A influência da hereditariedade na ocorrência de variáveis preditoras na gagueira crônica do desenvolvimento / The influence of heredity on the predictor variables of chronic developmental stuttering

RESUMO Objetivo Testar a variável da hereditariedade familiar para a gagueira crônica do desenvolvimento (GCD) como preditora de efeito direto no desfecho da fluência da fala em crianças. Métodos Participaram do estudo 200 crianças, de 2 a 12 anos, de ambos os gêneros, sem distinção de raça e nível sócio-econômico-cultural, que apresentaram queixa de GCD, sem outras intercorrências de linguagem e/ou audição, no período de cinco anos. Os 200 participantes deste estudo foram divididos em três grupos (baixo risco para GCD, médio risco para GCD e alto risco para GCD) conforme os indicadores de risco aferidos pelo Protocolo de risco para a gagueira do desenvolvimento. Para determinação da variável de controle (hereditariedade positiva para a gagueira) foi considerado afetado o participante que apresentava familiar de primeiro grau (pai, mãe, irmãos) que se auto identificava como pessoa com gagueira. Todos os participantes foram avaliados segundo o Protocolo de risco para a gagueira do desenvolvimento e pela Avaliação do Perfil da Fluência de Fala. Resultados Os grupos de baixo, médio e alto risco para GCD com hereditariedade positiva não se diferenciaram estatisticamente dos grupos de baixo, médio e alto risco para GCD com hereditariedade negativa para nenhuma das variáveis demográficas e resultado da análise do Perfil de Fluência da Fala. Conclusão A variável hereditariedade não indicou o grau de risco na manifestação da fala nem identificou, decisivamente, as crianças em risco de persistência para a GCD.

ABSTRACT Purpose To test if the variable family heredity for chronic developmental stuttering (CDS) is a direct predictor of the speech fluency outcome in children. Methods Participants of the study were 200 children, between 2 and 12 years of age, of both genders, with no racial and socioeconomic distinction, diagnosed with a complaint of CDS, and with no language and/or hearing comorbidity, over a period of 5 years. Participants were divided in three study groups (low risk for CDS, moderate risk for CDS, and high risk for CDS) according to the risk indicators determined by the Risk Protocol for Developmental Stuttering. In order to determine the control variable (positive heredity for stuttering), we considered the participant as being affected if he/she presented a first-degree family member (father, mother, siblings) who self-declared themselves as a person who stuttered. All of the participants were assessed according to Risk Protocol for Developmental Stuttering and to The Speech Fluency Profile Assessment. Results No significant difference was observed for the demographic variables and for the results on The Fluency Profile Assessment among the groups with mild, moderate and high risk of stuttering when comparing the groups with positive and negative family heredity. Conclusion The variable family heredity did not indicate the risk level for the manifestation of stuttering and also did not identify those at risk of presenting CDS.

A study of the role of the FOXP2 and CNTNAP2 genes in persistent developmental stuttering.

A number of speech disorders including stuttering have been shown to have important genetic contributions, as indicated by high heritability estimates from twin and other studies. We studied the potential contribution to stuttering from variants in the FOXP2 gene, which have previously been associated with developmental verbal dyspraxia, and from variants in the CNTNAP2 gene, which have been associated with specific language impairment (SLI). DNA sequence analysis of these two genes in a group of 602 unrelated cases, all with familial persistent developmental stuttering, revealed no excess of potentially deleterious coding sequence variants in the cases compared to a matched group of 487 well characterized neurologically normal controls. This was compared to the distribution of variants in the GNPTAB, GNPTG, and NAGPA genes which have previously been associated with persistent stuttering. Using an expanded subject data set, we again found that NAGPA showed significantly different mutation frequencies in North Americans of European descent (p=0.0091) and a significant difference existed in the mutation frequency of GNPTAB in Brazilians (p=0.00050). No significant differences in mutation frequency in the FOXP2 and CNTNAP2 genes were observed between cases and controls. To examine the pattern of expression of these five genes in the human brain, real time quantitative reverse transcription PCR was performed on RNA purified from 27 different human brain regions. The expression patterns of FOXP2 and CNTNAP2 were generally different from those of GNPTAB, GNPTG and NAPGA in terms of relatively lower expression in the cerebellum. This study provides an improved estimate of the contribution of mutations in GNPTAB, GNPTG and NAGPA to persistent stuttering, and suggests that variants in FOXP2 and CNTNAP2 are not involved in the genesis of familial persistent stuttering. This, together with the different brain expression patterns of GNPTAB, GNPTG, and NAGPA compared to that of FOXP2 and CNTNAP2, suggests that the genetic neuropathological origins of stuttering differ from those of verbal dyspraxia and SLI.

A genetic linkage study in Brazil identifies a new locus for persistent developmental stuttering on chromosome 10.

