Huntington's Disease Network REGISTRY Research Articles

Editors' note: Clinical manifestations of homozygote allele carriers in Huntington disease

In the article “Clinical manifestations of homozygote allele carriers in Huntington disease”, Dr. Cubo et al. examined the phenotypic differences between patients who were homozygous for Huntington disease (HD)—with both alleles carrying ≥36 CAG repeats—and those who were heterozygous with only one allele carrying such repeats, in 10,921 participants with HD in an international, longitudinal, case-control study (European Huntington's Disease Network Registry database). They found that homozygotes were infrequent (0.3%) and that the age at onset, HD phenotype, and disease progression did not differ significantly between homozygotes and heterozygotes. In response, Dr. Da Prat et al. noted a previous study that reported a more severe and rapid progression in homozygotes. They suggest using the term biallelic HD to refer to these patients to acknowledge the differences in the number of repeats that may exist between the 2 expanded alleles and cite a previous abstract from their group that also reported no differences in age at onset, cognition, motor capabilities, or disease evolution between a small sample of 7 patients with biallelic HD and heterozygous patients. Responding to these comments, Drs. Ramos-Arroyo and Cubo highlighted the potential drawbacks of using the term biallelic HD, noting the differences between patients with 2 expanded alleles carrying ≥36 CAG repeats vs those with one intermediate allele (27–35 repeats) who may have later-onset disease (both groups are combined under the biallelic definition), and noting the exclusion of compound heterozygotes with 2 nonfully penetrant repeat expansions from the conventional biallelic definition. They argue that these issues lead to imprecise categorization of patients with HD and potential noise in the analysis of clinical effects. This exchange illustrates the potential challenges that can arise in the interpretation of genotypic-phenotypic correlation studies from the use of what may appear at the first glance to be superficially discrepant definitions. In the article “Clinical manifestations of homozygote allele carriers in Huntington disease”, Dr. Cubo et al. examined the phenotypic differences between patients who were homozygous for Huntington disease (HD)—with both alleles carrying ≥36 CAG repeats—and those who were heterozygous with only one allele carrying such repeats, in 10,921 participants with HD in an international, longitudinal, case-control study (European Huntington's Disease Network Registry database). They found that homozygotes were infrequent (0.3%) and that the age at onset, HD phenotype, and disease progression did not differ significantly between homozygotes and heterozygotes. In response, Dr. Da Prat et al. noted a previous study that reported a more severe and rapid progression in homozygotes. They suggest using the term biallelic HD to refer to these patients to acknowledge the differences in the number of repeats that may exist between the 2 expanded alleles and cite a previous abstract from their group that also reported no differences in age at onset, cognition, motor capabilities, or disease evolution between a small sample of 7 patients with biallelic HD and heterozygous patients. Responding to these comments, Drs. Ramos-Arroyo and Cubo highlighted the potential drawbacks of using the term biallelic HD, noting the differences between patients with 2 expanded alleles carrying ≥36 CAG repeats vs those with one intermediate allele (27–35 repeats) who may have later-onset disease (both groups are combined under the biallelic definition), and noting the exclusion of compound heterozygotes with 2 nonfully penetrant repeat expansions from the conventional biallelic definition. They argue that these issues lead to imprecise categorization of patients with HD and potential noise in the analysis of clinical effects. This exchange illustrates the potential challenges that can arise in the interpretation of genotypic-phenotypic correlation studies from the use of what may appear at the first glance to be superficially discrepant definitions.

Clinical manifestations of homozygote allele carriers in Huntington disease.

Because patients homozygous for Huntington disease (HD) receive the gain-of-function mutation in a double dose, one would expect a more toxic effect in homozygotes than in heterozygotes. Our aim was to investigate the phenotypic differences between homozygotes with both alleles ≥36 CAG repeats and heterozygotes with 1 allele ≥36 CAG repeats. This was an international, longitudinal, case-control study (European Huntington's Disease Network Registry database). Baseline and longitudinal total functional capacity, motor, cognitive, and behavioral scores of the Unified Huntington's Disease Rating Scale (UHDRS) were compared between homozygotes and heterozygotes. Four-year follow-up data were analyzed using longitudinal mixed-effects models. To estimate the association of age at onset with the length of the shorter and larger allele in homozygotes and heterozygotes, regression analysis was applied. Of 10,921 participants with HD (5,777 female [52.9%] and 5,138 male [47.0%]) with a mean age of 55.1 ± 14.1 years, 28 homozygotes (0.3%) and 10,893 (99.7%) heterozygotes were identified. After correcting for multiple comparisons, homozygotes and heterozygotes had similar age at onset and UHDRS scores and disease progression. In the multivariate linear regression analysis, the longer allele was the most contributing factor to decreased age at HD onset in the homozygotes (p < 0.0001) and heterozygotes (p < 0.0001). CAG repeat expansion on both alleles of the HTT gene is infrequent. Age at onset, HD phenotype, and disease progression do not significantly differ between homozygotes and heterozygotes, indicating similar effect on the mutant protein. This study provides Class II evidence that age at onset, the motor phenotype and rate of motor decline, and symptoms and signs progression is similar in homozygotes compared to heterozygotes.

