RESUMO
BACKGROUND: Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES). METHODS: We performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria. RESULTS: Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes: a de novo variant in each of ATPase H+ transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2). CONCLUSIONS: Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.
Assuntos
Sequenciamento do Exoma , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Fenótipo , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Biologia Computacional/métodos , Variações do Número de Cópias de DNA , Ontologia Genética , Redes Reguladoras de Genes , Estudos de Associação Genética/métodos , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Scoliosis in cerebral palsy (CP) often occurs and causes a disturbance in daily life. The purpose of this study was to investigate the natural history of scoliosis in cerebral palsy and determine risk factors for the progression of scoliosis using multivariate analyses. METHODS: We revised 113 patients with CP (47 males and 66 females) who had scoliosis with a curve of at least 10° were reviewed and retrospectively investigated these cases of scoliosis and analyzed the risk factors for the progression of this condition. RESULTS: The mean follow-up period was 16.5 years and the mean age at onset of scoliosis was 6.6 years (range: 1-16 years). In 59 patients (52%), the age at onset of scoliosis was under 6 years. On the final radiographs, the mean Cobb angle was 55.1° (range: 10° to 169°). After the age of 20 years, 13 of 40 patients (32.5%) had a progression of over 10° in scoliosis. Multivariate analyses showed the risk factors for the progression of scoliosis to be hip displacement (p = 0.0038), the onset of scoliosis before the age of 6 years (p = 0.0024), and 30° of the Cobb angle before the age of 10 years (p < 0.001). A subtype of CP (spastic quadriplegia) was identified as a potential risk factor. CONCLUSIONS: After the age of 20 years, 32.5% patients had a progression of over 10° in scoliosis. Risk factors for the progression of scoliosis in CP included hip displacement, early-onset scoliosis, and Cobb angle of 30° before the age of 10 years. LEVEL OF EVIDENCE: Prognostic level IV - case series.
Assuntos
Paralisia Cerebral/complicações , Escoliose/etiologia , Escoliose/fisiopatologia , Adolescente , Adulto , Fatores Etários , Análise de Variância , Paralisia Cerebral/diagnóstico , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Humanos , Japão , Modelos Lineares , Análise Multivariada , Prognóstico , Radiografia Torácica/métodos , Estudos Retrospectivos , Escoliose/diagnóstico por imagem , Índice de Gravidade de Doença , Fatores Sexuais , Adulto JovemRESUMO
We developed a novel device, dynamic spinal brace (DSB), with the basic concept of automatic correction by maximizing posture control. Herein, we report the structure of the DSB and preliminary treatment outcomes for scoliosis in patients with cerebral palsy. The study cohort comprised 219 patients with cerebral palsy treated for scoliosis with Cobb angle of at least 20° and follow-up of more than 3 years under the DSB. Cobb angle, trunk shift, and pelvic obliquity were assessed by semi-sitting radiography, and a questionnaire on daily lifestyle was collected. The immediate correction of these parameters by wearing DSB was demonstrated. In those who aged older than 15 years, the annual progression was 1.0°, and trunk shift was not deteriorated statistically. The questionnaire survey indicated that the DSB led to improvements in QOL and caregiving, and only 3.5% of the patients discontinued DSB because of intolerance. However, we could not find clear evidence that DSB affects the natural history of scoliosis in children with cerebral palsy.