Severe Speech Disorder Research Articles

Mutation screening of FOXP2 in individuals diagnosed with autistic disorder.

Although it is well established that genetic factors play an important role in the etiology of autistic disorder (AD), no specific genes have as yet been implicated. Genetic epidemiological data, particularly the sharp fall in concordance rates from monozygotic to dizygotic twins, indicate that the mode of transmission of this disorder is complex and may involve several genes. The 7q31 locus has been repeatedly linked to AD, suggesting that this chromosomal region is likely to harbor a susceptibility gene for AD. Recently, variations in the FOXP2 gene were reported to be responsible for a severe speech and language disorder. Because of the chromosomal location of FOXP2 (7q31) and the putative implication of the 7q31 region both in autistic and in language disorders (a feature of AD), it has been hypothesized that FOXP2 may be implicated in the pathophysiology of AD. To test this hypothesis, we screened the FOXP2 gene coding sequence for mutations in subjects diagnosed with AD and in normal controls. We identified four silent polymorphisms that were equally distributed between patients and controls. Using an intra-family association design, we identified no transmission disequilibrium in any of the four identified alleles, suggesting that the FOXP2 gene does not play a significant role in AD.

DECIPHERING THE GENETIC BASIS OF SPEECH AND LANGUAGE DISORDERS

A significant number of individuals have unexplained difficulties with acquiring normal speech and language, despite adequate intelligence and environmental stimulation. Although developmental disorders of speech and language are heritable, the genetic basis is likely to involve several, possibly many, different risk factors. Investigations of a unique three-generation family showing monogenic inheritance of speech and language deficits led to the isolation of the first such gene on chromosome 7, which encodes a transcription factor known as FOXP2. Disruption of this gene causes a rare severe speech and language disorder but does not appear to be involved in more common forms of language impairment. Recent genome-wide scans have identified at least four chromosomal regions that may harbor genes influencing the latter, on chromosomes 2, 13, 16, and 19. The molecular genetic approach has potential for dissecting neurological pathways underlying speech and language disorders, but such investigations are only just beginning.

Molecular genetics of speech and language disorders.

In 2001, scientists characterized the first gene to be implicated in the cause of a speech and language disorder (FOXP2). Although FOXP2 was discovered using a unique family in which a severe speech and language disorder segregates in a monogenic fashion, at the time this discovery was heralded as "a milestone in understanding this uniquely human characteristic." Approximately 1 year later, we discuss the impact of this gene discovery on the study of language and review the relevance of this gene to both specific language impairment and language aspects of the autistic phenotype. We also discuss recent molecular genetic advances made in the study of generalized specific language impairment.

A forkhead-domain gene is mutated in a severe speech and language disorder.

Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity. Although studies of twins consistently indicate that a significant genetic component is involved, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language.

Phonological agraphia following a focal anterior insulo-opercular infarction

Following a unique infarction, restricted to the left anterior insula and the adjacent part of the intrasylvian frontal opercular cortex, an 83-year-old right-handed patient acutely developed a severe speech disorder that evolved into mere mutism within a few hours. After rapid recovery from mutism, oral language was characterized by severe apraxia of speech. In-depth language investigations further disclosed an isolated, highly selective disturbance of the spelling system (phonological agraphia) which resolved rapidly. One year after onset of neurological symptoms, the apraxia of speech had almost completely receded. The anatomoclinical findings in this first representative of pure and nearly isolated phonological agraphia complement previous neuroanatomical and neurolinguistic accounts of phonological agraphia. The data not only seem to enrich current insights in the anatomical locus for phonological agraphia, they also seem to contribute to a further delineation of the insular role in phonologically mediated aphasic manifestations.

The SPCH1 Region on Human 7q31: Genomic Characterization of the Critical Interval and Localization of Translocations Associated with Speech and Language Disorder

The KE family is a large three-generation pedigree in which half the members are affected with a severe speech and language disorder that is transmitted as an autosomal dominant monogenic trait. In previously published work, we localized the gene responsible (SPCH1) to a 5.6-cM region of 7q31 between D7S2459 and D7S643. In the present study, we have employed bioinformatic analyses to assemble a detailed BAC-/PAC-based sequence map of this interval, containing 152 sequence tagged sites (STSs), 20 known genes, and >7.75 Mb of completed genomic sequence. We screened the affected chromosome 7 from the KE family with 120 of these STSs (average spacing <100 kb), but we did not detect any evidence of a microdeletion. Novel polymorphic markers were generated from the sequence and were used to further localize critical recombination breakpoints in the KE family. This allowed refinement of the SPCH1 interval to a region between new markers 013A and 330B, containing approximately 6.1 Mb of completed sequence. In addition, we have studied two unrelated patients with a similar speech and language disorder, who have de novo translocations involving 7q31. Fluorescence in situ hybridization analyses with BACs/PACs from the sequence map localized the t(5;7)(q22;q31.2) breakpoint in the first patient (CS) to a single clone within the newly refined SPCH1 interval. This clone contains the CAGH44 gene, which encodes a brain-expressed protein containing a large polyglutamine stretch. However, we found that the t(2;7)(p23;q31.3) breakpoint in the second patient (BRD) resides within a BAC clone mapping >3.7 Mb distal to this, outside the current SPCH1 critical interval. Finally, we investigated the CAGH44 gene in affected individuals of the KE family, but we found no mutations in the currently known coding sequence. These studies represent further steps toward the isolation of the first gene to be implicated in the development of speech and language.

