CHILDHOOD APRAXIA OF SPEECH
CAS
SPCH1
DVD
Speech-language disorder type 1
developmental verbal dyspraxia
speech and language disorder with orofacial dyspraxia
Speech-language disorder-1 is an autosomal dominant disorder characterized by severe orofacial dyspraxia resulting in largely incomprehensible speech. Affected individuals were originally thought to have specific defects in the use of grammatical suffixation rules (Gopnik, 1990; Gopnik and Crago, ... Speech-language disorder-1 is an autosomal dominant disorder characterized by severe orofacial dyspraxia resulting in largely incomprehensible speech. Affected individuals were originally thought to have specific defects in the use of grammatical suffixation rules (Gopnik, 1990; Gopnik and Crago, 1991). The phenotype, however, is broader in nature, with virtually every aspect of grammar and language affected (Fisher et al., 1998). Vargha-Khadem et al. (1998) concluded that the disorder is characterized by abnormal development of several brain areas critical for both orofacial movements and sequential articulation, resulting in marked disruption of speech and expressive language. - Relation to Specific Language Impairment Children who fail to develop expressive and/or receptive language normally, in the absence of explanatory factors such as neurologic disorders, hearing impairment, or lack of adequate opportunity, are clinically described as having specific language impairment (SLI) (Bartlett et al., 2002). SLI has a prevalence of approximately 2% (Fisher et al., 1998) to 7% (Bartlett et al., 2002) in children entering school and is associated with later difficulties in learning to read. SLI aggregates in families, and increased monozygotic versus dizygotic twin concordance rates indicate that heredity, not just shared environment, is the cause of familial clustering (summary by Bartlett et al., 2002). The majority of families segregating such disorders show complex patterns of inheritance (Fisher et al., 1998). Quantitative trait loci (QTLs) involved in specific language impairment, a phenotype that shows some overlap with SPCH1, have been mapped to chromosomes 16q (SLI1; 606711), 19q (SLI2; 606712), 13q21 (SLI3; 607134), and 7q35-q36 (SLI4; 612514). See also familial developmental dysphasia (600117).
Hurst et al. (1990) reported a family, identified as 'KE,' in which 16 members spanning 3 generations had a severe developmental verbal dyspraxia with normal hearing and intelligence. Inheritance was autosomal dominant. Vargha-Khadem et al. (1995) restudied the ... Hurst et al. (1990) reported a family, identified as 'KE,' in which 16 members spanning 3 generations had a severe developmental verbal dyspraxia with normal hearing and intelligence. Inheritance was autosomal dominant. Vargha-Khadem et al. (1995) restudied the 'KE' family, and noted that about half of the male and female members of 4 generations suffered from the severe speech and language disorder. Gopnik (1990) and Gopnik and Crago (1991) reported findings suggesting that the affected members suffered from a specific impairment in grammar, namely, a selective inability to generate syntactic rules such as those for tense, number, and gender. Reported selectivity of the impairment led Gopnik (1990) and Gopnik and Crago (1991), as well as Pinker (1991, 1994) and Jackendoff (1994), to conclude that the KE family has an inherited grammar-specific disorder and thus provides evidence for the existence of 'grammar genes.' However, Vargha-Khadem et al. (1995) described investigations of the same family indicating that the affected members' disorder transcends the generation of morphosyntactic rules to include impaired processing and expression of other areas of grammar, grossly defective articulation of speech sounds, and a severe extralinguistic orofacial dyspraxia. The dyspraxia rendered their speech largely incomprehensible to the naive listener. In addition, the affected family members had both verbal and performance IQ scores that were on average 18 to 19 points below those of the unaffected members. This psychologic profile indicated that the inherited disorder does not affect morphosyntax exclusively, or even primarily; rather, it affects intellectual, linguistic, and orofacial praxic functions generally. Fisher et al. (1998) gave preliminary reports on brain imaging studies of affected and unaffected members of the KE pedigree. Findings suggested that the mutation at the SPCH1 locus results in functional abnormalities in motor-related areas of the frontal lobe, and that these are due, in turn, to abnormal anatomical development of several brain areas, with a key cytopathology being located in the neostriatum. Fisher et al. (1998) suggested that analysis of the gene could further understanding of both the structure and the function of the frontoneostriatal system. Extensive studies of the neural basis of the disorder in the KE family were reported by Vargha-Khadem et al. (1998). The core deficit responsible for the verbal dyspraxia involved sequential articulation and orofacial praxis. A positron emission tomography activation study revealed functional abnormalities in both cortical and subcortical motor-related areas of the frontal lobe, while quantitative analyses of magnetic resonance imaging scans revealed