Oliver Wj Quarrell

Background: Multidisciplinary care has been advocated for Juvenile‐onset Huntington's Disease but there has been no detailed analysis of this. Objectives: To evaluate the current economic costs of providing health care for patients with Juvenile‐onset Huntington's disease (JoHD) and to model the effects and economic costs of providing a multidisciplinary team (MDT) approach. Methods: Patients were recruited through the patients’ organization, the Huntington's Disease Association, and specialist Huntington's disease clinics. Thirty‐three adapted Client Service Receipt Inventories were completed following either a telephone or in‐person interview. The effects of delivering two models of providing a systematic MDT approach, traditional in‐person MDT and digital MDT were assessed. Results: The overall mean JoHD cost to the NHS per year (2020) was £126,966 which varied according to disease severity, costing just under £11,000 in mild disease, £132,419 in moderate disease, and £221,797 in advanced JoHD. The proportion of indirect costs to families and carers was 64% for mild disease and 17% for advanced disease. Assuming a 50% reduction in health care professionals seen, the alternative models saw reduction costs of £2490 and £2730, respectively. Conclusion: We document the high cost of care in JoHD, particularly as the disease progresses towards the later stages. We present estimates from modeling the effects of providing a systematic MDT approach to the care of patients and families with JoHD. These data have clear implications in the consideration of future JoHD models of care in an increasingly digital age and can be developed further as disease modifying treatments become available.

There is significant variation in the reported estimates of Huntington’s disease (HD) prevalence in different settings. This systematic review was undertaken to describe and assess the sources of heterogeneity in estimated prevalence values, and to consider the role of quantitative synthesis in the context of such heterogeneity. Observational studies from which a prevalence estimate (point or period) or cumulative incidence of HD could be calculated between 1993 and 2024 were sought from Medline and Embase databases. The study features are described and the sources of heterogeneity are discussed. A meta-regression was conducted including predictor variables: continent, median age of population, number of years since 1993, case ascertainment method, and Healthcare Access and Quality Index score. 43 studies met the inclusion criteria. Significant clinical and methodological heterogeneity between studies is described, including differences in case definitions and ascertainment methods, and in the estimates of disease burden calculated. There were differences in the estimated point prevalence between regions and populations within regions, while the estimated point prevalence was shown to be increasing since 1993. Wide prediction intervals in the overall pooled point prevalence (95% prediction interval: 0.32–37.55 cases per 100,000), and the European pooled point prevalence (95% prediction interval: 1.64–19.18 cases per 100,000), indicate the scale of heterogeneity between studies and settings. While such heterogeneity currently limits the validity and utility of quantitative synthesis, developing an accepted consensus on the minimum standards and reporting requirements for HD prevalence studies could reduce the methodological heterogeneity between future studies, enabling more valid and meaningful quantitative synthesis in future.

There is significant variation in estimates of Huntington’s Disease (HD) prevalence in different settings. Despite this heterogeneity, there continues to be much interest in quantitatively synthesizing prevalence estimates to produce global or regional pooled prevalence values. This systematic review was undertaken to describe and assess the sources of heterogeneity in estimated prevalence values, and to consequently evaluate the validity of pooled prevalence values produced. Observational studies from which a prevalence estimate (point or period) or cumulative incidence of HD could be calculated between 1993-2024 were sought from Medline and Embase databases. Features of included studies are described and evaluated, with sources of heterogeneity discussed. A meta-regression was conducted including predictor variables: continent, median age of population, number of years since 1993, case ascertainment method, and Healthcare Access and Quality Index score. A total of 43 studies met the criteria for inclusion in the review. Significant clinical and methodological heterogeneity between the included studies is described, including differences in case definitions and ascertainment methods, and in the estimates of disease burden calculated. There were differences in the estimated point prevalence between regions and population groups within regions, while the estimated point prevalence was shown to be increasing over time since 1993. Wide prediction intervals in the overall pooled point prevalence (95% prediction interval: 0.32 – 37.55 cases per 100,000), and the European pooled point prevalence (95% prediction interval: 1.64 – 19.18 cases per 100,000), indicate the scale of heterogeneity between studies and settings. Such heterogeneity precludes valid extrapolation of findings to settings in which HD prevalence is unknown, and greatly limits the utility of pooled prevalence values.

