RESUMO
Through an international multi-center collaboration, 13 individuals from nine unrelated families and affected by likely pathogenic biallelic variants in TBC1-domain-containing kinase (TBCK) were identified through whole-exome sequencing. All affected individuals were found to share a core phenotype of intellectual disability and hypotonia, and many had seizures and showed brain atrophy and white-matter changes on neuroimaging. Minor non-specific facial dysmorphism was also noted in some individuals, including multiple older children who developed coarse features similar to those of storage disorders. TBCK has been shown to regulate the mammalian target of rapamycin (mTOR) signaling pathway, which is also stimulated by exogenous leucine supplementation. TBCK was absent in cells from affected individuals, and decreased phosphorylation of phospho-ribosomal protein S6 was also observed, a finding suggestive of downregulation of mTOR signaling. Lastly, we demonstrated that activation of the mTOR pathway in response to L-leucine supplementation was retained, suggesting a possible avenue for directed therapies for this condition.
Assuntos
Deficiência Intelectual/genética , Hipotonia Muscular/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Alelos , Criança , Pré-Escolar , Feminino , Variação Genética , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Hipotonia Muscular/diagnóstico , Grupos Raciais/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Focal facial dermal dysplasias (FFDD) are characterized by congenital bitemporal or preauricular atrophic skin lesions, and either autosomal dominant or autosomal recessive inheritance. Setleis syndrome (SS), FFDD type III, is a severe form of FFDD with the ectodermal lesions plus other striking facial features. Autosomal recessive nonsense and frameshift mutations in TWIST2 have been found to cause SS in some but not all individuals. Here, we report on four unrelated individuals, one with an unclassified FFDD and the other three with classic SS. Chromosomal microarray analyses revealed unique copy number variants of 1p36 in two individuals with duplications at 1p36.22p36.21 and one with a triplication at 1p36.22p36.21. The fourth patient had normal chromosomes by microarray analysis. All four patients had normal TWIST2 exonic sequences. We propose that a dosage effect of one or more of the 30 genes in the 1.3 Mb 1p36.22p36.21 region of overlap is responsible for FFDD/SS manifestations in some individuals, and this mechanism would be inherited as an autosomal dominant trait. In patients with no duplication/triplication of the 1p36.22p36.21 region and no mutations in TWIST2, there are mutation(s) in one of the 30 genes in this region or mutations in other as yet unidentified genes at different locations that may affect the expressions of genes in this region or act independently to cause this developmental disease phenotype.
Assuntos
Duplicação Cromossômica , Displasia Ectodérmica/genética , Hipoplasia Dérmica Focal/genética , Proteínas Repressoras/genética , Dermatopatias/genética , Proteína 1 Relacionada a Twist/genética , Adolescente , Adulto , Pré-Escolar , Cromossomos Humanos Par 1/genética , Displasia Ectodérmica/fisiopatologia , Face/patologia , Feminino , Hipoplasia Dérmica Focal/fisiopatologia , Displasias Dérmicas Faciais Focais , Mutação da Fase de Leitura , Humanos , Lactente , Recém-Nascido , Masculino , Dermatopatias/fisiopatologiaRESUMO
The increasing prevalence of autism spectrum disorder (ASD) suggests that dental practices will be seeing patients with this diagnosis more frequently. Although patients with ASD have similar dental needs to other patients, the symptoms of the disorder may influence the ability of dental practitioners to provide necessary care. Dental professionals may be unaware of the difficulties with sensory processing common to patients with ASD. However, awareness of sensory processing issues and knowledge of strategies to improve the sensory experience for individuals with ASD may improve dental visits for these patients and allow for enhanced dental care provision.