RESUMEN
Juvenile Huntington's disease (JHD) is rare. In the first decade of life speech difficulties, rigidity, and dystonia are common clinical motor symptoms, whereas onset in the second decade motor symptoms may sometimes resemble adult-onset Huntington's disease (AOHD). Cognitive decline is mostly detected by declining school performances. Behavioral symptoms in general do not differ from AOHD but may be confused with autism spectrum disorder or attention deficit hyperactivity disorder and lead to misdiagnosis and/or diagnostic delay. JHD specific features are epilepsy, ataxia, spasticity, pain, itching, and possibly liver steatosis. Disease progression of JHD is faster compared to AOHD and the disease duration is shorter, particularly in case of higher CAG repeat lengths. The diagnosis is based on clinical judgement in combination with a positive family history and/or DNA analysis after careful consideration. Repeat length in JHD is usuallyâ>â55 and caused by anticipation, usually via paternal transmission. There are no pharmacological and multidisciplinary guidelines for JHD treatment. Future perspectives for earlier diagnosis are better diagnostic markers such as qualitative MRI and neurofilament light in serum.
Asunto(s)
Enfermedad de Huntington , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Adolescente , Niño , Progresión de la Enfermedad , Edad de InicioRESUMEN
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.
Asunto(s)
Canalopatías , Muerte Súbita del Lactante , Preescolar , Humanos , Autopsia , Corazón , Examen Físico , Muerte Súbita del Lactante/genéticaRESUMEN
PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported. METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp). RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period. CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.
Asunto(s)
Anomalías Múltiples , Trastornos Congénitos de Glicosilación , Epilepsia , Hernia Diafragmática , Embarazo , Femenino , Humanos , Hipotonía Muscular/genética , Epilepsia/genética , Anomalías Múltiples/genética , Hernia Diafragmática/genética , Convulsiones/genética , Fenotipo , Estudios de Asociación Genética , SíndromeRESUMEN
Craniofacial dysmorphism is associated with thousands of genetic and environmental disorders. Delineation of salient facial characteristics can guide clinicians towards a correct clinical diagnosis and understanding the pathogenesis of the disorder. Abnormal facial shape might require craniofacial surgical intervention, with the restoration of normal shape an important surgical outcome. Facial anthropometric growth curves or standards of single inter-landmark measurements have traditionally supported assessments of normal and abnormal facial shape, for both clinical and research applications. However, these fail to capture the full complexity of facial shape. With the increasing availability of 3D photographs, methods of assessment that take advantage of the rich information contained in such images are needed. In this article we derive and present open-source three-dimensional (3D) growth curves of the human face. These are sequences of age and sex-specific expected 3D facial shapes and statistical models of the variation around the expected shape, derived from 5443 3D images. We demonstrate the use of these growth curves for assessing patients and show that they identify normal and abnormal facial morphology independent from age-specific facial features. 3D growth curves can facilitate use of state-of-the-art 3D facial shape assessment by the broader clinical and biomedical research community. This advance in phenotype description will support clinical diagnosis and the understanding of disease pathogenesis including genotype-phenotype relations.
Asunto(s)
Anomalías Múltiples/patología , Anomalías Craneofaciales/patología , Cara/patología , Imagenología Tridimensional/métodos , Modelos Estadísticos , Atrofia Muscular/patología , Anomalías Múltiples/genética , Anomalías Múltiples/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antropometría , Estudios de Casos y Controles , Niño , Preescolar , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/metabolismo , Cara/anomalías , Femenino , Estudios de Seguimiento , Gráficos de Crecimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Atrofia Muscular/genética , Atrofia Muscular/metabolismo , Fenotipo , Pronóstico , Adulto JovenRESUMEN
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.
Asunto(s)
Proteínas Morfogenéticas Óseas/sangre , Codón sin Sentido , Factor 2 de Diferenciación de Crecimiento/sangre , Factor 2 de Diferenciación de Crecimiento/genética , Homocigoto , Hipertensión Arterial Pulmonar/diagnóstico , Hipertensión Arterial Pulmonar/etiología , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Telangiectasia Hemorrágica Hereditaria/etiología , Alelos , Angiografía , Línea Celular , Niño , Ensayo de Inmunoadsorción Enzimática , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , SíndromeRESUMEN
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.
