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El propósito de este proyecto ha sido elaborar una guía que recoja recomendaciones basadas en la evidencia científica para la mejora de la evaluación, el diagnóstico y la intervención en los casos de dispraxia verbal en población infantil con el objetivo de facilitar la labor de los logopedas y mejorar la atención que se les da a los pacientes con dicho trastorno. Para ello, se realizó una búsqueda bibliográfica en las bases de datos Web of Science, Pubmed y Scopus. Se revisaron artículos de 2012 a 2022 sobre la evaluación, el diagnóstico y la intervención logopédica de la dispraxia verbal y se seleccionaron un total de 9 artículos. Los estudios indican que los niños y niñas con dispraxia verbal pueden presentar algunos signos tempranos y describen distintas características de este trastorno, sin llegar a un consenso sobre las mismas. A pesar de ello, se recomienda analizar las habilidades articulatorias, motoras y segmentales de los niños y niñas con posible dispraxia verbal a partir de una evaluación clínica y formal, utilizando transcripciones del habla y empleando medidas cuantitativas. Los métodos de intervención logopédica que han probado eficacia para la mejora de las habilidades de los niños y niñas con dispraxia verbal y su mantenimiento son el de Dinámica Temporal e Indicación Táctil (DTTC), el de Transición Rápida de Sílabas (ReST), la Intervención de Conciencia Fonológica Integrada y el Programa de Dispraxia Nuffield. Es necesario seguir investigando sobre la dispraxia verbal con el fin de alcanzar un consenso sobre la evaluación, el diagnóstico y la intervención en este trastorno. The purpose of this project was to develop a guide that included recommendations based on scientific evidence to improve the evaluation, diagnosis and intervention in cases of verbal dyspraxia in children. In order to facilitate the work of speech therapists and improve the care given to patients with this disorder. To this end, a bibliographic search was carried out in the Web of Science, Pubmed and Scopus databases. Articles from 2012 to 2022 on assessment, diagnosis and treatment of verbal dyspraxia were reviewed and a total of 9 articles were selected. The studies indicate that children diagnosed with verbal dyspraxia may present some early signs and describe different characteristics of this disorder, without reaching a consensus on them. Despite this, the articulatory, motor and segmental skills of children with possible verbal dyspraxia should be analyzed from a clinical and formal evaluation, using speech transcripts and employing quantitative measures. Speech therapy intervention methods that have proven effective in improving the skills of children with verbal dyspraxia and their maintenance are Integral Stimulation / Dynamic Temporal and Tactile Cueing (DTTC), Rapid Syllable Transition Treatment (ReST), Integrated Phonological Awareness Intervention and the Nuffield Dyspraxia Program. Further research on verbal dyspraxia is needed in order to reach a consensus on assessment, diagnosis, and intervention in this disorder.

Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G N-glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and N-glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was, Patients with classical galactosemia frequently suffer from complications affecting the brain for which prognostic factors are lacking. In our cohort of classical galactosemia patients, we demonstrated a highly variable outcome, distinguished a subgroup of milder ‘variant patients’ and found an association between MRI abnormalities and lower intellectual outcomes and movement disorders., Graphical Abstract Graphical Abstract

Background Developmental Coordination Disorder (DCD) is a chronic neurological disorder observed in children. DCD is characterized by slowness in activities and motor impairment that affects the children’s daily living and academic achievements, and later their professional and social behavior. Our aim in this work was to report characteristics frequencies in a group of children with DCD and to propose a subtyping of DCD characteristics. Methods Thirty three clinical DCD characteristics, the mostly reported in the literature, were assessed in 129 patients, boys and girls aged from 4 years to 18 years, and their subtyping was proposed. The statistical analyses were carried out with the Chi square, the t-test and the correlation for the statistical differences, and with the Ward clustering method for subtyping. Results We found that there were 3.17 boys for one girl, all patients were characterized as slow, 47% were left-handers or ambidextrous, 36% and 26% had orofacial and verbal dyspraxia, respectively, 83% were found anxious, and 84% were described as being clumsy. Conclusions It appears from these results that a child with DCD expresses more than a single difficulty. Three subtypes emerged from the statistical analysis in this study: (1) clumsiness and other characteristics except language difficulties; (2) self-esteem and peer relation without clumsiness and language difficulties; (3) language difficulties and orofacial dyspraxia.

