018 05 5;135(5):801-803. Epub 2018 Mar 5.

Département de Neuropathologie Raymond Escourolle, GH Pitié-Salpêtrière, Faculté de médecine Sorbonne Université, Paris, France.

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http://dx.doi.org/10.1007/s00401-018-1828-9DOI Listing
May 2018

Rare RNF213 variants in the C-terminal region encompassing the RING-finger domain are associated with moyamoya angiopathy in Caucasians.

Eur J Hum Genet 2017 08 21;25(8):995-1003. Epub 2017 Jun 21.

Inserm UMR-S1161, Génétique et Physiopathologie des Maladies Cérébro-vasculaires, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

Moyamoya angiopathy (MMA) is a cerebral angiopathy affecting the terminal part of internal carotid arteries. Its prevalence is 10 times higher in Japan and Korea than in Europe. In East Asian countries, moyamoya is strongly associated to the R4810K variant in the RNF213 gene that encodes for a protein containing a RING-finger and two AAA+ domains. This variant has never been detected in Caucasian MMA patients, but several rare RNF213 variants have been reported in Caucasian cases. Using a collapsing test based on exome data from 68 European MMA probands and 573 ethnically matched controls, we showed a significant association between rare missense RNF213 variants and MMA in European patients (odds ratio (OR)=2.24, 95% confidence interval (CI)=(1.19-4.11), P=0.01). Variants specific to cases had higher pathogenicity predictive scores (median of 24.2 in cases versus 9.4 in controls, P=0.029) and preferentially clustered in a C-terminal hotspot encompassing the RING-finger domain of RNF213 (P<10). This association was even stronger when restricting the analysis to childhood-onset and familial cases (OR=4.54, 95% CI=(1.80-11.34), P=1.1 × 10). All clinically affected relatives who were genotyped were carriers. However, the need for additional factors to develop MMA is strongly suggested by the fact that only 25% of mutation carrier relatives were clinically affected.
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http://dx.doi.org/10.1038/ejhg.2017.92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567158PMC
August 2017

Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel.

Neurosurgery 2017 May;80(5):665-680

Department of Cardiovascular Medicine, University of Utah, Salt Lake City, Utah.

Background: Despite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies.

Objective: To develop guidelines for CCM management.

Methods: The Angioma Alliance ( www.angioma.org ), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol.

Results: Of 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was level A (because of the absence of randomized controlled trials), 11 (48%) were level B, and 12 (52%) were level C. Recommendations were class I in 8 (35%), class II in 10 (43%), and class III in 5 (22%).

Conclusion: Current evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines .
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http://dx.doi.org/10.1093/neuros/nyx091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808153PMC
May 2017

De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy.

J Med Genet 2017 08 25;54(8):550-557. Epub 2017 Mar 25.

French Center for Pediatric Stroke, University Hospital Necker-Enfants malades, Paris, France.

Background: Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome.

Methods: A WES was performed in four unrelated early-onset moyamoya sporadic cases and their parents (trios). Exome data were analysed under dominant de novo, autosomal recessive and X-linked hypotheses. A panel of 17 additional sporadic cases with early-onset moyamoya was available for mutation recurrence analysis.

Results: We identified two germline de novo mutations in in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA. Both mutations were predicted to alter the ubiquitin ligase activity of the CBL protein that acts as a negative regulator of the RAS pathway. These two germline mutations have previously been described in association with a developmental Noonan-like syndrome and susceptibility to juvenile myelomonocytic leukaemia (JMML). Notably, the two mutated girls never developed JMML and presented only subtle signs of RASopathy that did not lead to evoke this diagnosis during follow-up.

Conclusions: These data suggest that gene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy.
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http://dx.doi.org/10.1136/jmedgenet-2016-104432DOI Listing
August 2017
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