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1.
Brain ; 146(12): 5086-5097, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37977818

RESUMO

Stuttering is a common speech disorder that interrupts speech fluency and tends to cluster in families. Typically, stuttering is characterized by speech sounds, words or syllables which may be repeated or prolonged and speech that may be further interrupted by hesitations or 'blocks'. Rare variants in a small number of genes encoding lysosomal pathway proteins have been linked to stuttering. We studied a large four-generation family in which persistent stuttering was inherited in an autosomal dominant manner with disruption of the cortico-basal-ganglia-thalamo-cortical network found on imaging. Exome sequencing of three affected family members revealed the PPID c.808C>T (p.Pro270Ser) variant that segregated with stuttering in the family. We generated a Ppid p.Pro270Ser knock-in mouse model and performed ex vivo imaging to assess for brain changes. Diffusion-weighted MRI in the mouse revealed significant microstructural changes in the left corticospinal tract, as previously implicated in stuttering. Quantitative susceptibility mapping also detected changes in cortico-striatal-thalamo-cortical loop tissue composition, consistent with findings in affected family members. This is the first report to implicate a chaperone protein in the pathogenesis of stuttering. The humanized Ppid murine model recapitulates network findings observed in affected family members.


Assuntos
Gagueira , Humanos , Animais , Camundongos , Gagueira/genética , Gagueira/patologia , Peptidil-Prolil Isomerase F , Fala , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Mapeamento Encefálico
2.
Brain ; 145(3): 1177-1188, 2022 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-35296891

RESUMO

Developmental stuttering is a condition of speech dysfluency, characterized by pauses, blocks, prolongations and sound or syllable repetitions. It affects around 1% of the population, with potential detrimental effects on mental health and long-term employment. Accumulating evidence points to a genetic aetiology, yet gene-brain associations remain poorly understood due to a lack of MRI studies in affected families. Here we report the first neuroimaging study of developmental stuttering in a family with autosomal dominant inheritance of persistent stuttering. We studied a four-generation family, 16 family members were included in genotyping analysis. T1-weighted and diffusion-weighted MRI scans were conducted on seven family members (six male; aged 9-63 years) with two age and sex matched controls without stuttering (n = 14). Using Freesurfer, we analysed cortical morphology (cortical thickness, surface area and local gyrification index) and basal ganglia volumes. White matter integrity in key speech and language tracts (i.e. frontal aslant tract and arcuate fasciculus) was also analysed using MRtrix and probabilistic tractography. We identified a significant age by group interaction effect for cortical thickness in the left hemisphere pars opercularis (Broca's area). In affected family members this region failed to follow the typical trajectory of age-related thinning observed in controls. Surface area analysis revealed the middle frontal gyrus region was reduced bilaterally in the family (all cortical morphometry significance levels set at a vertex-wise threshold of P < 0.01, corrected for multiple comparisons). Both the left and right globus pallidus were larger in the family than in the control group (left P = 0.017; right P = 0.037), and a larger right globus pallidus was associated with more severe stuttering (rho = 0.86, P = 0.01). No white matter differences were identified. Genotyping identified novel loci on chromosomes 1 and 4 that map with the stuttering phenotype. Our findings denote disruption within the cortico-basal ganglia-thalamo-cortical network. The lack of typical development of these structures reflects the anatomical basis of the abnormal inhibitory control network between Broca's area and the striatum underpinning stuttering in these individuals. This is the first evidence of a neural phenotype in a family with an autosomal dominantly inherited stuttering.