Background: Sudden infant death syndrome (SIDS) is the leading cause of death up to age 1. Sudden unexplained death in childhood (SUDC) is similar but affects mostly toddlers aged 1 to 4. SUDC is rarer than SIDS, and although cardiogenetic testing (molecular autopsy) identifies an underlying cause in a fraction of SIDS, less is known about SUDC. Methods and Results: Seventy‐seven SIDS and 16 SUDC cases underwent molecular autopsy with 25 definitive‐evidence arrhythmia‐associated genes. In 18 cases, another 76 genes with varying degrees of evidence were analyzed. Parents were offered cascade screening. Double‐blind review of clinical‐genetic data established genotype–phenotype correlations. The yield of likely pathogenic variants in the 25 genes was higher in SUDC than in SIDS (18.8% [3/16] versus 2.6% [2/77], respectively; P =0.03), whereas novel/ultra‐rare variants of uncertain significance were comparably represented. Rare variants of uncertain significance and likely benign variants were found only in SIDS. In cases with expanded analyses, likely pathogenic/likely benign variants stemmed only from definitive‐evidence genes, whereas all other genes contributed only variants of uncertain significance. Among 24 parents screened, variant status and phenotype largely agreed, and 3 cases positively correlated for cardiac channelopathies. Genotype–phenotype correlations significantly aided variant adjudication. Conclusions: Genetic yield is higher in SUDC than in SIDS although, in both, it is contributed only by definitive‐evidence genes. SIDS/SUDC cascade family screening facilitates establishment or dismissal of a diagnosis through definitive variant adjudication indicating that anonymity is no longer justifiable. Channelopathies may underlie a relevant fraction of SUDC. Binary classifications of genetic causality (pathogenic versus benign) could not always be adequate.

Background: Disrupted endothelial BMP9/10 signaling may contribute to the pathophysiology of both hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH), yet loss of circulating BMP9 has not been confirmed in individuals with ultra‐rare homozygous GDF2 (BMP9 gene) nonsense mutations. We studied two pediatric patients homozygous for GDF2 (BMP9 gene) nonsense mutations: one with PAH (c.[76C>T];[76C>T] or p.[Gln26Ter];[Gln26Ter] and a new individual with pulmonary arteriovenous malformations (PAVMs; c.[835G>T];[835G>T] or p.[Glu279Ter];[Glu279Ter]); both with facial telangiectases.Methods: Plasma samples were assayed for BMP9 and BMP10 by ELISA. In parallel, serum BMP activity was assayed using an endothelial BRE‐luciferase reporter cell line (HMEC1‐BRE). Proteins were expressed for assessment of secretion and processing.Results: Plasma levels of both BMP9 and BMP10 were undetectable in the two homozygous index cases and this corresponded to low serum‐derived endothelial BMP activity in the patients. Measured BMP9 and BMP10 levels were reduced in the asymptomatic heterozygous p.[Glu279Ter] parents, but serum activity was normal. Although expression studies suggested alternate translation can be initiated at Met57 in the p.[Gln26Ter] mutant, this does not result in secretion of functional BMP9.Conclusion: Collectively, these data show that homozygous GDF2 mutations, leading to a loss of circulating BMP9 and BMP10, can cause either pediatric PAH and/or “HHT‐like” telangiectases and PAVMs. Although patients reported to date have manifestations that overlap with those of HHT, none meet the Curaçao criteria for HHT and seem distinct from HHT in terms of the location and appearance of telangiectases, and a tendency for tiny, diffuse PAVMs.

We report the case of a consanguineous couple who lost four pregnancies associated with skeletal dysplasia. Radiological examination of one fetus was inconclusive. Parental exome sequencing showed that both parents were heterozygous for a novel missense variant, p.(Pro133Leu), in the SLC35D1 gene encoding a nucleotide sugar transporter. The affected fetus was homozygous for the variant. The radiological features were reviewed, and being similar, but atypical, the phenotype was classified as a ‘Schneckenbecken-like dysplasia.’ The effect of the missense change was assessed using protein modelling techniques and indicated alterations in the mouth of the solute channel. A detailed biochemical investigation of SLC35D1 transport function and that of the missense variant p.(Pro133Leu) revealed that SLC35D1 acts as a general UDP-sugar transporter and that the p.(Pro133Leu) mutation resulted in a significant decrease in transport activity. The reduced transport activity observed for p.(Pro133Leu) was contrasted with in vitro activity for SLC35D1 p.(Thr65Pro), the loss-of-function mutation was associated with Schneckenbecken dysplasia. The functional classification of SLC35D1 as a general nucleotide sugar transporter of the endoplasmic reticulum suggests an expanded role for this transporter beyond chondroitin sulfate biosynthesis to a variety of important glycosylation reactions occurring in the endoplasmic reticulum.

Background: Huntington’s disease can present at almost any age but traditionally, those with an onset ≤20 years are described as having juvenile onset Huntington’s disease (JOHD). They are more likely to have bradykinesia and dystonia earlier in the