RESUMEN
In a sporadic case of autism and language deficit due to auditory processing defects, molecular genetic studies revealed that a chromosomal deletion occurred in the 13q12-->q13 region. No chromosome abnormalities were detected in the parents. We determined that the deletion occurred on the paternally derived chromosome 13. There are two previous reports of chromosome 13 abnormalities in patients with autism. The deletion in the subject described in this paper maps between the two chromosome 13 linkage peaks described by Bradford et al. (2001) in studies of subjects with autism and language deficits. The 9-Mb region deleted in the patient described here contains at least four genes that are expressed in brain and that play a role in brain development. They are NBEA, MAB21L1, DCAMKL1 and MADH9. These genes therefore represent candidate genes for autism and specific language deficits.
Asunto(s)
Trastorno Autístico/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 13 , Trastornos de la Audición/genética , Percepción del Habla , Preescolar , Mapeo Cromosómico , Ligamiento Genético , Humanos , Hibridación Fluorescente in Situ , Trastornos del Lenguaje/genética , MasculinoRESUMEN
BACKGROUND: Oxytocin (OT) is synthesized as a prohormone that is sequentially processed to peptides. These peptides are the bioactive amidated form (OT) and the C-terminal extended peptides, OT-Gly, OT-Gly-Lys and OT-Gly-Lys-Arg, which are designated together as OT-X. As an extension of our previous study finding decreased plasma OT in autism, studies were conducted to determine whether there were changes in OT peptide forms in autistic children. METHODS: Twenty eight male subjects (97 +/- 20 months; range, 70-139 months), diagnosed with DSM-IV autistic disorder through observation and semi-structured interview, were compared with 31 age-matched nonpsychiatric control subjects (106 +/- 22 months; range, 74-140 months). Using OT antisera with different specificity for the peptide forms, we measured plasma OT and OT-X in each group. RESULTS: T tests showed that there was a decrease in plasma OT (t = 4.4, p <.0001), an increase in OT-X (t = 2.3, p <.03) and an increase in the ratio of OT-X/OT (t = 4.5, p <.0001) in the autistic sample, compared with control subjects. CONCLUSIONS: The results suggest that children with autistic disorder show alterations in the endocrine OT system. Deficits in OT peptide processing in children with autism may be important in the development of this syndrome.
Asunto(s)
Trastorno Autístico/sangre , Oxitocina/análogos & derivados , Oxitocina/sangre , Precursores de Proteínas/sangre , Adolescente , Trastorno Autístico/diagnóstico , Trastorno Autístico/psicología , Niño , Preescolar , Humanos , Masculino , Determinación de la Personalidad , Valores de ReferenciaRESUMEN
OBJECTIVE: To examine the efficacy of intravenous porcine secretin for the treatment of autistic disorder. METHOD: Randomized, double-blind, placebo-controlled, crossover design. Fifty-six subjects with autistic disorder received either a secretin or placebo infusion at baseline and the other substance at week 4. Subjects were given the Autism Diagnostic Observation Schedule (ADOS) and other pertinent developmental measures at baseline and at weeks 4 and 8 to assess drug effects. RESULTS: For the primary efficacy analysis, change of ADOS social-communication total score from week 0 to week 4, no statistically significant difference was obtained between placebo (-0.8 +/- 2.9) and secretin groups (-0.6 +/- 1.4; t54 = 0.346, p < .73). The other measures showed no treatment effect for secretin compared with placebo. CONCLUSION: There was no evidence for efficacy of secretin in this randomized, placebo-controlled, double-blind trial.
Asunto(s)
Trastorno Autístico/tratamiento farmacológico , Secretina/administración & dosificación , Trastorno Autístico/diagnóstico , Trastorno Autístico/psicología , Niño , Preescolar , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Lactante , Infusiones Intravenosas , Masculino , Determinación de la Personalidad , Secretina/efectos adversosRESUMEN
We recently studied a patient who meets criteria for autistic disorder and has a 2q37 deletion. Molecular cytogenetic studies were carried out using DNA isolated from 22 different 2q37 mapped BACs to more precisely define the extent of the chromosome deletion. We also analyzed 2q37 mapped polymorphic markers. In addition DNA sequences of BACs in the deletion region were scanned to identify microsatellite repeats. We describe four new polymorphic microsatellite repeat markers in the 2q37.3 region. These markers enabled us to determine the parental origin of the deletion in our patient. DNA from 8-13 unrelated individuals was used to determine heterozygosity estimates for these markers. We review four genes deleted in our patient - genes whose known functions and sites of expression in the brain and/or bone make them candidates for involvement in autism and/or the osteodystrophy observed in patients with 2q37.3 deletions.