Bilateral volume reduction in the caudate nucleus has been established as a prominent brain abnormality associated with a FOXP2 mutation in affected members of the ‘KE family’, who present with developmental orofacial and verbal dyspraxia in conjunction with pervasive language deficits. Despite the gene’s early and prominent expression in the cerebellum and the evidence for reciprocal cerebellum-basal ganglia connectivity, very little is known about cerebellar abnormalities in affected KE members. Using cerebellum-specific voxel-based morphometry (VBM) and volumetry, we provide converging evidence from subsets of affected KE members scanned at three time points for grey matter (GM) volume reduction bilaterally in neocerebellar lobule VIIa Crus I compared with unaffected members and unrelated controls. We also show that right Crus I volume correlates with left and total caudate nucleus volumes in affected KE members, and that right and total Crus I volumes predict the performance of affected members in non-word repetition and non-verbal orofacial praxis. Crus I also shows bilateral hypo-activation in functional MRI in the affected KE members relative to controls during non-word repetition. The association of Crus I with key aspects of the behavioural phenotype of this FOXP2 point mutation is consistent with recent evidence of cerebellar involvement in complex motor sequencing. For the first time, specific cerebello-basal ganglia loops are implicated in the execution of complex oromotor sequences needed for human speech. Electronic supplementary material The online version of this article (10.1007/s12311-018-0989-3) contains supplementary material, which is available to authorized users.

Gli scienziati hanno trovato un gene chiamato FOXP2 che sembra ad essere essenziale per la produzione del linguaggio. Quindi è spesso chiamato „il gene del linguaggio“. È probabilmente solo uno dei molti geni coinvolti nella comunicazione umana, ma recente scoperte sembravano sottolineare la sua importanza. Il fattore di trascrizione FOXP2 è stato implicato nell'evoluzione del cervello umano, linguaggio, cognizione, integrazione vocal-motoria e sviluppo neurale nel sistema nervoso centrale (CNS). La versione umana della proteina prodotta dal gene differisce di due aminoacidi da quella degli scimpanzé, e sembra di aver subito una selezione naturale. Negli anni successivi, FOXP2 è stato implicato nelle vocalizzazioni di altri animali, tra cui topi, uccelli canori e anche pipistrelli. Il gene FOXP2 è stato scoperto come risultato degli indagini su una famiglia inglese nota come famiglia KE con diversi membri affetti dalla disprassia verbale dello sviluppo accompagnata da un grave disturbo articolatorio. Questa famiglia KE è stata trovata portatrice di un allele mutato, ma c'è un altro individuo non correlato che è stato trovato portatore di una traslocazione bilanciata con una pausa in FOXP2. FOXP2 è il primo gene implicato in un disturbo delle vocalizzazioni e del linguaggio. Fin dalla sua scoperta, sono stati condotti molti studi dagli scienziati incuriositi, nel tentativo di spiegare il meccanismo con cui influenza questi tratti umani caratteristici e di identificare i geni regolati dal FOXP2. I ricercatori suggeriscono che FOXP2 potrebbe regolare sia lo sviluppo neurale del linguaggio, sia quello delle strutture anatomiche necessarie alla fonoarticolazione. Nelle pagine seguenti sarànno spiegate le caratteristiche del gene responsabile per la produzione del linguaggio, attraverso le differenze evolutive in sequenze del genoma e le proteine che sono specifici per l'uomo, la sua l'importanza per ill sistema nervoso, in particolare il cervello e attraverso le mutazioni geneticche che si traducono nei disturbi linguistici. Znanstvenici su pronašli gen koji je relevantan za govornu produkciju, a naziva se FOXP2. Taj takozvani "gen za jezik", vjerojatno je samo jedan od mnogih gena ključnih za ljudsku