Assuntos
Gagueira , Substância Branca , Área de Broca/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Humanos , Imageamento por Ressonância Magnética , Masculino , Gagueira/diagnóstico por imagem , Gagueira/genética
3.
Brain ; 142(4): 966-977, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30796815

RESUMO

Speech disorders are highly prevalent in the preschool years, but frequently resolve. The neurobiological basis of the most persistent and severe form, apraxia of speech, remains elusive. Current neuroanatomical models of speech processing in adults propose two parallel streams. The dorsal stream is involved in sound to motor speech transformations, while the ventral stream supports sound/letter to meaning. Data-driven theories on the role of these streams during atypical speech and language development are lacking. Here we provide comprehensive behavioural and neuroimaging data on a large novel family where one parent and 11 children presented with features of childhood apraxia of speech (the same speech disorder associated with FOXP2 variants). The genetic cause of the disorder in this family remains to be identified. Importantly, in this family the speech disorder is not systematically associated with language or literacy impairment. Brain MRI scanning in seven children revealed large grey matter reductions over the left temporoparietal region, but not in the basal ganglia, relative to typically-developing matched peers. In addition, we detected white matter reductions in the arcuate fasciculus (dorsal language stream) bilaterally, but not in the inferior fronto-occipital fasciculus (ventral language stream) nor in primary motor pathways. Our findings identify disruption of the dorsal language stream as a novel neural phenotype of developmental speech disorders, distinct from that reported in speech disorders associated with FOXP2 variants. Overall, our data confirm the early role of this stream in auditory-to-articulation transformations. 10.1093/brain/awz018_video1 awz018media1 6018582401001.


Assuntos
Distúrbios da Fala/genética , Distúrbios da Fala/fisiopatologia , Percepção da Fala/genética , Adolescente , Adulto , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Criança , Pré-Escolar , Família , Feminino , Humanos , Idioma , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa , Vias Neurais , Neuroimagem , Linhagem , Fala/fisiologia , Percepção da Fala/fisiologia
4.
Folia Phoniatr Logop ; 71(5-6): 203-215, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31330526

RESUMO

OBJECTIVE: The clinical course of childhood apraxia of speech (CAS) is poorly understood. Of the few longitudinal studies in the field, only one has examined adolescent outcomes in speech, language, and literacy. This study is the first to report long-term speech, language, and academic outcomes in an adolescent, Liam, with CAS. METHODS: Speech, language, literacy, and academic outcome data were collected, including 3 research-based assessments. Overall, data were available at 17 time points from 3;10 to 15 years. RESULTS: Liam had moderate-to-severe expressive language impairment and poor reading, writing, and spelling up to 10 years. His numeracy was at or above the national average from 8 to 14 years. He made gains in preadolescence, with average expressive language at 11 years and above average reading and writing at 14 years. Nonword reading, reading comprehension, and spelling remained areas of weakness. Receptive language impairment was evident at 13 years, which was an unexpected finding. CONCLUSION: Findings from single cases can be hypothesis generating but require verification in larger cohorts. This case shows that at least some children with CAS may gain ground in adolescence, relative to same age peers, in expressive language and academic areas such as reading and writing.


Assuntos
Apraxias/diagnóstico , Disartria/diagnóstico , Disartria/terapia , Escolaridade , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Adolescente , Apraxias/terapia , Criança , Pré-Escolar , Dislexia/diagnóstico , Dislexia/terapia , Humanos , Alfabetização , Estudos Longitudinais , Masculino , Fonoterapia , Resultado do Tratamento , Aprendizagem Verbal
5.
Curr Neurol Neurosci Rep ; 15(6): 35, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25921602

RESUMO

The last 2 years have seen exciting advances in the genetics of Landau-Kleffner syndrome and related disorders, encompassed within the epilepsy-aphasia spectrum (EAS). The striking finding of mutations in the N-methyl-D-aspartate (NMDA) receptor subunit gene GRIN2A as the first monogenic cause in up to 20% of patients with EAS suggests that excitatory glutamate receptors play a key role in these disorders. Patients with GRIN2A mutations have a recognizable speech and language phenotype that may assist with diagnosis. Other molecules involved in RNA binding and cell adhesion have been implicated in EAS; copy number variations are also found. The emerging picture highlights the overlap between the genetic determinants of EAS with speech and language disorders, intellectual disability, autism spectrum disorders and more complex developmental phenotypes.


