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  1. Olusanya BO, Gulati S, Berman BD, Hadders-Algra M, Williams AN, Smythe T, et al.
    Nat Med, 2023 May;29(5):1056-1060.
    PMID: 37055569 DOI: 10.1038/s41591-023-02291-x
  2. Olusanya BO, Wright SM, Nair MKC, Boo NY, Halpern R, Kuper H, et al.
    Pediatrics, 2020 Jul;146(1).
    PMID: 32554521 DOI: 10.1542/peds.2019-2623
    BACKGROUND: Estimates of children and adolescents with disabilities worldwide are needed to inform global intervention under the disability-inclusive provisions of the Sustainable Development Goals. We sought to update the most widely reported estimate of 93 million children <15 years with disabilities from the Global Burden of Disease Study 2004.

    METHODS: We analyzed Global Burden of Disease Study 2017 data on the prevalence of childhood epilepsy, intellectual disability, and vision or hearing loss and on years lived with disability (YLD) derived from systematic reviews, health surveys, hospital and claims databases, cohort studies, and disease-specific registries. Point estimates of the prevalence and YLD and the 95% uncertainty intervals (UIs) around the estimates were assessed.

    RESULTS: Globally, 291.2 million (11.2%) of the 2.6 billion children and adolescents (95% UI: 249.9-335.4 million) were estimated to have 1 of the 4 specified disabilities in 2017. The prevalence of these disabilities increased with age from 6.1% among children aged <1 year to 13.9% among adolescents aged 15 to 19 years. A total of 275.2 million (94.5%) lived in low- and middle-income countries, predominantly in South Asia and sub-Saharan Africa. The top 10 countries accounted for 62.3% of all children and adolescents with disabilities. These disabilities accounted for 28.9 million YLD or 19.9% of the overall 145.3 million (95% UI: 106.9-189.7) YLD from all causes among children and adolescents.

    CONCLUSIONS: The number of children and adolescents with these 4 disabilities is far higher than the 2004 estimate, increases from infancy to adolescence, and accounts for a substantial proportion of all-cause YLD.

  3. Thomsen M, Ott F, Loens S, Kilic-Berkmen G, Tan AH, Lim SY, et al.
    medRxiv, 2024 Dec 05.
    PMID: 39677454 DOI: 10.1101/2024.12.02.24316741
    Dystonia is one of the most prevalent movement disorders, characterized by significant clinical and etiological heterogeneity. Despite considerable heritability (∼25%) and the identification of several disease-linked genes, the etiology in most patients remains elusive. Moreover, understanding the correlations between clinical manifestation and genetic variants has become increasingly complex. To comprehensively unravel dystonia's genetic spectrum, we performed exome sequencing on 1,924 dystonia patients [40.3% male, 92.9% White, 93.2% isolated dystonia, median age at onset (AAO) 33 years], including 1,895 index patients, who were previously genetically unsolved. The sample was mainly based on two dystonia registries (DysTract and the Dystonia Coalition). Further, 72 additional patients of Asian ethnicity, mainly from Malaysia, were also included. We prioritized patients with negative genetic prescreening, early AAO, positive family history, and multisite involvement of dystonia. Rare variants in genes previously linked to dystonia ( n =405) were examined. Variants were confirmed via Sanger sequencing, and segregation analysis was performed when possible. We identified 137 distinct likely pathogenic or pathogenic variants (according to ACMG criteria) across 51 genes in 163/1,924 patients [42.9% male, 85.9% White, 68.7% isolated dystonia, median AAO 19 years]. This included 153/1,895 index patients, resulting in a diagnostic yield of 8.1%. Notably, 77/137 (56.2%) of these variants were novel, with recurrent variants in EIF2AK2 , VPS16 , KCNMA1 , and SLC2A1 , and novel variant types such as two splice site variants in KMT2B , supported by functional evidence. Additionally, 321 index patients (16.9%) harbored variants of uncertain significance in 102 genes. The most frequently implicated genes included VPS16 , THAP1 , GCH1 , SGCE , GNAL , and KMT2B. Presumably pathogenic variants in less well-established dystonia genes were also found, including KCNMA1 , KIF1A , and ZMYND11. At least six variants (in ADCY5 , GNB1 , IR2BPL, KCNN2 , KMT2B , and VPS16 ) occurred de novo, supporting pathogenicity. ROC curve analysis indicated that AAO and the presence of generalized dystonia were the strongest predictors of a genetic diagnosis, with diagnostic yields of 28.6% in patients with generalized dystonia and 20.4% in those with AAO < 30 years. This study provides a comprehensive examination of the genetic landscape of dystonia, revealing valuable insights into the frequency of dystonia-linked genes and their associated phenotypes. It underscores the utility of exome sequencing in establishing diagnoses within this heterogeneous condition. Despite prescreening, presumably pathogenic variants were identified in almost 10% of patients. Our findings reaffirm several dystonia candidate genes and expand the phenotypic spectrum of some of these genes to include prominent, sometimes isolated dystonia.
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