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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.

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.

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.

The current study analyzed possible relation between the dialogic interaction of the duo mother-child with praxic limitations and the exercise of maternal function. It tries, specifically, to categorize the types of dialogic interactions found, to analyze the interference or not of praxic limitation of children on the interpretation process by the mother and the reflexes of maternal function over the mother-child dialog. Five mother-child diad took part on the study, with the interaction of these duos being filmed, on which the play, the relation mother-child, as well the exercise of maternal function were filmed. Precarious bonds on the relation mother-child, difficulty on the exercise of maternal function, directive, intrusive or apathetic and away mothers were observed. For subjects, children of mothers that could evolve on the exercise of maternal function, cases which the bond had a significant improvement, it was observed a greater language evolution. The dialogic analyzes demonstrated that verbal dyspraxia doesn't prevent the interpretation process, it can only limit it. However, the exercise of maternal function seems to have a more important effect on the mother-child dialog.

In spite of adequate dietary regimen, many patients with galactosemia have developmental abnormalities. We studied 8 patients with galactosemia, aged 9 months to 19 years who had all been treated with a galactose-free diet from an early stage. Neurological functioning, general developmental, and language and speech development were assessed in all cases. The results show that even medically well treated children and young adults with galactosemia are at risk to develop disabilities, including mental retardation, speech and language disabilities. Verbal dyspraxia was diagnosed in 3 of 6 patients, who had acquired verbal language, all with IQ 70 or below. This may indicate that verbal dyspraxia is just one symptom among others in patients with galactosemia and mental retardation.

The idea of developmental dyspraxia has been discussed in the research literature for almost 100 years. However, there continues to be a lack of consensus regarding both the definition and description of this disorder. This paper presents a neuropsychologically based operational definition of developmental dyspraxia that emphasizes that developmental dyspraxia is a disorder of gesture. Research that has investigated the development of praxis is discussed. Further, different types of gestural disorders displayed by children and different mechanisms that underlie developmental dyspraxia are compared to and contrasted with adult acquired apraxia. The impact of perceptual-motor, language, and cognitive impairments on children's gestural development and the possible associations between these developmental disorders and developmental dyspraxia are also examined. Also, the relationship among limb, orofacial, and verbal dyspraxia is discussed. Finally, problems that exist in the neuropsychological assessment of developmental dyspraxia are discussed and recommendations concerning what should be included in such an assessment are presented.

This paper discusses the relationship between the dysarthrias and verbal dyspraxia in adults and children, and examines these conditions with reference to current theories and a model. The empirical basis for the study described here was the examination in depth of the speech of six subjects, each of whom presented with neurological disorders of different origins: two adults, chosen to exemplify the acquired conditions of dysarthria and dyspraxia, and four children. The speech analyses used profiling techniques of segmental phonological and prosodic assessment, and electropalatographic (EPG) examination, and the profiles thus obtained were compared between subjects and across client groups. The hypothesis was that in-depth analyses would provide distinguishing characteristics between the two neurological conditions, such that the children with suspected developmental verbal dyspraxia would demonstrate differences from those with developmental dysarthria, and clear similarities to the dyspraxic adult. The ...

This paper discusses the relationship between the dysarthrias and verbal dyspraxia in school-aged children. Using perceptual profiling and instrumental (electropalatographic) techniques, the speech of a small subject group was analysed in depth, in order to compare the two neurological conditions. The aim of the study was to provide distinguishing characteristics between the conditions. The rationale for the conclusion from the study is examined in relation to clinical implications.

Objective To describe specific language impairment in four children with velocardiofacial syndrome (VCFS). Design A descriptive, retrospective study of four cases. Setting University Hospital Groningen, tertiary clinical care. Patients Of 350 patients with cleft plate, 18 children were diagnosed with VCFS. Four children are described. Interventions In all children, cardiac and plastic surgery was carried out in the first year of life. Afterward, interventions consisted of hearing improvement, pharyngoplasty, and speech therapy. Main Outcome Inadequate and uncharacteristic development of articulation and expressive language in four children with VCFS were observed. They differed from the majority in two ways: their nonverbal IQ was in the normal range, and their language skills were below expectations for their IQ. Results Four of 18 patients with VCFS (22%) showed poor response to therapy and did not develop language in accordance with their normal learning abilities (nonverbal learning capacities and language comprehension). Persistent hypernasal resonance and severe articulation problems remained in all four children. In two children the expressive language profile was also not in agreement with the nonverbal profile: they produced only two- and three-word utterances at the age of 6.0 and 5.3 years. The other two children at the age of 6.8 and 6.4 years produced very long sentences, but they were unintelligible. Conclusions The speech and language impairment of the four children may be characterized as a phonological or verbal programming deficit syndrome and as such can be described as a specific language impairment in conjunction with VCFS.