komunikaciju, međutim, nedavna otkrića naglašavaju njegov značaj. FOXP2 gen je transkripcijski faktor te ima vaţnu ulogu u evoluciji ljudskog mozga, jezika, spoznaje, vokalno-motorne integracije i neuralnog razvoja u središnjem ţivčanom sustavu - SŢS (ili CNS). Ljudska verzija proteina FOXP2 gena razlikuje se u dvije aminokiseline od čimpanza te je podvrgnuta prirodnoj selekciji. Tijekom godina, FOXP2 je postao čimbenik zasluţan za vokalizaciju drugih ţivotinja, uključujući miševe, ptice pjevice, pa čak i šišmiše. FOXP2 gen je otkriven kao rezultat istraţivanja engleske obitelji, poznate kao KE obitelj. Nekolicini članova KE obitelji dijagnosticirana je razvojna verbalna dispraksija, koja je popraćena s teškim artikulacijskim poremećajem. Otkriveno je da obitelj KE nosi mutirani alel. No, utvrđena je uravnoteţena translokacija s prekidom u FOXP2 u još jednog pojedinca, koji nije genetski povezan s obitelji KE. Kao rezultat toga, FOXP2 je postao prvi gen povezan s poremećajima govora i jezika. Otkrićem tog gena, mnogi znanstvenici provodili su istraţivanja nastojeći objasniti mehanizam s kojim utječe na ljude i ţeljeli su identificirati ostale gene koje FOXP2 regulira. Znanstvenici smatraju da FOXP2 moţe utjecati na neuralni razvoj jezika te na anatomske strukture potrebne za fonoartikulaciju. Na sljedećim stranicama, objašnjene su karakteristike gena odgovornog za govornu produkciju – FOXP2, i to preko evolucijskih razlika u sekvencijama genoma i proteina specifičnih za ljudska bića. Zatim, preko genetskih mutacija manifestiranih u jezične poremećaje i vaţnosti koju ima za ţivčani sustav, točnije za mozak. Scientists have found a gene called FOXP2 that seems to be essential for language production. Thus it is often called "the language gene". It is probably just one of many genes involved in human communication, but recent discoveries seemed to underline its importance. The transcription factor FOXP2 has been implicated in the evolution of the human brain, language, cognition, vocal-motor integration and neural development in the central nervous system (CNS). The human version of the protein produced by the gene differs from two amino acids from that of a chimpanzee, and seems to have undergone a natural selection. In later years, FOXP2 has been a great factor in the vocalizations of other animals, including mice, songbirds and even bats. The FOXP2 gene was discovered as a result of research on an English family known as the KE family with several members affected by developmental dyspraxia of speech accompanied by severe articulatory disorder. This KE family has been found to carry a mutated allele, but there is another unrelated individual who has been found to have a balanced translocation with a break in FOXP2. As a result, FOXP2 is the first gene involved in a disorder of vocalizations and language. Since its discovery, many studies have been conducted by intrigued scientists in an attempt to explain the mechanism by which it influences these characteristic human traits and to identify the genes regulated by FOXP2. The researchers suggest that FOXP2 could regulate both the neural development of language and the anatomical structures necessary for phonoarticulation. The following pages will explain the characteristics of the gene responsible for the production of language, through the evolutionary differences in sequences of the genome and proteins that are specific to humans, its importance for the nervous system, in particular, the brain and through mutations that translate into linguistic disorders isolated after genetic mutation. In the following pages, the characteristics of the gene responsible for the production of language will be explained, through the evolutionary differences in sequences of the genome and proteins that are specific to humans, its importance for the nervous system, more specifically, the brain and through genetic mutations that translate into linguistic disorders.