Asunto(s)
Trastorno Autístico/complicaciones , Trastorno Autístico/genética , Enfermedades Óseas/complicaciones , Enfermedades Óseas/genética , Deleción Cromosómica , Cromosomas Humanos Par 2/genética , Adolescente , Adulto , Trastorno Autístico/fisiopatología , Huesos/metabolismo , Encéfalo/metabolismo , Niño , Preescolar , Cromosomas Artificiales Bacterianos , Mapeo Contig , Sondas de ADN , Femenino , Eliminación de Gen , Marcadores Genéticos/genética , Humanos , Hibridación Fluorescente in Situ , Masculino , Repeticiones de Microsatélite/genética , Polimorfismo Genético/genética , PsicometríaRESUMEN
We have identified a one megabase deletion in the 15q22-15q23 region in a patient with autism, developmental delay, and mild dysmorphism. Genes that map within the deletion region and genes that are interrupted or rearranged at the deletion breakpoints are candidate genes for autism. Fluroescence in situ hybridization studies in this patient revealed that part or all of the PML gene is absent from one chromosome 15 and a BAC clone containing the D15S124 gene locus hybridizes to only one chromosome 15. BAC clones containing the PTPN9, and SLP-1[hUNC24] genes showed markedly reduced hybridization in the 15q22-q23 region on one chromosome 15 in the patient. These BACs also hybridize to the 15q11-q13 region in close proximity to SNRPN and HERC2, and in this region there is equal intensity of signal on the normal and on the deleted chromosome. There are previous reports of deletions and duplications of the 15q11-q13 region in patients with autism. Our patient represents the first report of a 15q22-q23 deletion. Hybridization of the PTPN9 and Slp-1 Bac clones to the 15q11-q13 and the 15q22-q23 regions of chromosome 15 may be due to the presence of PTPN9 or SLP-1 gene sequences or to the presence of other gene sequences or to non-coding homologous DNA sequences. The PTPN9 gene encodes a non-receptor protein tyrosine phosphatase. The Slp-1 [hUNC24] gene is expressed mainly in the brain. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:765-770, 2000.
Asunto(s)
Trastorno Autístico/genética , Deleción Cromosómica , Cromosomas Humanos Par 15/genética , Adulto , Trastorno Autístico/patología , Niño , Predisposición Genética a la Enfermedad/genética , Humanos , Hibridación Fluorescente in Situ , Repeticiones de MicrosatéliteRESUMEN
BACKGROUND: Social impairments are central to the syndrome of autism. The neuropeptide oxytocin (OT) has been implicated in the regulation of social behavior in animals but has not yet been examined in autistic subjects. METHODS: To determine whether autistic children have abnormalities in OT, midday plasma samples from 29 autistic and 30 age-matched normal children, all prepubertal, were analyzed by radioimmunoassay for levels of OT. RESULTS: Despite individual variability and overlapping group distributions, the autistic group had significantly lower plasma OT levels than the normal group. OT increased with age in the normal but not the autistic children. Elevated OT was associated with higher scores on social and developmental measures for the normal children, but was associated with lower scores for the autistic children. These relationships were strongest in a subset of autistic children identified as aloof. CONCLUSIONS: Although making inferences to central OT functioning from peripheral measurement is difficult, the data suggest that OT abnormalities may exist in autism, and that more direct investigation of central nervous system OT function is warranted.
Asunto(s)
Trastorno Autístico/sangre , Oxitocina/sangre , Trastorno Autístico/psicología , Niño , Humanos , Entrevistas como Asunto , Masculino , Pruebas Neuropsicológicas , Padres , Escalas de Valoración Psiquiátrica , RadioinmunoensayoRESUMEN
Behavioral impairments in autism are theorized to result from abnormal neuronal organization in brain development generating 4 systemically related neurofunctional impairments: (a) canalesthesia, wherein abnormal hippocampal system function "canalizes" sensory records, disrupting integration of information; (b) impaired assignment of the affective significance of stimuli, wherein abnormal amygdaloid system function disrupts affect association; (c) asociality, wherein impaired oxytocin system function flattens social bonding and affiliativeness; and (d) extended selective attention, wherein abnormal organization of temporal and parietal polysensory regions yields aberrant overprocessing of primary representations. This model proposes that complex human behaviors may be guided by multiple overlapping neural mechanisms.