Janis Oram Cardy

Absence of a Paternally Inherited FOXP2 Gene in Developmental Verbal Dyspraxia

Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.

Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2

We report detailed clinical, cytogenetic, and molecular findings in a girl with a deletion of chromosome 7q31‐q32. This child has a severe communication disorder with evidence of oromotor dyspraxia, dysmorphic features, and mild developmental delay. She is unable to cough, sneeze, or laugh spontaneously. Her deletion is on the paternally inherited chromosome and includes the FOXP2 gene, which has recently been associated with speech and language impairment and a similar form of oromotor dyspraxia in at least three other published cases. We hypothesize that our patients communication disorder and oromotor deficiency are due to haploinsufficiency for FOXP2 and that her dysmorphism and developmental delay are a consequence of the absence of the other genes involved in the microdeletion. We propose that this patient, together with others reported in the literature, may define a new contiguous gene deletion syndrome encompassing the 7q31‐FOXP2 region. Cytogenetic and molecular analysis of this region should be considered for other individuals displaying similar characteristics.

Language lateralization development in children with autism : Insights from the late field magnetoencephalogram

Left hemisphere dominance represents the typical language lateralization profile for the majority of neurologically healthy, right-handed individuals. We investigated hemispheric dominance for language in language-impaired children with autism and typically developing controls to investigate the hypothesis that atypical functional specialization for language represents one component of developmental language impairment in autism. Late field magnetoencephalography (MEG) recordings were used to calculate a hemispheric Lateralization Index from the neuromagnetic activity evoked by passive auditory presentation of vowel stimuli. Results indicate that children with autism and typically developing children follow opposite maturational trajectories in language lateralization; while leftward lateralization (i.e. left hemisphere dominance) emerged from bilaterally symmetric neuronal activation as age increased in our sample of typically developing children, rightward lateralization emerged from bilaterally symmetric activity as age increased in our sample of children with autism.

Magnetoencephalography identifies rapid temporal processing deficit in autism and language impairment.

Deficient rapid temporal processing may contribute to impaired language development by interfering with the processing of brief acoustic transitions crucial for speech perception. Using magnetoencephalography, evoked neural activity (M50, M100) to two 40 ms tones passively presented in rapid succession was recorded in 10 neurologically normal adults and 40 8–17-year-olds with autism, specific language impairment, Asperger syndrome or typical development. While 80% of study participants with intact language (Asperger syndrome, typical development, adults) showed identifiable responses to the second tone, which presented rapid temporal processing demands, 65% of study participants with impaired language (autism, specific language impairment) did not, despite having shown identifiable responses to the first tone. Rapid temporal processing impairments may be fundamentally associated with impairments in language rather than autism spectrum disorder.

Auditory evoked fields predict language ability and impairment in children.

Recent evidence suggests that a subgroup of children with autism show similarities to children with Specific Language Impairment (SLI) in the pattern of their linguistic impairments, but the source of this overlap is unclear. We examined the ability of auditory evoked magnetic fields to predict language and other developmental abilities in children and adolescents. Following standardized assessment of language ability, nonverbal IQ, and autism-associated behaviors, 110 trails of a tone were binaurally presented to 45 7-18 year olds who had typical development, autism (with LI), Asperger Syndrome (i.e., without LI), or SLI. Using a 151-channel MEG system, latency of left hemisphere (LH) and right hemisphere (RH) auditory M50 and M100 peaks was recorded. RH M50 latency (and to a lesser extent, RH M100 latency) predicted overall oral language ability, accounting for 36% of the variance. Nonverbal IQ and autism behavior ratings were not predicted by any of the evoked fields. Latency of the RH M50 was the best predictor of clinical LI (i.e., irrespective of autism diagnosis), and demonstrated 82% accuracy in predicting Receptive LI; a cutoff of 84.6 ms achieved 92% specificity and 70% sensitivity in classifying children with and without Receptive LI. Auditory evoked responses appear to reflect language functioning and impairment rather than non-specific brain (dys)function (e.g., IQ, behavior). RH M50 latency proved to be a relatively useful indicator of impaired language comprehension, suggesting that delayed auditory perceptual processing in the RH may be a key neural dysfunction underlying the overlap between subgroups of children with autism and SLI.

Delayed mismatch field for speech and non-speech sounds in children with autism.