Mice produce ultrasonic vocalizations (USVs) in a variety of social situations, and USVs have been leveraged to study many neurological diseases including verbal dyspraxia, depression, autism and stuttering. Pups produce isolation calls, a common USV, spontaneously when they are isolated from their mother during the first 2 weeks of life. Several genetic manipulations affect (and often reduce) pup isolation calls in mice. To facilitate the use of this assay as a means of testing whether significant functional differences in genotypes exist instead of contextual differences, we test the variability inherent in many commons measures of mouse vocalizations. Here we use biological consistency as a way of determining which are reproducible in mouse pup vocalizations. We present a comprehensive analysis of the normal variability of these vocalizations in groups of mice, individual mice and different strains of mice. To control for maturation effects, we recorded pup isolation calls in the same group of C57BL/6J 5 days old mice twice, with 1 h of rest in between recordings. In almost all cases, the group averages between the first and second recordings were the same. We also found that there were high correlations in some parameters in individual mice across recording while others were not well correlated. These findings could be replicated for the majority of features in a separate group of C57BL/6J mice and a group of 129/SvEvBrd-C57BL/6J mice. The averages of these mouse USV features are highly consistent and represent a robust assay to test the effects of genetic and other interventions in the experimental setting.

FOXP2 gen je transkripcijski faktor iz obitelji FOX gena zadužen za regulaciju ekspresije mnogih drugih gena u organizmu. Smješten je na dugom kraku 7. kromosoma. Gen je prvotno otkriven proučavanjem engleske obitelji KE kod koje je više od polovice članova iskazivalo poteškoće u kontroliranju pokreta usana, razvojne dispraksije i sveobuhvatni deficit govora i pisanja. Na temelju ovih nalaza pretpostavljeno je da gen FOXP2 ima važnu ulogu u razvoju jezika i govora kod čovjeka; da je FOXP2 „gen za govor“. ----- Detaljnom analizom sekvence DNA i proteina FOXP2 uočeno je da se ljudska varijanta proteina razlikuje od mišje u samo tri, a od ostalih primata u samo dvije aminokiseline, što čini ovaj gen jednim od najbolje očuvanih gena tijekom evolucije. Nadalje, utvrđeno je da su se ove promjene specifične za čovjeka pojavile relativno nedavno (unutar posljednjih 200,000 godina) tijekom evolucije čovjeka te da je gen FOXP2 s pozitivnom selekcijom tijekom ljudske evolucije prošao proces ubrzane evolucije kod čovjeka. ----- Analizom ekspresije FOXP2 gena utvrđeno je da je prisutan u strukturama bitnim za motorički sustav (motorička moždana kora, bazalni gangliji, mali mozak) i u strukturama bitnim za jezik i govor (Brocino područje za govor, gornja sljepoočna vijuga). Iako postoje mnogi dokazi da poremećaji FOXP2 gena dovode do poremećaja govora kod čovjeka, novija istraživanja sugeriraju da FOXP2 ima mnogo šire učinke na organizam te da poremećaji govora nastaju samo kao sekundarna posljedica mutacije gena. Čini se da je osnovni problem povezivanja gena FOXP2 s razvojem govora u činjenici da se pokušava povezati multifunkcionalni gen s pleiotropnim učincima (mozak, pluća, crijeva) sa složenim fenotipom kao što je govor. Točna uloga gena FOXP2 u nastanku i razvoju govora do danas još uvijek nije poznata te je predmet mnogih znanstvenih istraživanja., FOXP2 gene is a transcriptional factor belonging to FOX family of genes responsible for regulation of expression of many other genes. It is situated on the long arm of 7th chromosome. The gene was first discovered during the study of English KE family of which more than half family members had difficulties with mouth control, developing dyspraxia and total speech and writing impairment. Based on these findings it was assumed that FOXP2 gene has a major role in the development of speech and language in humans making FOXP2 “a gene for speech”. ----- During detail analyses of the DNA sequence and the protein FOXP2 it was noted that human version of the protein differs from the mouse version in only 3 components, while the version of other primates differs from the human version in 2 components, which makes this gene very well preserved during evolution. Furthermore, it was proven that these human specific changes occurred relatively recently (over last 200,000 years) during human evolution, that FOXP2 is a gene with positive selection during human evolution and that it underwent a process of accelerated evolution in humans. ----- Analyses of the expression of FOXP2 gene brought evidences about its existence in structures which are an important part of the motoric system (motoric cortex, basal ganglia, cerebellum) and in the structures important for speech and language (Broca’s area and superior temporal gyrus). Although many evidences suggest that FOXP2 gene impairment leads to speech difficulties in humans, recent studies suggest that FOXP2 has a much wider effect and that the language impairment is only a secondary consequence of the mutation of this gene. It seems that the core problem of establishing the connection between the FOXP2 gene with the development of speech is the fact that multifunctional gene with pleiotropic effect is trying to be connected with complex fenotype which speech is. The exact role of FOXP2 gene in the development of speech is not established yet and it still is in focus of many scientific studies.

Interstitial deletions encompassing chromosome 16p13.3-13.2 are rarely described in the literature, whereas terminal deletions or duplications involving this region are slightly more frequently described. The authors describe a boy harboring a de novo 16p13.3-13.2 interstitial deletion, with intellectual disability, verbal dyspraxia, epilepsy, and a distinctive brain magnetic resonance finding, namely a nodular heterotopia. The authors found partial genotype–phenotype correspondences regarding epilepsy and intellectual disability, which have been associated with 16p1 region. Conversely, nodular heterotopia and verbal dyspraxia have not been clearly related to this region. These data are in agreement with the emerging concept that similar copy number variants may be the general risk factors for distinct disorders. Verbal dyspraxia, which has not responded to speech therapy, is the child’s most disabling trait. In view of the above, genetic studies should be appraised in cases of serious speech difficulties, especially if they are associated with intellectual disability and epilepsy.

Why do some children fail to acquire speech and language skills despite adequate environmental input and overtly normal neurological and anatomical development? It has been suspected for several decades, based on indirect evidence, that the human genome might hold some answers to this enigma. These suspicions have recently received dramatic confirmation with the discovery of specific genetic changes which appear sufficient to derail speech and language development. Indeed, researchers are already using information from genetic studies to aid early diagnosis and to shed light on the neural pathways that are perturbed in these inherited forms of speech and language disorder. Thus, we have entered an exciting era for dissecting the neural bases of human communication, one which takes genes and molecules as a starting point. In the current article I explain how this recent paradigm shift has occurred and describe the new vistas that have opened up. I demonstrate ways of bridging the gaps between molecules, neurons and the brain, which will provide a new understanding of the aetiology of speech and language impairments.