Assuntos
Epilepsias Parciais/genética , Transtornos da Linguagem/genética , Antígenos Nucleares/genética , Variações do Número de Cópias de DNA , Humanos , Proteínas do Tecido Nervoso/genética , Fatores de Processamento de RNA , Proteínas de Ligação a RNA/genética , Receptores de N-Metil-D-Aspartato/genética , Fala
6.
Neurol Genet ; 10(2): e200129, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38715655

RESUMO

Background and Objectives: Pathogenic variants in GRIN2A are associated with a spectrum of epilepsy-aphasia syndromes (EASs). Seizures as well as speech and language disorders occur frequently but vary widely in severity, both between individuals and across the life span. The link between this phenotypic spectrum and brain characteristics is unknown. Specifically, altered brain networks at the root of speech and language deficits remain to be identified. Patients with pathogenic variants in GRIN2A offer an opportunity to interrogate the impact of glutamate receptor dysfunction on brain development. Methods: We characterized brain anomalies in individuals with pathogenic GRIN2A variants and EASs, hypothesizing alterations in perisylvian speech-language regions and the striatum. We compared structural MRI data from 10 individuals (3 children and 7 adults, 3 female) with pathogenic GRIN2A variants with data from age-matched controls (N = 51 and N = 203 in a secondary analysis). We examined cortical thickness and volume in 4 a priori hypothesized speech and language regions (inferior frontal, precentral, supramarginal, and superior temporal) and across the whole brain. Subcortical structures (hippocampus, basal ganglia, thalamus) and the corpus callosum were also compared. Results: Individuals with pathogenic GRIN2A variants showed increased thickness and volume in the posterior part of Broca's area (inferior frontal gyrus, pars opercularis). For thickness, the effects were bilateral but more pronounced in the left (large effect size, η2 = 0.37) than the right (η2 = 0.12) hemisphere. Both volume and thickness were also higher in the bilateral superior temporal region while the supramarginal region showed increased thickness only. Whole-brain analyses confirmed left-sided thickness increases in Broca's area, with additional increases in the occipital and superior frontal cortices bilaterally. Hippocampal volume was reduced in the left hemisphere. There were no age-dependent effects or corpus callosum group differences. Discussion: Anomalies in perisylvian regions, with largest differences in Broca's area, suggest an altered development of classical speech-language networks in GRIN2A-related EAS. Left hippocampal reduction suggests a role for this structure in early speech and language development and is consistent with GRIN2A gene expression in that region. Overall, elucidating the neural correlates of EAS provides insights into the impact of GRIN2A dysfunction, opening avenues for targeted intervention in developmental syndromes with compromised speech-language development.

7.
Am J Med Genet A ; 161A(9): 2321-6, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23918746

RESUMO

Relatively little is known about the neurobiological basis of speech disorders although genetic determinants are increasingly recognized. The first gene for primary speech disorder was FOXP2, identified in a large, informative family with verbal and oral dyspraxia. Subsequently, many de novo and familial cases with a severe speech disorder associated with FOXP2 mutations have been reported. These mutations include sequencing alterations, translocations, uniparental disomy, and genomic copy number variants. We studied eight probands with speech disorder and their families. Family members were phenotyped using a comprehensive assessment of speech, oral motor function, language, literacy skills, and cognition. Coding regions of FOXP2 were screened to identify novel variants. Segregation of the variant was determined in the probands' families. Variants were identified in two probands. One child with severe motor speech disorder had a small de novo intragenic FOXP2 deletion. His phenotype included features of childhood apraxia of speech and dysarthria, oral motor dyspraxia, receptive and expressive language disorder, and literacy difficulties. The other variant was found in a family in two of three family members with stuttering, and also in the mother with oral motor impairment. This variant was considered a benign polymorphism as it was predicted to be non-pathogenic with in silico tools and found in database controls. This is the first report of a small intragenic deletion of FOXP2 that is likely to be the cause of severe motor speech disorder associated with language and literacy problems.


