RESUMO
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder caused by a repeat expansion in the fragile X mental retardation 1 (FMR1) gene. The disorder is characterized by kinetic tremor and cerebellar ataxia, shows age-dependent penetrance, and occurs more frequently in men. This paper summarizes the key emerging issues in FXTAS as presented at the Second International Conference on the FMR1 Premutation: Basic Mechanisms & Clinical Involvement in 2015. The topics discussed include phenotype-genotype relationships, neurobehavioral function, and updates on FXTAS genetics and imaging.
Assuntos
Ataxia/diagnóstico por imagem , Ataxia/fisiopatologia , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/diagnóstico por imagem , Síndrome do Cromossomo X Frágil/fisiopatologia , Heterozigoto , Tremor/diagnóstico por imagem , Tremor/fisiopatologia , Animais , Ataxia/genética , Ataxia/terapia , Congressos como Assunto , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/terapia , Humanos , Fenótipo , Tremor/genética , Tremor/terapiaAssuntos
Síndrome de Angelman/classificação , Síndrome de Angelman/genética , Aconselhamento Genético , Síndrome de Prader-Willi/classificação , Síndrome de Prader-Willi/genética , Síndrome de Angelman/diagnóstico , Chile , Metilação de DNA/genética , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase , Síndrome de Prader-Willi/diagnósticoRESUMO
BACKGROUND: Fragile X syndrome (FXS) is a common cause of intellectual disability and autism spectrum disorder (ASD) usually associated with a CGG expansion, termed full mutation (FM: CGG ≥ 200), increased DNA methylation of the FMR1 promoter and silencing of the gene. Mosaicism for presence of cells with either methylated FM or smaller unmethylated pre-mutation (PM: CGG 55-199) alleles in the same individual have been associated with better cognitive functioning. This study compares age- and sex-matched FM-only and PM/FM mosaic individuals on intellectual functioning, ASD features and maladaptive behaviours. METHODS: This study comprised a large international cohort of 126 male and female participants with FXS (aged 1.15 to 43.17 years) separated into FM-only and PM/FM mosaic groups (90 males, 77.8% FM-only; 36 females, 77.8% FM-only). Intellectual functioning was assessed with age appropriate developmental or intelligence tests. The Autism Diagnostic Observation Schedule-2nd Edition was used to examine ASD features while the Aberrant Behavior Checklist-Community assessed maladaptive behaviours. RESULTS: Comparing males and females (FM-only + PM/FM mosaic), males had poorer intellectual functioning on all domains (p < 0.0001). Although females had less ASD features and less parent-reported maladaptive behaviours, these differences were no longer significant after controlling for intellectual functioning. Participants with PM/FM mosaicism, regardless of sex, presented with better intellectual functioning and less maladaptive behaviours compared with their age- and sex-matched FM-only counterparts (p < 0.05). ASD features were similar between FM-only and PM/FM mosaics within each sex, after controlling for overall intellectual functioning. CONCLUSIONS: Males with FXS had significantly lower intellectual functioning than females with FXS. However, there were no significant differences in ASD features and maladaptive behaviours, after controlling for intellectual functioning, independent of the presence or absence of mosaicism. This suggests that interventions that primarily target cognitive abilities may in turn reduce the severity of maladaptive behaviours including ASD features in FXS.
Assuntos
Transtorno do Espectro Autista , Sintomas Comportamentais , Síndrome do Cromossomo X Frágil , Deficiência Intelectual , Mosaicismo , Adolescente , Adulto , Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Sintomas Comportamentais/etiologia , Sintomas Comportamentais/genética , Sintomas Comportamentais/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Lactente , Deficiência Intelectual/etiologia , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Fenótipo , Fatores Sexuais , Adulto JovemRESUMO
Complete achromatopsia is genetically heterogeneous and segregates with mutations in CNGA3 or CNGB3 genes, which respectively encode for alpha- and beta-subunits of the cyclic-nucleotide-gated (CNG) cation channel expressed in cone photoreceptors. High incidence of the disease (1 in 60) was detected in a rural isolate in central Chile. We excluded previously reported mutations in a consanguineous kindred with five affected members. Genotype analysis with short tandem repeat polymorphic (STRP) markers provided evidence to search for the causative mutation in CNGB3. Two sequence variations, c.492_493insT and c.488A>G, flanking an adenosine (A(5)) repeat in exon 4 were identified. The frameshift mutation creates two consecutive stop codons in exon 5 that would induce premature translation termination. The severely truncated beta-subunit is likely to render a nonfunctional cone CNG channel and cause total colour blindness in this kindred.