Purpose: This study evaluates a genotype/phenotype relationship between developmental verbal dyspraxia (DVD) and the common, missense mutation of the galactose-l-phosphate uridyltransferase gene, Q188R, in patients with classic galactosemia (G/G). Methods: As part of this study, we devised a questionnaire for “speech problems” to be completed by the patient's clinician. To validate the questionnaire and determine its accuracy in detecting DVD, we analyzed questionnaire responses for 21 patients by testing them independently and directly for DVD through a speech pathologist blinded to the patients' genotype. Results: We found that the questionnaire had a sensitivity of 0.56 and a specificity of 0.75. We then calculated the prevalence of DVD for a larger set of 113 patients with G/G galactosemia whose biochemical phenotype, molecular genotypes, and clinical status were known. The prevalence of “speech problems” from raw data were 50 of 113 (44.2%). After adjusting for misclassification, 43 (38.1%) were classified as cases of DVD. Using multivariate, logistic, regression analyses we found a significant interaction between genotype and mean red blood cell (RBC) galactose-1-phosphate (Gal-1-P). When corrected, using mean RBC Gal-1-P > 3.28 mg%, the Q188R/Q188R genotype was the best predictor of DVD. There was a significant risk (odds ratio = 9.6, p = 0.0504) of having DVD associated with homozygosity for Q188R compared with other genotypes. Conclusions: We conclude that homozygosity for Q188R mutations in the GALT gene is a significant risk factor for DVD. However, poor metabolic control obviates this relationship as indicated by RBC Gal-1-P greater than 3.28 mg%.

Speech/language disorders are common in the fragile X syndrome. [Howard-Peebles, 1979: Am J Hom Genet 31:214-222; Renier et al., 1983: J Ment Defic Res 27:51-59; Sparks, 1984: Birth Defects and Speech-Language Disorders, pp. 39-43; Hanson et al., 1986: Am J Med Genet 23:195-206]. Verbal paraphasias have been considered a rare feature and word-finding difficulties have seldom been reported. Here we report on ten Brazilian patients who were evaluated for speech/language disturbances and found that word-finding difficulties were present in 50% of the cases, which is a slightly higher frequency than that of clear dyspraxia. We suggest, therefore, that word-finding difficulties and verbal dyspraxia can be a common feature within the spectrum of this syndrome. Additional speech findings are discussed.

Developmental verbal dyspraxia is examined from four perspectives: clinical, phonetic, linguistic and cognitive. The paper critically discusses the problems encountered when criteria for identifying acquired speech disorders in the adult population are applied to children's speech difficulties without modifications. It is argued that studies of verbal dyspraxia in children have ignored the unfolding nature of this condition and that a developmental perspective has been lacking in the literature. A need for the inclusion of appropriate control groups and longitudinal case studies is identified. The issue and process of differential diagnosis are addressed and a checklist of criteria for identifying developmental verbal dyspraxia is included. It is noted that this process will inevitably be lengthy with data needed from different aspects of a child's development. Phonetic characteristics alone may not be sufficient to recognise this medical condition with its complex psycholinguistic and educational consequences.

It is our clinical experience that in a number of aphasics, a distinctive articulatory disorder is found in the absence of the observable paralysis or paresis of the speech musculature. The term “motor aphasia” or “Broca's aphasia” has generally been applied to designate this type of disorder.The studies in recent years, however, have disclosed that this kind of disorder, a disorder of programming and executing articulatory movements (verbal apraxia or apraxia of speech), can be distinguished from the disorder of symbolic processes, i. e. aphasia.In this paper, the characteristics of verbal apraxia were described as well as the methods of testing oral and verbal apraxias. The therapy methods of verbal apraxia were reviewed with a special emphasis on the works done by Luria, et al..It was suggested that verbal apraxia, though a clearly definable clinical entity, might not be a homogeneous disorder. More comprehensive investigation of the nature of this disorder will be necessary before we can set up more systematic therapeutic procedures.