Assuntos
Apraxias/genética , Disartria/genética , Fatores de Transcrição Forkhead/genética , Deleção de Sequência , Adolescente , Adulto , Sequência de Bases , Criança , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Destreza Motora , Linhagem , Fala , Adulto Jovem
8.
Epilepsia ; 54(2): 280-7, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23294109

RESUMO

PURPOSE: To characterize the frequency and nature of the family history of seizures in probands with epilepsy falling within the epilepsy-aphasia spectrum (EAS) in order to understand the genetic architecture of this group of disorders. METHODS: Patients with epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), Landau-Kleffner syndrome (LKS), atypical benign partial epilepsy (ABPE), and intermediate epilepsy-aphasia disorders (IEAD) were recruited. All affected and available unaffected relatives up to three degrees of relatedness underwent phenotyping using a validated seizure questionnaire. Pedigrees were constructed for all families. The proportion of affected relatives according to each degree of relatedness was calculated. The epilepsy phenotypes in close relatives were analyzed. The data were compared to the families of probands with benign childhood epilepsy with centrotemporal spikes (BECTS) using the same methodology. KEY FINDINGS: Thirty-one probands, including five ECSWS, three LKS, one ABPE, and 22 IEAD were recruited. The mean age of seizure onset was 3.9 (range 0.5-7) years. A male predominance was seen (68%, 21/31) . Sixteen (51.6%) of 31 had a positive family history of seizures. Among 1,254 relatives, 30 (2.4%) had a history of seizures: 13 (10.2%) of 128 first-degree relatives, 5 (1.7%) of 291 second-degree relatives, and 12 (1.4%) of 835 third-degree relatives. Thirteen had febrile seizures, including two who had both febrile seizures and epilepsy. Of the 19 relatives with epilepsy, 4 had BECTS, 4 epilepsies with focal seizures of unknown cause, 3 IEAD, and 7 unclassified. One had genetic generalized epilepsy. In the families of the BECTS probands, 9.8% of first-degree, 3% of second-degree, and 1.5% of third-degree relatives had seizures, which was not significantly different from the EAS cohort families. SIGNIFICANCE: The frequencies of seizures in relatives of probands with EAS suggest that the underlying genetic influence of EAS is consistent with complex inheritance and similar to BECTS. The phenotypic pattern observed in the affected relatives comprised predominantly febrile seizures and focal seizures. These findings suggest that a shared genetic predisposition to focal epilepsies underpins the epilepsy-aphasia spectrum.


Assuntos
Afasia/genética , Epilepsia/genética , Adolescente , Adulto , Idade de Início , Idoso , Austrália , Encéfalo/patologia , Criança , Pré-Escolar , Transtornos Cognitivos/genética , Transtornos Cognitivos/psicologia , Interpretação Estatística de Dados , Epilepsias Parciais/genética , Epilepsias Parciais/psicologia , Epilepsia/psicologia , Epilepsia Rolândica/genética , Epilepsia Rolândica/psicologia , Família , Feminino , Humanos , Lactente , Síndrome de Landau-Kleffner/genética , Síndrome de Landau-Kleffner/psicologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Linhagem , Convulsões Febris/complicações , Adulto Jovem
9.
J Med Genet ; 47(3): 211-6, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19752159

RESUMO

BACKGROUND: Epilepsy and mental retardation limited to females (EFMR) is an intriguing X-linked disorder affecting heterozygous females and sparing hemizygous males. Mutations in the protocadherin 19 (PCDH19) gene have been identified in seven unrelated families with EFMR. METHODS AND RESULTS: Here, we assessed the frequency of PCDH19 mutations in individuals with clinical features which overlap those of EFMR. We analysed 185 females from three cohorts: 42 with Rett syndrome who were negative for MECP2 and CDKL5 mutations, 57 with autism spectrum disorders, and 86 with epilepsy with or without intellectual disability. No mutations were identified in the Rett syndrome and autism spectrum disorders cohorts suggesting that despite sharing similar clinical characteristics with EFMR, PCDH19 mutations are not generally associated with these disorders. Among the 86 females with epilepsy (of whom 51 had seizure onset before 3 years), with or without intellectual disability, we identified two (2.3%) missense changes. One (c.1671C-->G, p.N557K), reported previously without clinical data, was found in two affected sisters, the first EFMR family without a multigenerational family history of affected females. The second, reported here, is a novel de novo missense change identified in a sporadic female. The change, p.S276P, is predicted to result in functional disturbance of PCDH19 as it affects a highly conserved residue adjacent to the adhesion interface of EC3 of PCDH19. CONCLUSIONS: This de novo PCDH19 mutation in a sporadic female highlights that mutational analysis should be considered in isolated instances of girls with infantile onset seizures and developmental delay, in addition to those with the characteristic family history of EFMR.