Paediatric assessment in a residential child and adolescent psychiatry unit.

To document the health status, comorbidity and functional impairments experienced by a group of psychiatrically disturbed children and adolescents. A detailed study of consecutive admissions to a residential unit over a two-year period was undertaken. All admissions had a comprehensive paediatric, speech pathology and psychiatric assessment. Compared to the general population, there was a significant history of developmental delay and low birthweight, but only a slightly greater prevalence of antenatal problems. Clumsiness (37%), severe speech and language disorder (32%), and hearing loss (15%) were prominent. Only 25% had no history of comorbid medical or neurological disorders. Children and adolescents presenting with moderate to severe mental health morbidity may have pre-existing comorbid medical problems, as well as unrecognised difficulties and impairments in other skills areas. Multidisciplinary assessment and intervention should be an integral part of the residential programme.

Correction: Localisation of a gene implicated in a severe speech and language disorder

Correction: Localisation of a gene implicated in a severe speech and language disorder

Localisation of a gene implicated in a severe speech and language disorder.

Between 2 and 5% of children who are otherwise unimpaired have significant difficulties in acquiring expressive and/or receptive language, despite adequate intelligence and opportunity. While twin studies indicate a significant role for genetic factors in developmental disorders of speech and language, the majority of families segregating such disorders show complex patterns of inheritance, and are thus not amenable for conventional linkage analysis. A rare exception is the KE family, a large three-generation pedigree in which approximately half of the members are affected with a severe speech and language disorder which appears to be transmitted as an autosomal dominant monogenic trait. This family has been widely publicised as suffering primarily from a defect in the use of grammatical suffixation rules, thus supposedly supporting the existence of genes specific to grammar. The phenotype, however, is broader in nature, with virtually every aspect of grammar and of language affected. In addition, affected members have a severe orofacial dyspraxia, and their speech is largely incomprehensible to the naive listener. We initiated a genome-wide search for linkage in the KE family and have identified a region on chromosome 7 which co-segregates with the speech and language disorder (maximum lod score = 6.62 at theta = 0.0), confirming autosomal dominant inheritance with full penetrance. Further analysis of microsatellites from within the region enabled us to fine map the locus responsible (designated SPCH1) to a 5.6-cM interval in 7q31, thus providing an important step towards its identification. Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental process that culminates in speech and language.

Speech delay in seven siblings with unusual sound preferences.

By the age of 8 years, children who are developing normally show almost adult speech skills. Children with serious phonological disorders, however, may exhibit significant differences in development well beyond the age of 8 years with little or no improvement in speech if therapy is not provided. This is a descriptive study of seven siblings, ranging in age from 6 to 14 years of age who had never attended school or received speech therapy until these ages. All of the children exhibited moderate to severe speech disorder with no evidence of predisposing genetic factors, hearing loss, physical abuse, or prenatal drug exposure. These cases, which would obviously be impossible to duplicate in a controlled study, provide strong support for the efficacy of speech therapy. Children with serious speech delays will not improve appreciably without direct intervention.

Dysarthria and Apraxia of Speech Associated With FK-506(Tacrolimus)

Dysarthria and Apraxia of Speech Associated With FK-506(Tacrolimus)

Augmentative and alternative communication (AAC)

121 000 children in Great Britain have been identified as having a severe communication difficulty and 39000 as having severe problems with dexterity? A significant number of these children are unable to speak or to write and will need forms of augmentative and alternative communication (AAC) to interact with family, friends and teachers and to access the school curriculum. Without an alternative means of communication their social and cognitive skills are severely constrained and they may become frustrated and develop behavioural problems. The majority of this group has a physical disability which may be caused by cerebral palsy, juvenile rheumatoid arthritis, muscular dystrophy or a head or neck injury amongst other conditions. A smaller group has such a severe speech and language disorder that they may need to use AAC and there are also children with severe learning difficulties whose language can be enhanced by AAC. Some of the children described above may have associated sensory difficulties and communication strategies need to take these into account. However, the focus here is not on children whose primary presenting condition is a visual or hearing impairment.

