Clinical and genetic characteristics of late-onset Huntington's disease

BACKGROUND: The frequency of late-onset Huntington\u27s disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. OBJECTIVE: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. METHODS: Participants with late- and common-onset (30-50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. RESULTS: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P < .001). Overall motor and cognitive performance (P < .001) were worse, however only disease motor progression was slower (coefficient, -0.58; SE 0.16; P < .001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P < .001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P < .001). CONCLUSIONS: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients

Prenatal exome sequencing: a useful tool for the fetal neurologist

Prenatal exome sequencing (pES) is a promising tool for diagnosing genetic disorders when structural anomalies are detected on prenatal ultrasound. The aim of this study was to investigate the diagnostic yield and clinical impact of pES as an additional modality for fetal neurologists who counsel parents in case of congenital anomalies of the central nervous system (CNS). We assessed 20 pregnancies of 19 couples who were consecutively referred to the fetal neurologist for CNS anomalies. pES had a diagnostic yield of 53% (10/19) with most diagnosed pregnancies having agenesis or hypoplasia of the corpus callosum (7/10). Overall clinical impact was 63% (12/19), of which the pES result aided parental decision making in 55% of cases (6/11), guided perinatal management in 75% of cases (3/4), and was helpful in approving a late termination of pregnancy request in 75% of cases (3/4). Our data suggest that pES had a high diagnostic yield when CNS anomalies are present, although this study is limited by its small sample size. Moreover, pES had substantial clinical impact, which warrants implementation of pES in the routine care of the fetal neurologist in close collaboration with gynecologists and clinical geneticists.Neuro Imaging Researc

Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature

BACKGROUND: We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern. RESULTS: Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This "episignature" was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying this model to a cohort of undiagnosed probands allowed us to reach diagnosis in one subject. CONCLUSIONS: We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis

ANK3 related neurodevelopmental disorders: expanding the spectrum of heterozygous loss-of-function variants

ANK3 encodes multiple isoforms of ankyrin-G, resulting in variegated tissue expression and function, especially regarding its role in neuronal development. Based on the zygosity, location, and type, ANK3 variants result in different neurodevelopmental phenotypes. Autism spectrum disorder has been associated with heterozygous missense variants in ANK3, whereas a more severe neurodevelopmental phenotype is caused by isoform-dependent, autosomal-dominant, or autosomal-recessive loss-of-function variants. Here, we present four individuals affected by a variable neurodevelopmental phenotype harboring a heterozygous frameshift or nonsense variant affecting all ANK3 transcripts. Thus, we provide further evidence of an isoform-based phenotypic continuum underlying ANK3-associated pathologies and expand its phenotypic spectrum.Genetics of disease, diagnosis and treatmen

APC mosaicism, not always isolated: two first-degree relatives with apparently distinct APC mosaicism

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Efficacy of Baricitinib in the Treatment of Chilblains Associated With Aicardi-Goutieres Syndrome, a Type I Interferonopathy

Genetics of disease, diagnosis and treatmen

Predictive testing of minors for Huntington's disease: The UK and Netherlands experiences

A consistent feature of predictive testing guidelines for Huntington's disease (HD) is the recommendation not to undertake predictive tests on those < 18 years. Exceptions are made but the extent of, and reasons for, deviation from the guidelines are unknown. The UK Huntington's Prediction Consortium has collected data annually on predictive tests undertaken from the 23 UK genetic centers. DNA analysis for HD in the Netherlands is centralized in the Laboratory for Diagnostic Genome Analysis in Leiden. In the UK, 60 tests were performed on minors between 1994 and 2015 representing 0.63% of the total number of tests performed. In the Netherlands, 23 tests were performed on minors between 1997 and 2016. The majority of the tests were performed on those aged 16 and 17 years for both countries (23% and 57% for the UK, and 26% and 57% for the Netherlands). Data on the reasons for testing were identified for 36 UK and 22 Netherlands cases and included: close to the age of 18 years, pregnancy, currently in local authority care and likely to have less support available after 18 years, person never having the capacity to consent and other miscellaneous reasons. This study documents the extent of HD testing of minors in the UK and the Netherlands and suggests that, in general, the recommendation is being followed. We provide some empirical evidence as to reasons why clinicians have departed from the recommendation. We do not advise changing the recommendation but suggest that testing of minors continues to be monitored

De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder

Genetics of disease, diagnosis and treatmen

Correction to: Putting genome-wide sequencing in neonates into perspective

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article