Assuntos
Caderinas/genética , Epilepsia/genética , Família , Deficiência Intelectual Ligada ao Cromossomo X/genética , Mutação , Adulto , Sequência de Aminoácidos , Sequência de Bases , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Epilepsia/complicações , Características da Família , Feminino , Humanos , Deficiência Intelectual Ligada ao Cromossomo X/complicações , Dados de Sequência Molecular , Mutação/fisiologia , Linhagem , Protocaderinas , Homologia de Sequência de Aminoácidos
11.
Brain ; 131(Pt 4): 918-27, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18234694

RESUMO

Epilepsy and Mental Retardation limited to Females (EFMR) which links to Xq22 has been reported in only one family. We aimed to determine if there was a distinctive phenotype that would enhance recognition of this disorder. We ascertained four unrelated families (two Australian, two Israeli) where seizures in females were transmitted through carrier males. Detailed clinical assessment was performed on 58 individuals, using a validated seizure questionnaire, neurological examination and review of EEG and imaging studies. Gene localization was examined using Xq22 microsatellite markers. Twenty-seven affected females had a mean seizure onset of 14 months (range 6-36) typically presenting with convulsions. All had convulsive attacks at some stage, associated with fever in 17 out of 27 (63%). Multiple seizure types occurred including tonic-clonic (26), tonic (4), partial (11), absence (5), atonic (3) and myoclonic (4). Seizures ceased at mean 12 years. Developmental progress varied from normal (7), to always delayed (4) to normal followed by regression (12). Intellect ranged from normal to severe intellectual disability (ID), with 67% of females having ID or being of borderline intellect. Autistic (6), obsessive (9) and aggressive (7) features were prominent. EEGs showed generalized and focal epileptiform abnormalities. Five obligate male carriers had obsessional tendencies. Linkage to Xq22 was confirmed (maximum lod 3.5 at = 0). We conclude that EFMR is a distinctive, under-recognized familial syndrome where girls present with convulsions in infancy, often associated with intellectual impairment and autistic features. The unique inheritance pattern with transmission by males is perplexing. Clinical recognition is straightforward in multiplex families due to the unique inheritance pattern; however, this disorder should be considered in smaller families where females alone have seizures beginning in infancy, particularly in the setting of developmental delay. In single cases, diagnosis will depend on identification of the molecular basis.


Assuntos
Epilepsia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Cromossomos Humanos X/genética , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Eletroencefalografia , Epilepsia/complicações , Feminino , Ligação Genética , Heterozigoto , Humanos , Deficiência Intelectual/complicações , Masculino , Transtornos Mentais/complicações , Transtornos Mentais/genética , Pessoa de Meia-Idade , Linhagem , Fenótipo
12.
Brain ; 130(Pt 1): 100-9, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17020904

RESUMO

SCN1B, the gene encoding the sodium channel beta 1 subunit, was the first gene identified for generalized epilepsy with febrile seizures plus (GEFS+). Only three families have been published with SCN1B mutations. Here, we present four new families with SCN1B mutations and characterize the associated phenotypes. Analysis of SCN1B was performed on 402 individuals with various epilepsy syndromes. Four probands with missense mutations were identified. Detailed electroclinical phenotyping was performed on all available affected family members including quantitative MR imaging in those with temporal lobe epilepsy (TLE). Two new families with the original C121W SCN1B mutation were identified; novel mutations R85C and R85H were each found in one family. The following phenotypes occurred in the six families with SCN1B missense mutations: 22 febrile seizures, 20 febrile seizures plus, five TLE, three other GEFS+ phenotypes, two unclassified and ten unaffected individuals. All individuals with confirmed TLE had the C121W mutation; two underwent temporal lobectomy (one with hippocampal sclerosis and one without) and both are seizure free. We confirm the role of SCN1B in GEFS+ and show that the GEFS+ spectrum may include TLE alone. TLE with an SCN1B mutation is not a contraindication to epilepsy surgery.