Junction in developmental speech disorder: A case study

Although it is accepted that children with developmental speech disorders are harder to understand in continuous speech than in single word production, current phonological assessment procedures are concerned almost exclusively with single words, and their focus is primarily on the child's inability to signal paradigmatic segmental contrasts. This study presents a detailed phonological analysis of a child with a severe developmental speech disorder, whose speech is rhythmically disjointed and prosodically unusual. Focusing on syntagmatic phonological relationships rather than on paradigmatic systems, the analysis begins with properties of the sentence, i.e. phonological delimitation of the sentence/turn, and information focus. There follows a presentation of syntagmatic features of various types of syllable junction, within and between words. Throughout, the child's syntagmatic phonology is compared to that of adult English speakers, and that of children whose speech is developing normally, drawing on the small amount of research reported in the child phonology literature. Some tentative conclusions are drawn about the normal development of syntagmatic phonological relationships, and about this child's atypical development. It is suggested that a syntagmatic phonological analysis of the type presented here is a necessary precondition for planning appropriate therapy for the remediation of connected speech problems.

Speech therapy for Parkinson's disease.

Twenty-six patients with the speech disorder of Parkinson's disease received daily speech therapy (prosodic exercises) at home for 2 to 3 weeks. There were significant improvements in speech as assessed by scores for prosodic abnormality and intelligibility' and these were maintained in part for up to 3 months. The degree of improvement was clinically and psychologically important, and relatives commented on the social benefits. The use of a visual reinforcement device produced limited benefit over and above that from prosodic exercises alone, except to patients with severe speech disorder.

1218 A FAMILIAL X-LINKED MENTAL RETARDATION SYNDROME ASSOCIATED WITH MULTIPLE CONGENITAL ANOMALIES, MEGALOGENITALIA AND A FRAGILE X CHROMOSOME

The availability of improved diagnostic services for mentally handicapped persons and the recent development of refined cytogenetic techniques have permitted the identification of subgrpups within the general diagnostic category of familial X-linked mental retardation.We studied a unique Azorian family whose three affected sons ages 17 (A), 22 (B), and 30 (C) years displayed moderate to severe mental retardation, speech disorder and self-stimulating behaviors. They had atypical facial features with a prominent glabella, large nose, abnormally structured ears, high arched palate, broad alveolar ridges, malocclusion, clinodactyly of the fifth finger, and single palmar creases. The most outstanding features were large genitalia [length of penis 112mm (A), 130mm (B), and 94mm (C); length of testes, left/right 70/75mm (A), 82/80mm (B), and 80/85mm (C)].The cytogenetic analyses revealed a fragile X chromosome (Xq27 FRA) in all three sons [8% (A), 4% (B), and 2% (C)].The phenotypic characteristics of the probands with familial X-linked mental retardation, fragile X chromosome and megalo-genitalia have not been described previously. It is conceivable that these patients present another subgroup of the familial X-linked mental retardation category.

Klinefelter's syndrome in a three-year old severely disturbed child.

A case study of a 3-year-old boy, said to be the youngest known Klinefelter patient (47 XXY) with severe psychopathology, mental retardation, and speech disorder is presented and discussed. The possibility of childhood schizophrenia was raised and a diagnosis of “emotional disturbance” formulated by other specialists on the basis of the child's stressful home environment. Pertinent psychiatric observations and laboratory findings are detailed and the interplay of environmental and biological factors related to the final diagnosis of Klinefelter's syndrome with borderline to mild retardation, dysarthria and a superimposed withdrawing reaction of childhood. The importance of complete diagnostic work-up, including cytogenetic studies, for retarded and/or severely disturbed children of preschool age is emphasized. Such studies showed sex chromosome anomalies in 2 out of 25 patients consecutively admitted to a psychiatric hospital nursery.

Treatment of a severe speech disorder by behavior modification: A case study

The treatment of an 18-year-old male with a severe speech disorder is described. In admission he was experiencing spasms of the jaw muscles, and his EEG reflected a significant degree of electrical cortical dysrhythmia. He was instructed to read slowly and his performance was monitored by a voice-operated relay and television from an adjacent room. Positive and negative feedback were given by lights flashing to indicate meeting or exceeding the word-per-minute criterion for a particular session. Twenty-seven sessions of feedback reduced his speaking rate from 200 to 139 words per minute. Six sessions of role-playing and 14 sessions of graded practice were given to generalize the therapeutic effects. The patient returned to college, and follow-ups at 9 and 18 months revealed that he was receiving excellent grades in all subjects.