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008-11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003-13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10-10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10-8DHFR p=8·37 × 10-7 MTRNR2L2 p=2·15 × 10-9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10-4DHFR p=8·45 × 10-4MTRNR2L2 p=1·20 × 10-3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10-8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16-0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06-0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

The societal cost of Huntington's disease: are we underestimating the burden?

Background and purposeApproximately 9000 people in the UK are affected by Huntington's disease (HD). People with HD require ongoing health and social care support. There is a knowledge gap about costs of health and social care use associated with HD in the UK. This paper estimates the economic cost in the UK.MethodsData on UK patients for the year 2013 were extracted from the European Huntington's Disease Network REGISTRY study, a full clinical dataset, including the full medical history and medication history for patients with HD. National unit costs for the price year 2013 were applied to health and social care services.ResultsData were available for 131 people. The mean annual cost per person with HD was £21 605. The largest proportion of this cost (65%) was due to informal care (£14 085).ConclusionsInformal care was the largest driver of costs across all stages of HD; thus there is a need to also consider the needs of carers when planning services for people with HD.

FACTORS INFLUENCING THE PRESENCE OF BEHAVIOURAL SYMPTOMS IN HUNTINGTON'S DISEASE

ObjectiveHuntington's Disease (HD) is a degenerative disease with characteristic motor and behavioural symptoms, caused by an autosomal-dominant CAG repeat expansion mutation. Behavioural symptoms are important features of HD they contribute...

Better global and cognitive functioning in choreatic versus hypokinetic‐rigid Huntington's disease

Understanding the relation between predominantly choreatic and hypokinetic-rigid motor subtypes and cognitive and general functioning may contribute to knowledge about different motor phenotypes in Huntington's disease. In the European Huntington's Disease Network Registry study, 1882 subjects were classified as being predominantly choreatic (n=528) or hypokinetic-rigid (n=432), according to their scores on items of the total motor score a priori labeled as choreatic or hypokinetic-rigid; the other 922 patients were of a mixed type. The relationship between motor type and cognitive (verbal fluency, symbol digit modalities, Stroop color, word and interference tests) and functional (total functional capacity) capacity was investigated using multiple linear regression. Motor subtype contributed significantly to the total functional capacity score (partial r(2) : 7.8%; P<.001) and to the 5 cognitive scores (partial r(2) ranged from 2.0% to 8.4%; all P<.001). Patients with a predominantly choreatic motor phenotype performing better in all areas than patients with a hypokinetic-rigid motor phenotype.

M04 European huntington's disease network registry: current status

BackgroundThe European Huntington's disease Network's (EHDN) REGISTRY is an observational, prospective, longitudinal, multi-national, multi-centre cohort study of Huntington's disease (HD). It is the largest study of HD to date, and...

Current Pharmacological Management in Juvenile Huntington's Disease.

Background: The clinical presentation of Juvenile Huntington’s Disease (JHD) can be very different from adult-onset HD with little evidence to guide symptomatic management.Aim: To survey the current use of pharmacological treatments for JHD.Methods: Patients were identified through the HD Association, Hospital Doctors and the European Huntington’s Disease Network REGISTRY study.Results: The most commonly prescribed agents were anti-psychotics (24/45), anti-depressants (17/45) and anti-parkinsonian medications (15/45). 5 patients were taking more than 8 medications.Conclusions: The most commonly prescribed group of medication was the anti-psychotic. Many patients were on multiple therapies, highlighting the need to rationalise medications.

Discrepancies in reporting the CAG repeat lengths for Huntington's disease.

Huntington's disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntington's Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original results from 121 laboratories across 15 countries. We report on 1326 duplicate results; a discrepancy in reporting the upper allele occurred in 51% of cases, this reduced to 13.3% and 9.7% when we applied acceptable measurement errors proposed by the American College of Medical Genetics and the Draft European Best Practice Guidelines, respectively. Duplicate results were available for 1250 lower alleles; discrepancies occurred in 40% of cases. Clinically significant discrepancies occurred in 4.0% of cases with a potential unexplained misdiagnosis rate of 0.3%. There was considerable variation in the discrepancy rate among 10 of the countries participating in this study. Out of 1326 samples, 348 were re-analysed by an accredited diagnostic laboratory, based in Germany, with concordance rates of 93% and 94% for the upper and lower alleles, respectively. This became 100% if the acceptable measurement errors were applied. The central laboratory correctly reported allele sizes for six standard reference samples, blind to the known result. Our study differs from external quality assessment (EQA) schemes in that these are duplicate results obtained from a large sample of patients across the whole diagnostic range. We strongly recommend that laboratories state an error rate for their measurement on the report, participate in EQA schemes and use reference materials regularly to adjust their own internal standards.

D02 Discrepancies in reporting the upper CAG repeat allele between a central EHDN and local laboratories for centres participating in the REGISTRY project

AimThe European Huntington's Disease Network REGISTRY project analyses CAG repeat length measurements centrally which can be compared with the original laboratory result held at the local study site from 15...