Assuntos
Epilepsia Generalizada/genética , Epilepsia do Lobo Temporal/genética , Mutação de Sentido Incorreto/genética , Canais de Sódio/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Saúde da Família , Feminino , Genótipo , Humanos , Lactente , Imageamento por Ressonância Magnética/métodos , Masculino , Linhagem , Fenótipo , Mutação Puntual/genética , Convulsões/genética , Subunidade beta-1 do Canal de Sódio Disparado por Voltagem
13.
Arterioscler Thromb Vasc Biol ; 26(3): 663-9, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16385083

RESUMO

OBJECTIVE: The platelet glycoprotein (GP) Ib/V/IX complex plays an important role in regulating the morphology of resting platelets and can induce shape change during adhesion to immobilized von Willebrand factor (vWf). In this study we have examined the effects of fluid shear stress on GPIb-dependent changes in platelet morphology during translocation on vWf. METHODS AND RESULTS: We demonstrate that translocating platelets undergo a unique series of morphological changes in response to increasing fluid shear stress. Under moderately low shear conditions (600 s(-1)), initial shape change involved extension of membrane tethers and/or filopodia from the platelet surface. With increasing shear rate, platelets adopted a spherical morphology with numerous surface projections (1800 to 5000 s(-1)). At high wall shear rates (10000 to 20,000 s(-1)), translocating platelets retracted filopodia, developing a smooth ball-like appearance. These changes in morphology were dependent on reorganization of the actin and microtubule components of the cytoskeleton and were regulated by intracellular signaling processes linked to Src kinases. Functionally, alterations in platelet shape had a major effect on translocation dynamics in that conversion from discs to spheres resulted in a 3- to 8-fold increase in rolling velocity. CONCLUSIONS: These studies demonstrate that platelets undergo shear-specific morphological changes during surface translocation on vWf that may serve to regulate translocation dynamics under flow.


Assuntos
Plaquetas/fisiologia , Adesividade Plaquetária/fisiologia , Trombose/fisiopatologia , Citoesqueleto de Actina/fisiologia , Adulto , Plaquetas/ultraestrutura , Forma Celular/fisiologia , Humanos , Técnicas In Vitro , Microscopia Eletrônica de Varredura , Microtúbulos/fisiologia , Complexo Glicoproteico GPIb-IX de Plaquetas/fisiologia , Pseudópodes/fisiologia , Fluxo Sanguíneo Regional , Transdução de Sinais/fisiologia , Estresse Mecânico , Fator de von Willebrand
14.
Neurology ; 88(8): 743-749, 2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-28148630

RESUMO

OBJECTIVE: To analyze the oral motor, speech, and language phenotype in 20 children and adults with Dravet syndrome (DS) associated with mutations in SCN1A. METHODS: Fifteen verbal and 5 minimally verbal DS patients with SCN1A mutations (aged 15 months-28 years) underwent a tailored assessment battery. RESULTS: Speech was characterized by imprecise articulation, abnormal nasal resonance, voice, and pitch, and prosody errors. Half of verbal patients had moderate to severely impaired conversational speech intelligibility. Oral motor impairment, motor planning/programming difficulties, and poor postural control were typical. Nonverbal individuals had intentional communication. Cognitive skills varied markedly, with intellectual functioning ranging from the low average range to severe intellectual disability. Language impairment was congruent with cognition. CONCLUSIONS: We describe a distinctive speech, language, and oral motor phenotype in children and adults with DS associated with mutations in SCN1A. Recognizing this phenotype will guide therapeutic intervention in patients with DS.