Although twin, adoption, and family studies demonstrate that genetic factors are involved in the origins of stuttering, the mode of transmission of the disorder in families is not well defined and stuttering is considered a genetically complex trait. We performed a genome-wide linkage scan in a group of 43 Brazilian families, each containing multiple cases of persistent developmental stuttering. Linkage analysis under a dominant model of inheritance generated significant evidence of linkage in two Brazilian families, with a combined maximum single-point LOD score of 4.02 and a multipoint LOD score of 4.28 on chromosome 10q21. This demonstrated the presence of a novel variant gene at this locus that predisposes individuals to stuttering, which provides an opportunity to identify novel genetic mechanisms that underlie this disorder.

Fatores de risco para gagueira em crianças disfluentes com recorrência familial / Risk factors for stuttering in disfluent children with familial recurrence

OBJETIVO: Caracterizar os fatores gênero, idade, tempo de duração e tipologia das disfluências, fatores estressantes físicos e emocionais em crianças com alto risco para a gagueira e com recorrência familial do distúrbio. MÉTODOS: Participaram 65 crianças com alto risco para a gagueira desenvolvimental familial, de ambos os gêneros, na faixa etária de três a 11anos. A coleta de dados foi realizada por meio do Protocolo de Risco para a Gagueira do Desenvolvimento (PRGD). RESULTADOS: A razão masculino/feminino de crianças disfluentes encontrada foi de 2,8:1, com predominância do grupo na faixa etária de três anos. Os resultados revelaram diferença significativa quanto ao tempo de duração: mais crianças apresentaram um período maior de 12 meses de duração das disfluências em relação às crianças que apresentaram de seis a 12 meses de duração. A maioria apresentou algum fator estressante emocional e não apresentou fator estressante físico. CONCLUSÃO: Os resultados sugerem que crianças com recorrência familial da gagueira no gênero masculino, na faixa etária de três anos, com presença de disfluências gagas por mais de 12 meses e com ocorrência de fatores estressantes emocionais são as que apresentam maior risco para o desenvolvimento da gagueira persistente.

PURPOSE: To characterize the factors gender, age, duration and typology of the disfluencies; physical and emotional stresses in children with high risk for stuttering and with familial recurrence of the disorder. METHODS: Sixty-five children with high risk for developmental familial stuttering of both genders, with ages between 3 and 11 years and 11 months. The data were gathered through the Protocol of Risk for the Developmental Stuttering. RESULTS: In our findings the ratio male:female was 2.8:1, and the majority of the children were aged 3 years old. Significantly more children presented more than 12 months' duration of the disfluencies when compared to children that presented 6 to 12 months' duration. The majority showed some emotional stress and didn't show any physical stress. CONCLUSION: The results of this study suggest that children with familial recurrence of stuttering, male, with 3 years old, with stuttering-like disfluencies (SLD) lasting for more than 12 months and with the occurrence of emotional stresses are the children that present the higher risk for the development of the persistent stuttering.

Speech fluency family profile--a linguistic, acoustic and electromyographic study.

BACKGROUND: genetic factors as a possible cause of stuttering. AIM: to identify the speech fluency family profile (linguistic, electromyographic and acoustic aspects) in children with and without a close family history of stuttering. METHOD: the study included a total of 127 individuals, 32 children (probands) and 95 members of the immediate family (father, mother, sisters and brothers). The individuals were divided in two groups: GI (SC) was composed of 17 probands with a diagnosis of stuttering, 17 fathers, 17 mothers, 10 brothers, and 13 sisters, and GII (NSC) was composed of 15 fluent probands, 15 fathers, 15 mothers, no brothers, and 8 sisters. All testing procedures were applied to all participants as follows: 1) identification of disruption typology; 2) electromyographic analyses; and 3) acoustic analyses. RESULTS: the percentage of affected mothers was 41.1%, and the percentage of affected fathers was 35.3%. In addition, the percentage of affected sisters was 6.7%, and 40% of the brothers were affected. Similarity was observed in the typology of speech disruptions in all of the affected individuals of the same family; however, a trend towards a greater severity of the disorder in probands was observed. Similarity was found in muscle activation for diadochokinesia rates in all the affected individuals in the same family. This suggests the existence of a speech motor pattern within the same family that can be measured by capturing peripheral muscle activation. Similarity was found in the acoustic variation for diadochokinetic rates in all affected individuals of the same family. CONCLUSION: this study represents one of the first endophenotypic research proposals on stuttering characterized by two aspects: objective inclusion criteria and the type of stuttering symptomatology manifested.

Identification of a microdeletion at the 7q33-q35 disrupting the CNTNAP2 gene in a Brazilian stuttering case.

