Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589

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

Background: The frequency of late-onset Huntington's disease (&gt;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\u201350 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 6435 or a UHDRS motor score of 645 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 &lt;.001). Overall motor and cognitive performance (P &lt;.001) were worse, however only disease motor progression was slower (coefficient, 120.58; SE 0.16; P &lt;.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 &lt;.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P &lt;.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

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

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