This study investigated the magnetic mismatch field elicited by changes in streams of vowels or spectrally matched tones in children with autism spectrum disorder (ASD) relative to children with typical development to explore whether impaired sound discrimination may contribute to language impairments in autism spectrum disorder. Using magnetoencephalography, we recorded evoked neural activity to 300-Hz and 700-Hz tones (and /u/ and /a/ vowels) presented in an oddball paradigm with deviant stimuli (15%) occurring within a train of standards (85%). The magnetic mismatch field was robustly observed in both groups, but children with autism spectrum disorder demonstrated a significantly delayed magnetic mismatch field compared with typically developing peers. Difficulty parsing transient differences in sounds may lead to impaired acoustic or phonological representations and subsequent language impairment in autism spectrum disorder.

Prominence of M50 auditory evoked response over M100 in childhood and autism.

This study investigated the 50 ms (M50) and 100 ms (M100) components of the auditory evoked field to explore their change during development. Using MEG, neuromagnetic fields elicited by a 1 kHz sinusoidal tone were recorded in adults and two groups of children and adolescents with typical development or autism spectrum disorder. M50 amplitude was larger in children than in adults, suggesting a developmental trajectory with M50 amplitude decreasing and M100 increasing with age. Child M50 and M100 latencies were prolonged relative to adults. Children with autism did not differ from control children with respect to these observations. The M50 in relation to the M100 is a robust index of early auditory system maturation suitable for future developmental investigations.

The contribution of processing impairments to SLI: Insights from attention-deficit/hyperactivity disorder

UNLABELLED Slowed speed of processing and impaired rapid temporal processing (RTP) have been proposed to underlie specific language impairment (SLI), but it is not clear that these dysfunctions are unique to SLI. We considered the contribution of attention-deficit/hyperactivity disorder (ADHD), which frequently co-occurs with language impairments, to performances on processing tasks. School-aged children who had SLI without concurrent ADHD (n=14), ADHD without concurrent SLI (n=14), and typical development (TD, n=28) performed two nonverbal speeded tasks and one auditory RTP task. RTP impairments were found in many children with SLI and ADHD, and some children with TD. Children with ADHD demonstrated slower processing speed than children with SLI or TD. Overall, findings questioned the uniqueness of these processing dysfunctions to language impairments and the validity of the behavioural paradigms traditionally used to estimate processing dysfunctions. Accounts of SLI should be further scrutinized by considering the influence of other disorders. LEARNING OUTCOMES Readers will (1) become familiar with areas of overlap between SLI and ADHD, (2) understand some of the confounds associated with behavioural measures of processing speed in children, and (3) recognize the value in testing models of language disorders by including participants with other types of disorders.

Differentiating autism spectrum disorder from other developmental delays in the first two years of life.

Advances in the identification of the early signs of autism spectrum disorder (ASD) have occurred despite the heterogeneity of the disorder and its variable onset and presentation. Using various methodologies including retrospective studies, community samples, and sibling cohorts, researchers have identified behavioral markers of the disorder that emerge over the first 2 years of life. However, there are characteristics of ASD that overlap with other types of developmental delay (DD), which may complicate differential diagnosis in young children. A review of the literature was conducted to identify the most promising behavioral markers that distinguish ASD from other types of DD in the first 2 years of life. The review identified profiles of behavioral markers in the social realm by 12 months and in the communication realm by 18 months, which along with additional atypical motor behaviors could distinguish ASD from DD. This constellation of features coupled with a flat or declining trajectory in specific aspects of social and communication development, may assist clinicians in targeting early interventions to at-risk infants.

Language, reading, and math learning profiles in an epidemiological sample of school age children.

Dyscalculia, dyslexia, and specific language impairment (SLI) are relatively specific developmental learning disabilities in math, reading, and oral language, respectively, that occur in the context of average intellectual capacity and adequate environmental opportunities. Past research has been dominated by studies focused on single impairments despite the widespread recognition that overlapping and comorbid deficits are common. The present study took an epidemiological approach to study the learning profiles of a large school age sample in language, reading, and math. Both general learning profiles reflecting good or poor performance across measures and specific learning profiles involving either weak language, weak reading, weak math, or weak math and reading were observed. These latter four profiles characterized 70% of children with some evidence of a learning disability. Low scores in phonological short-term memory characterized clusters with a language-based weakness whereas low or variable phonological awareness was associated with the reading (but not language-based) weaknesses. The low math only group did not show these phonological deficits. These findings may suggest different etiologies for language-based deficits in language, reading, and math, reading-related impairments in reading and math, and isolated math disabilities.