Speech and language disorders are some of the most common referral reasons to child development centers accounting for approximately 40% of cases. Stuttering is a disorder in which involuntary repetition, prolongation, or cessation of the sound precludes the flow of speech. About 5% of individuals in the general population have a stuttering problem, and about 80% of the affected children recover naturally. The causal factors of stuttering remain uncertain in most cases; studies suggest that genetic factors are responsible for 70% of the variance in liability for stuttering, whereas the remaining 30% is due to environmental effects supporting a complex cause of the disorder. The use of high-resolution genome wide array comparative genomic hybridization has proven to be a powerful strategy to narrow down candidate regions for complex disorders. We report on a case with a complex set of speech and language difficulties including stuttering who presented with a 10 Mb deletion of chromosome region 7q33-35 causing the deletion of several genes and the disruption of CNTNAP2 by deleting the first three exons of the gene. CNTNAP2 is known to be involved in the cause of language and speech disorders and autism spectrum disorder and is in the same pathway as FOXP2, another important language gene, which makes it a candidate gene for causal studies speech and language disorders such as stuttering.

Perfil familial da fluência da fala: estudo linguístico, acústico e eletromiográfico / Speech fluency family profile: a linguistic, acoustic and electromyographic study

TEMA: fatores genéticos como possíveis responsáveis pela gagueira. OBJETIVO: identificar o perfil familial da fluência da fala - aspectos linguísticos, eletromiográficos e acústicos - em crianças com e sem história familiar próxima para a gagueira. MÉTODO: participaram do estudo 127 indivíduos, 32 crianças (probandos) e 95 membros da família imediata (pai, mãe, irmãs e irmãos) divididos em dois grupos: GI (CCG): 17 probandos com diagnóstico de gagueira; 17 pais, 17 mães, 10 irmãos e 13 irmãs; e GII (CSG): 15 probandos fluentes; 15 pais, 15 mães, 0 irmãos e 8 irmãs. Todos os procedimentos de testagem foram aplicados em todos os participantes: 1. Coleta das tipologias das rupturas; 2. Coleta eletromiográfica; 3. Coleta acústica. RESULTADOS: foi encontrado o percentual de 41,1 por cento de mães afetadas; 35,3 por cento de pais afetados; 16,7 por cento de irmãs afetadas e 40 por cento de irmãos afetados. Foi observada similaridade na tipologia das rupturas da fala em todos os afetados de uma mesma família, mesmo havendo uma tendência a maior gravidade do distúrbio nos probandos. Foi encontrada similaridade na ativação muscular para as taxas de diadococinesia em todos os afetados de uma mesma família. Sugere-se um padrão motor para a fala, numa relação passível de ser mensurada pala captação da ativação muscular periférica, dentro de uma mesma família. Foi encontrada similaridade na variação acústica para as taxas de diadococinesia em todos os afetados de uma mesma família. CONCLUSÃO: esta pesquisa se caracteriza como uma primeira proposta de estudo endofenotípico da gagueira, em dois aspectos: critérios objetivos de inclusão e tipo de sintomatologia manifesta da gagueira.

BACKGROUND: genetic factors as a possible cause of stuttering. AIM: to identify the speech fluency family profile (linguistic, electromyographic and acoustic aspects) in children with and without a close family history of stuttering. METHOD: the study included a total of 127 individuals, 32 children (probands) and 95 members of the immediate family (father, mother, sisters and brothers). The individuals were divided in two groups: GI (SC) was composed of 17 probands with a diagnosis of stuttering, 17 fathers, 17 mothers, 10 brothers, and 13 sisters, and GII (NSC) was composed of 15 fluent probands, 15 fathers, 15 mothers, no brothers, and 8 sisters. All testing procedures were applied to all participants as follows: 1) identification of disruption typology; 2) electromyographic analyses; and 3) acoustic analyses. RESULTS: the percentage of affected mothers was 41.1 percent, and the percentage of affected fathers was 35.3 percent. In addition, the percentage of affected sisters was 6.7 percent, and 40 percent of the brothers were affected. Similarity was observed in the typology of speech disruptions in all of the affected individuals of the same family; however, a trend towards a greater severity of the disorder in probands was observed. Similarity was found in muscle activation for diadochokinesia rates in all the affected individuals in the same family. This suggests the existence of a speech motor pattern within the same family that can be measured by capturing peripheral muscle activation. Similarity was found in the acoustic variation for diadochokinetic rates in all affected individuals of the same family. CONCLUSION: this study represents one of the first endophenotypic research proposals on stuttering characterized by two aspects: objective inclusion criteria and the type of stuttering symptomatology manifested.

A study of familial stuttering.

Here we study 13 families with stuttering. Of the 13 families, 9 were persistent stutterers and 4 were recovered stutterers. In the 9 families with persistent stuttering, 24 were male and 10 were females. Of the 4 families with recovered stutterers, 17 were male and 3 were female. Of the 17 males, 12 were persistent stutterers and 5 recovered after adolescence. All females were recovered stutterers. We conclude with a short discussion of recent molecular studies.