structural abnormalities in several of the same areas, particularly the caudate nucleus, which was found to be abnormally small bilaterally. The authors concluded that genetic mutation or deletion of the SPCH1 gene resulted in the abnormal development of several brain areas that appear to be critical for both orofacial movements and sequential articulation, resulting in marked disruption of speech and expressive language. Watkins et al. (1999) reviewed studies of brain morphometry and function in developmental language disorders and described studies of the autosomal dominant trait in the KE family. Studies of brain morphometry were stimulated by the landmark study of Geschwind and Levitsky (1968), which provided evidence of asymmetry in brain structure that correlated with the well-established functional asymmetry and dominance of the left hemisphere for language. By autopsy of 100 normal brains, they found that the planum temporale (which falls within Wernicke's area, known to be associated with language disorders when damaged in adulthood) was longer on the left in 65%, symmetric in 25%, and shorter on the left in 10% of the sample. This pattern has been found not only in adults but also in fetuses and neonates. Galaburda et al. (1978) showed that the gross asymmetry was associated with microscopic cytoarchitectonic differences between the hemispheres. Watkins et al. (1999) stated that half the members of the first 3 generations of the KE family were affected by a severe disorder of speech and language, which often made their speech unintelligible. The fourth-generation children were all born to unaffected parents and did not demonstrate the disorder; the affected family members of the third generation did not have children. Although no instance of male-to-male transmission was noted, the involvement of 9 females and 6 males suggested that the disorder is not X-linked. It was in this family that linkage to 7q31 was demonstrated for the locus, designated SPCH1. On the basis of their findings with imaging methods, Watkins et al. (1999) suggested that the genetic abnormality in the KE family may directly and selectively affect the development of the caudate nucleus or, perhaps, that of the basal ganglia more generally, resulting in both structural and functional abnormalities of the caudate nuclei bilaterally. Liegeois et al. (2003) performed functional MRI (fMRI) language experiments on several members of the KE family. During covert (silent) verb generation and overt (spoken) verb generation and word repetition, 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 morphologic abnormalities, the affected members showed significant underactivation relative to unaffected members in Broca's area and its right homolog, as well as in other cortical language-related regions and in the putamen. The findings suggested that the FOXP2 gene is critically involved in the development of the neural systems that mediate speech and language. MacDermot et al. (2005) reported a 4-year-old boy with developmental delay in speech, language, and social skills. He communicated mainly using single words and was unable to repeat multisyllabic words. His 20-month-old sister had a history of motor and oropharyngeal dyspraxia, was unable to speak any words, could not identify objects, and had poor vocalization. Their mother reported a history of speech delay in childhood and showed severe problems in communication, with poor speech clarity and simple grammatical construction. All 3 patients were found to have a heterozygous nonsense mutation in the FOXP2 gene (605317.0002).
Lai et al. (2001) demonstrated that the FOXP2 gene, which encodes a putative transcription factor containing a polyglutamine tract and forkhead DNA-binding domain, is directly disrupted in the translocation breakpoint in patient CS (unrelated to the family KE). ... Lai et al. (2001) demonstrated that the FOXP2 gene, which encodes a putative transcription factor containing a polyglutamine tract and forkhead DNA-binding domain, is directly disrupted in the translocation breakpoint in patient CS (unrelated to the family KE). This patient, initially reported by Lai et al. (2000), had speech and language impairment associated with the chromosomal translocation involving the SPCH1 interval. Lai et al. (2001) also identified a point mutation affecting members of the KE family that alters an invariant amino acid residue in the forkhead domain (605317.0001). In 1 of 49 probands with a specific diagnosis of verbal dyspraxia, MacDermot et al. (2005) identified a heterozygous mutation in the FOXP2 gene (605317.0002). The proband's sister and mother also had the mutation. O'Brien et al. (2003) used samples from children with specific language impairment (SLI) and their family members to study linkage and association of SLI to markers within and around the FOXP2 gene, and samples from 96 probands with SLI were directly sequenced for the mutation in exon 14 of the FOXP2 gene (R553H). No mutations were found in exon 14 of FOXP2, but strong association was found to a marker within the cystic fibrosis gene, CFTR (602421), and another marker on 7q31, D7S3052, both adjacent to FOXP2, suggesting that genetic factors for regulation of common language impairment reside in the vicinity of FOXP2.