Assuntos
Disartria/fisiopatologia , Discinesias/fisiopatologia , Epilepsias Mioclônicas/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Disartria/genética , Discinesias/genética , Epilepsias Mioclônicas/genética , Feminino , Humanos , Lactente , Idioma , Masculino , Destreza Motora , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Fenótipo , Fala , Adulto Jovem
15.
Eur J Med Genet ; 60(8): 437-443, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28602933

RESUMO

Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1. Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made. Whole exome sequencing of two affected sisters followed by filtering for rare and potentially disease causing variants in all genes identified compound heterozygous variants in NM_030582.3 (COL18A1): c.3690G > A: p.(Trp1230*) and NM_030582.3 (COL18A1): c.4063_4064delCT: p.(Leu1355Valfs*72). The two variants co-segregated with the affected individuals in the family. Identification of COL18A1 mutations in individuals with a Lennox-Gastaut phenotype and anterior polymicrogyria but lacking the classical occipital encephalocele expands the COL18A1 clinical spectrum.


Assuntos
Colágeno Tipo VIII/genética , Encefalocele/genética , Síndrome de Lennox-Gastaut/genética , Mutação , Descolamento Retiniano/congênito , Adulto , Colágeno Tipo XVIII , Encefalocele/diagnóstico , Feminino , Heterozigoto , Humanos , Síndrome de Lennox-Gastaut/diagnóstico , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Degeneração Retiniana , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/genética
16.
Sci Rep ; 6: 35192, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27734906

RESUMO

FOXP2 is the major gene associated with severe, persistent, developmental speech and language disorders. While studies in the original family in which a FOXP2 mutation was found showed volume reduction and reduced activation in core language and speech networks, there have been no imaging studies of different FOXP2 mutations. We conducted a multimodal MRI study in an eight-year-old boy (A-II) with a de novo FOXP2 intragenic deletion. A-II showed marked bilateral volume reductions in the hippocampus, thalamus, globus pallidus, and caudate nucleus compared with 26 control males (effect sizes from -1 to -3). He showed no detectable functional MRI activity when repeating nonsense words. The hippocampus is implicated for the first time in FOXP2 diseases. We conclude that FOXP2 anomaly is either directly or indirectly associated with atypical development of widespread subcortical networks early in life.


Assuntos
Fatores de Transcrição Forkhead/genética , Deleção de Sequência/genética , Criança , Códon sem Sentido/genética , Hipocampo/metabolismo , Humanos , Idioma , Transtornos da Linguagem/genética , Transtornos da Linguagem/metabolismo , Imageamento por Ressonância Magnética/métodos , Masculino , Mutação/genética , Neuroimagem/métodos , Fala/fisiologia
17.
Neurology ; 84(6): 586-93, 2015 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-25596506

RESUMO

OBJECTIVE: To delineate the specific speech deficits in individuals with epilepsy-aphasia syndromes associated with mutations in the glutamate receptor subunit gene GRIN2A. METHODS: We analyzed the speech phenotype associated with GRIN2A mutations in 11 individuals, aged 16 to 64 years, from 3 families. Standardized clinical speech assessments and perceptual analyses of conversational samples were conducted. RESULTS: Individuals showed a characteristic phenotype of dysarthria and dyspraxia with lifelong impact on speech intelligibility in some. Speech was typified by imprecise articulation (11/11, 100%), impaired pitch (monopitch 10/11, 91%) and prosody (stress errors 7/11, 64%), and hypernasality (7/11, 64%). Oral motor impairments and poor performance on maximum vowel duration (8/11, 73%) and repetition of monosyllables (10/11, 91%) and trisyllables (7/11, 64%) supported conversational speech findings. The speech phenotype was present in one individual who did not have seizures. CONCLUSIONS: Distinctive features of dysarthria and dyspraxia are found in individuals with GRIN2A mutations, often in the setting of epilepsy-aphasia syndromes; dysarthria has not been previously recognized in these disorders. Of note, the speech phenotype may occur in the absence of a seizure disorder, reinforcing an important role for GRIN2A in motor speech function. Our findings highlight the need for precise clinical speech assessment and intervention in this group. By understanding the mechanisms involved in GRIN2A disorders, targeted therapy may be designed to improve chronic lifelong deficits in intelligibility.


