RESUMEN
BACKGROUND: Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the E3 ubiquitin protein ligase gene (UBE3A); or (5) unidentified mechanism(s). All classical patients from these classes exhibit four cardinal features, including severe developmental delay and/or mental retardation, profound speech impairment, a movement and balance disorder, and AS specific behaviour typified by an easily excitable personality with an inappropriately happy affect. In addition, patients can display other characteristics, including microcephaly, hypopigmentation, and seizures. METHODS: We restricted the present study to 104 patients (93 families) with a classical AS phenotype. All of our patients were evaluated for 22 clinical variables including growth parameters, acquisition of motor skills, and history of seizures. In addition, molecular and cytogenetic analyses were used to assign a molecular class (I-V) to each patient for genotype-phenotype correlations. RESULTS: In our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations within UBE3A, the largest percentage found to date. Our data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients, UBE3A mutation patients, and subjects with unknown aetiology. Deletion patients are the most severely affected, while UPD and ID patients are the least. Differences in body mass index, head circumference, and seizure activity are the most pronounced among the classes. CONCLUSIONS: Clinically, we were unable to distinguish between UPD and ID patients, suggesting that 15q11-q13 contains the only significant maternally expressed imprinted genes on chromosome 15.
Asunto(s)
Síndrome de Angelman/clasificación , Síndrome de Angelman/genética , Cromosomas Humanos Par 15/genética , Ligasas/genética , Mutación/genética , Adulto , Síndrome de Angelman/etiología , Síndrome de Angelman/fisiopatología , Southern Blotting , Estatura/genética , Índice de Masa Corporal , Preescolar , Metilación de ADN , Análisis Mutacional de ADN , Femenino , Impresión Genómica/genética , Genotipo , Trastornos del Crecimiento/genética , Trastornos del Crecimiento/fisiopatología , Humanos , Hibridación Fluorescente in Situ , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/fisiopatología , Masculino , Fenotipo , Polimorfismo Genético/genética , Desempeño Psicomotor , Convulsiones/genética , Convulsiones/fisiopatología , Ubiquitina-Proteína LigasasRESUMEN
About 1% of individuals with autism or types of pervasive developmental disorder have a duplication of the 15q11-q13 region. These abnormalities can be detected by routine G-banded chromosome study, showing an extra marker chromosome, or demonstrated by fluorescence in situ hybridization (FISH) analysis, revealing an interstitial duplication. We report here the molecular, cytogenetic, clinical and neuropsychiatric evaluations of a family in whom 3 of 4 siblings inherited an interstitial duplication of 15q11-q13. This duplication was inherited from their mother who also had a maternally derived duplication. Affected family members had apraxia of speech, phonological awareness deficits, developmental language disorder, dyslexia, as well as limb apraxia but did not have any dysmorphic clinical features. The observations in this family suggest that the phenotypic manifestations of proximal 15q duplications may also involve language-based learning disabilities.