Asunto(s)
Enfermedades Fetales/genética , Proteínas de Transporte de Monosacáridos/genética , Osteocondrodisplasias/genética , Alelos , Animales , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Femenino , Enfermedades Fetales/metabolismo , Enfermedades Fetales/patología , Heterocigoto , Humanos , Mutación con Pérdida de Función , Masculino , Ratones , Proteínas de Transporte de Monosacáridos/metabolismo , Mutación Missense , Osteocondrodisplasias/embriología , Osteocondrodisplasias/metabolismoRESUMEN
Huntington's disease (HD) is a severe neurodegenerative condition that impacts the whole family. Prenatal diagnosis by direct or exclusion testing is available for couples at risk of transmitting HD to their children. An ethical problem can arise after prenatal diagnosis for HD if a known 'high risk' pregnancy is continued to term: international guidelines emphasise that this situation should be avoided where possible, as it removes the resulting child's future right to make an informed, autonomous decision about predictive testing. The UK Huntington's Disease Predictive Testing Consortium recorded 21 pregnancies that were tested, identified as high-risk and then continued. In this qualitative study, health professionals reviewed the case notes of 15 of these pregnancies. This analysis generated guidelines for clinical practice. It is recommended that practitioners: (i) remind couples of the long-term consequences of continuing a high risk pregnancy, (ii) ensure couples understand the information provided, (iii) collaborate closely with other professionals involved in the couple's prenatal care, (iv) prepare couples for the procedural aspects of prenatal diagnosis and a possible termination of pregnancy, (v) allow time for in-depth pre-test counselling, (vi) explain the rationale for only making prenatal diagnosis available subject to conditions, whilst allowing for human ambivalence and acknowledging that these 'conditions' cannot be enforced, (vii) monitor the whole clinical process to ensure that it works 'smoothly', (viii) recommend couples do not disclose the result of the prenatal test to protect the confidentiality and autonomy of the future 'high-risk' child, and (ix) offer on-going contact and support.
Asunto(s)
Asesoramiento Genético/métodos , Pruebas Genéticas/métodos , Enfermedad de Huntington/genética , Diagnóstico Prenatal/métodos , Adolescente , Adulto , Femenino , Humanos , Enfermedad de Huntington/diagnóstico , Masculino , Embarazo , Factores de Riesgo , Adulto JovenRESUMEN
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 course of the disease. The Total Motor Score of the Unified Huntington's Disease Rating Scale (UHDRS-TMS) is often used as the principal outcome measure in clinical trials. OBJECTIVE: To identify a motor scale more suitable for JOHD patients. METHODS: A working group reviewed the UHDRS-TMS and modified it by adding four further assessment items. Rasch analysis was used to study the performance of the modified scale in 95 patients with a mean age of 19.4 (SD 6.6) years. RESULTS: The initial analysis showed a significant overall misfit to the Rasch model and a number of individual items displayed poor measurement properties: all items relating to chorea displayed significant misfit due to under-discrimination. Additionally, a number of items displayed disordered response category thresholds, and a large amount of dependency was present within the item set (96 out of 741 pairwise differencesâ=â13%). An iterative process of scale re-structuring and evaluation was then undertaken, with a view to eliminating the largest sources of misfit and generating a set of items that would conform to Rasch model expectations. CONCLUSION: This post-hoc scale restructuring appears to provide a valid motor score that is psychometrically robust in a JOHD population. This scale restructuring offers a pragmatic solution to measuring motor function in a JOHD population, and it could provide the basis for the further iterative development of a more useful clinical rating scale for patients with JOHD.
Asunto(s)
Enfermedad de Huntington , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Psicometría , Adulto JovenRESUMEN
BACKGROUND: Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). METHODS: In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. FINDINGS: The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4-11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). INTERPRETATION: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. FUNDING: UK Department of Health and Social Care and The Wellcome Trust.
