Half the members of the KE family suffer from a speech and language disorder caused by a mutation in the FOXP2 gene. We examined functional brain abnormalities associated with this mutation using two fMRI language experiments, one involving covert (silent) verb generation and the other overt (spoken) verb generation and word repetition. The unaffected family members showed a typical left-dominant distribution of activation involving Broca's area in the generation tasks and a more bilateral distribution in the repetition task, whereas the affected members showed a more posterior and more extensively bilateral pattern of activation in all tasks. Consistent with previously reported bilateral morphological abnormalities, the affected members showed significant underactivation relative to the unaffected members in Broca's area and its right homolog, as well as in other cortical language-related regions and in the putamen. Our findings suggest that the FOXP2 gene is critically involved in the development of the neural systems that mediate speech and language.

It is widely assumed that following extensive damage to the left hemisphere sustained in early childhood, language functions are likely to reorganize and develop in the right hemisphere, especially if the lesion affects the classical Broca's or Wernicke's language areas. In the present study, functional MRI (fMRI) was used to examine language lateralization in 10 children and adolescents with intractable epilepsy who sustained an early lesion in the left hemisphere. Lesions were adjacent to or within anterior language cortex in five patients, while they were remote from both Broca's and Wernicke's areas in the remainder. A lateralization index was calculated on the basis of the number of voxels activated in the left and right inferior frontal gyri when performing a covert verb generation task. Only two patients were right-handed, suggesting a high incidence of functional reorganization for motor control in the remaining patients. Five out of 10 showed bilateral or right language lateralization, but lateralization could not be inferred from the proximity of lesions to classical language areas on an individual basis. Lesions in or near Broca's area were not associated with inter-hemispheric language reorganization in four out of five cases, but with perilesional activation within the damaged left hemisphere. Paradoxically, lesions remote from the classical language areas were associated with non-left language lateralization in four out of five cases. Finally, handedness, age at onset of chronic seizures, and site of EEG abnormality also showed no obvious association with language lateralization. In conclusion, it is difficult to infer intra- versus inter-hemispheric language reorganization on the basis of clinical observations in the presence of early pathology to the left hemisphere.

Although language difficulties are common in children born prematurely, robust neuroanatomical correlates of these impairments remain to be established. This study investigated whether the greater prevalence of language problems in preterm (versus term-born) children might reflect injury to major intra- or interhemispheric white matter pathways connecting frontal and temporal language regions. To investigate this, we performed a comprehensive assessment of language and academic abilities in a group of adolescents born prematurely, some of whom had evidence of brain injury at birth (n = 50, mean age: 16 years, mean gestational age: 27 weeks) and compared them to a term-born control group (n = 30). Detailed structural magnetic resonance imaging and diffusion-tractography analyses of intrahemispheric and interhemispheric white matter bundles were performed. Analysis of intrahemispheric pathways included the arcuate fasciculus (dorsal language pathway) and uncinate fasciculus/extreme capsule (ventral language pathway). Analysis of interhemispheric pathways (in particular, connections between the temporal lobes) included the two major commissural bundles: the corpus callosum and anterior commissure. We found language impairment in 38% of adolescents born preterm. Language impairment was not related to abnormalities of the arcuate fasciculus (or its subsegments), but was associated with bilateral volume reductions in the ventral language pathway. However, the most significant volume reduction was detected in the posterior corpus callosum (splenium), which contains interhemispheric connections between the occipital, parietal and temporal lobes. Diffusion tractography showed that of the three groups of interhemispheric fibres within the splenium, only those connecting the temporal lobes were reduced. Crucially, we found that language impairment was only detectable if the anterior commissure (a second temporal lobe commissural pathway) was also small. Regression analyses showed that a combination of anatomical measures of temporal interhemispheric connectivity (through the splenium of the corpus callosum and anterior commissure) explained 57% of the variance in language abilities. This supports recent theories emphasizing the importance of interhemispheric connections for language, particularly in the developing brain.

Preterm birth has a long-term effect on cognition, behavior, and future academic success primarily as a consequence of global brain WM reduction. This emphasizes the need for early therapeutic efforts to prevent WM injury and promote or optimize its development in preterm neonates.

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ObjectiveDetermining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS).MethodsPrecise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates.ResultsThirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain.ConclusionWe identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.

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