Assuntos
Apraxias/genética , Disartria/genética , Mutação , Receptores de N-Metil-D-Aspartato/genética , Distúrbios da Fala/genética , Inteligibilidade da Fala , Adolescente , Adulto , Afasia de Broca/genética , Epilepsia/complicações , Feminino , Humanos , Transtornos da Linguagem/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Desempenho Psicomotor , Adulto Jovem
18.
Nat Genet ; 45(9): 1073-6, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23933818

RESUMO

Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes. We identified four probands with GRIN2A variants that segregated with the disorder in their families. Notably, all four families presented with EAS, accounting for 9% of epilepsy-aphasia cases. We did not detect pathogenic variants in GRIN2A in other epileptic encephalopathies (n = 475) nor in probands with benign childhood epilepsy with centrotemporal spikes (n = 81). We report the first monogenic cause, to our knowledge, for EAS. GRIN2A mutations are restricted to this group of cases, which has important ramifications for diagnostic testing and treatment and provides new insights into the pathogenesis of this debilitating group of conditions.


Assuntos
Síndrome de Landau-Kleffner/genética , Mutação , Receptores de N-Metil-D-Aspartato/genética , Eletroencefalografia , Feminino , Humanos , Síndrome de Landau-Kleffner/diagnóstico , Masculino , Linhagem , Fenótipo
19.
Nat Genet ; 40(6): 776-81, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18469813

RESUMO

Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.


Assuntos
Caderinas/genética , Cromossomos Humanos X , Códon sem Sentido/genética , Transtornos Cognitivos/genética , Epilepsia/genética , Impressão Genômica , Mutação de Sentido Incorreto/genética , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Transtornos Cognitivos/patologia , Epilepsia/patologia , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Genes Ligados ao Cromossomo X/genética , Humanos , Hibridização In Situ , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/patologia , Camundongos/embriologia , Linhagem , Fenótipo , Protocaderinas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/citologia , Pele/metabolismo
20.
Epilepsia ; 45(5): 467-78, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15101828

RESUMO

PURPOSE: In families with idiopathic generalized epilepsy (IGE), multiple IGE subsyndromes may occur. We performed a genetic study of IGE families to clarify the genetic relation of the IGE subsyndromes and to improve understanding of the mode(s) of inheritance. METHODS: Clinical and genealogic data were obtained on probands with IGE and family members with a history of seizures. Families were grouped according to the probands' IGE subsyndrome: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with tonic-clonic seizures only (IGE-TCS). The subsyndromes in the relatives were analyzed. Mutations in genes encoding alpha1 and gamma 2 gamma-aminobutyric acid (GABA)-receptor subunits, alpha1 and beta1 sodium channel subunits, and the chloride channel CLC-2 were sought. RESULTS: Fifty-five families were studied. 122 (13%) of 937 first- and second-degree relatives had seizures. Phenotypic concordance within families of CAE and JME probands was 28 and 27%, respectively. JAE and IGE-TCS families had a much lower concordance (10 and 13%), and in the JAE group, 31% of relatives had CAE. JME was rare among affected relatives of CAE and JAE probands and vice versa. Mothers were more frequently affected than fathers. No GABA-receptor or sodium or chloride channel gene mutations were identified. CONCLUSIONS: The clinical genetic analysis of this set of families suggests that CAE and JAE share a close genetic relation, whereas JME is a more distinct entity. Febrile seizures and epilepsy with unclassified tonic-clonic seizures were frequent in affected relatives of all IGE individuals, perhaps representing a nonspecific susceptibility to seizures. A maternal effect also was seen. Our findings are consistent with an oligogenic model of inheritance.


Assuntos
Epilepsia Generalizada/genética , Família , Adolescente , Adulto , Criança , Canais de Cloreto/genética , Epilepsia Tipo Ausência/genética , Feminino , Frequência do Gene/genética , Heterogeneidade Genética , Ligação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Modelos Genéticos , Mutação , Epilepsia Mioclônica Juvenil/genética , Linhagem , Fenótipo , Receptores de GABA/genética , Canais de Sódio/genética
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