Asunto(s)
Cariotipo Anormal/estadística & datos numéricos , Anomalías Congénitas/genética , Secuenciación del Exoma/estadística & datos numéricos , Desarrollo Fetal/genética , Feto/anomalías , Cariotipo Anormal/embriología , Aborto Eugénico/estadística & datos numéricos , Aborto Espontáneo/epidemiología , Anomalías Congénitas/diagnóstico , Anomalías Congénitas/epidemiología , Variaciones en el Número de Copia de ADN/genética , Femenino , Feto/diagnóstico por imagen , Humanos , Recién Nacido , Nacimiento Vivo/epidemiología , Masculino , Medida de Translucencia Nucal , Padres , Muerte Perinatal/etiología , Embarazo , Estudios Prospectivos , Mortinato/epidemiología , Secuenciación del Exoma/métodosRESUMEN
PURPOSE: There is little long-term, population-based data on uptake of prenatal diagnosis for Huntington disease (HD), a late-onset autosomal dominant neurodegenerative disorder, and the effect of the availability of preimplantation genetic diagnosis (PGD) on families' decisions about conventional prenatal diagnosis is not known. We report trends in prenatal diagnosis and preimplantation diagnosis for HD in the United Kingdom since services commenced. METHODS: Long-term UK-wide prospective case record-based service evaluation in 23 UK Regional Genetic Centres 1988-2015, and four UK PGD centers 2002-2015. RESULTS: From 1988 to 2015, 479 prenatal diagnoses were performed in the UK for HD. An exclusion approach was used in 150 (31%). The annual rate of HD prenatal diagnosis has remained around 18 (3.5/million) over 27 years, despite a steady increase in the use of PGD for HD since 2002. CONCLUSION: Although increasing number of couples are choosing either direct or exclusion PGD to prevent HD in their offspring, both direct and exclusion prenatal diagnosis remain important options in a health system where both PGD and prenatal diagnosis are state funded. At-risk couples should be informed of all options available to them, preferably prepregnancy.
Asunto(s)
Enfermedad de Huntington/diagnóstico , Diagnóstico Prenatal , Femenino , Humanos , Masculino , Embarazo , Diagnóstico Preimplantación , Estudios Prospectivos , Reino UnidoRESUMEN
Epidermolysis bullosa pruriginosa (EBP) is a rare subtype of EB which is characterized by intense pruritus with blistering and nodular or lichenoid lesions most prominent on the lower extremities. It is caused by variants in COL7A1 which encodes for type VII collagen. There is wide phenotypic and genotypic variability between affected individuals. We report 2 potentially pathogenic variants in COL7A1 occurring on the same allele in a family with EBP and autosomal dominant inheritance. Late-onset EBP and incomplete penetrance may lead to delayed presentation in affected family members with the same variants. The broad phenotypic variability seen in EBP suggests that further genotypic and environmental factors may influence presentation. Genetic and histopathological diagnosis is essential, given the considerable overlap with clinically similar presentations such as hypertrophic lichen planus.
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Colágeno Tipo VII/genética , Epidermólisis Ampollosa Distrófica/genética , Heterocigoto , Mutación Missense , Adolescente , Epidermólisis Ampollosa Distrófica/diagnóstico , Femenino , Marcadores Genéticos , Humanos , Masculino , LinajeRESUMEN
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.
Asunto(s)
Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Enfermedad de Huntington/diagnóstico , Adolescente , Femenino , Pruebas Genéticas/ética , Humanos , Masculino , Menores , Países Bajos/epidemiología , Reino Unido/epidemiologíaRESUMEN
AIM: The symptoms of Huntington's disease are well known, yet the symptoms of juvenile Huntington's disease (JHD) are less established due to its rarity. The study examined a cluster of symptoms considered to be common, but under-recognized in JHD: pain, itching, sleeping difficulties, psychosis and tics. MATERIALS & METHODS: A symptom survey was constructed using the online tool Qualtrics and dispersed to JHD caregivers through websites. RESULTS: A total of 33 surveys were completed. Disrupted sleep was the most prevalent symptom (87%), followed by tics (78%), pain (69%), itching (60%) and psychosis (39%). CONCLUSION: Despite limitations, the study supports that there are symptoms in the JHD population that are not considered classic, however, are common and significant for patients and caregivers.
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Enfermedad de Huntington/fisiopatología , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/epidemiología , Enfermedad de Huntington/genética , Masculino , Fenotipo , Encuestas y Cuestionarios , Expansión de Repetición de Trinucleótido , Adulto JovenRESUMEN
The ascertained prevalence of Huntington's disease (HD) increased significantly following the provision of diagnostic testing. A systematic review was conducted to estimate the prevalence of HD in the post-diagnostic testing era. 22 studies with original data pertaining to the prevalence of HD (1993-2015) were included and analyzed. A global meta-analysis was not performed due to heterogeneity in study methods and geographical variation. The prevalence of HD is significantly lower in Asian populations compared with western Europe, North America and Australia. The global variation in HD prevalence is partly explained by the average CAG repeat lengths and frequency of different HTT gene haplotypes in the general population. Understanding the prevalence of HD has significant implications for healthcare resource planning.