Health-related quality of life in Huntington’s disease patients: a comparison of proxy assessment and patient self-rating using the disease-specific Huntington’s disease health-related quality of life questionnaire (HDQoL)

Huntington's disease (HD) is a fatal, neurodegenerative disease for which there is no known cure. Proxy evaluation is relevant for HD as its manifestation might limit the ability of persons to report their health-related quality of life (HrQoL). This study explored patient-proxy ratings of HrQoL of persons at different stages of HD, and examined factors that may affect proxy ratings. A total of 105 patient-proxy pairs completed the Huntington's disease health-related quality of life questionnaire (HDQoL) and other established HrQoL measures (EQ-5D and SF-12v2). Proxy-patient agreement was assessed in terms of absolute level (mean ratings) and intraclass correlation. Proxies' ratings were at a similar level to patients' self-ratings on an overall Summary Score and on most of the six Specific Scales of the HDQoL. On the Specific Hopes and Worries Scale, proxies on average rated HrQoL as better than patients' self-ratings, while on both the Specific Cognitive Scale and Specific Physical and Functional Scale proxies tended to rate HrQoL more poorly than patients themselves. The patient's disease stage and mental wellbeing (SF-12 Mental Component scale) were the two factors that primarily affected proxy assessment. Proxy scores were strongly correlated with patients' self-ratings of HrQoL, on the Summary Scale and all Specific Scales. The patient-proxy correlation was lower for patients at moderate stages of HD compared to patients at early and advanced stages. The proxy report version of the HDQoL is a useful complementary tool to self-assessment, and a promising alternative when individual patients with advanced HD are unable to self-report.     

Bradykinesia in Huntington's disease. A prospective, follow-up study

Bradykinesia is a frequent finding in Huntington's disease (HD), but some aspects are presently unknown; including the natural evolution of bradykinesia over time and the correlation between bradykinesia and functional capacity. We studied the motor performance of 20 genetically confirmed patients with HD (age: 40±10.8 years; age at onset 33.6±11 years; total functional capacity (TFC): 9.57±3; UHDRS total motor scale: 31.4±13, triplet length (CAG)n: 46.7±4 triplets).These patients were studied in baseline conditions and after 18.7±6 months of follow-up. In addition, HD patients were compared with 20 age-matched normal controls. Motor study included the four CAPIT timed tests commonly used for Parkinson's disease: pronation-supination (PS), finger dexterity (FD), movement between two points (MTP) and walking test (WT). HD patients were significantly slower than controls in all motor tasks. A significant deterioration occurred over time in three of the four motor tasks (especially FD and WT). A significant correlation between timed tests and TFC score was found (for MTP, r: −0.845; p < 0,0001). In addition a significant correlation between timed tests and the UHDRDS total motor scale was also found (for MTP, r: 0.864; p < 0.0001) In conclusion, simple timed motor tests can detect a deterioration of motor activity over time in HD. Timed tests might be useful to follow the natural evolution of HD and to assess the efficacy of new therapies. Received: 17 May 2001, Received in revised form: 7 August 2001, Accepted: 20 August 2001     

Epidemiology of Huntington's disease in Slovenia

Objectives – The objective of this study was to estimate the prevalence of Huntington’s disease (HD) in Slovenia using direct mutation analysis. Materials and methods – Symptomatic patients and presymptomatic individuals at risk for HD referred to the Institute of Medical Genetics between 1997 and 2007 were included in the study. The patients were ascertained through multiple sources. The prevalence was estimated on 31 December 2006. Results – A total of 116 and 68 individuals with CAG repeat number >36 were symptomatic and presymptomatic, respectively. The prevalence of HD in Slovenia was estimated at 5.16/10⁵ (95% confidence interval 4.16–6.16). Conclusions – This is the first report on the epidemiology and prevalence of HD in Slovenia. The prevalence of HD is comparable with previously reported data in other European countries. In Slovenia, a higher proportion of individuals at risk for HD decide on predictive mutational testing as compared with the estimated numbers for Europe, United States, Canada and Australia.     

Un tremblement d’attitude révélant une maladie de Huntington

Introduction

Initial manifestations of Huntington's disease (HD) are varied and chorea is not always the first motor symptom.

Case report

We report the case of a 44-year-old woman, with a family history of HD, who presented isolated head and upper limbs tremor for 4 years. Genetic testing confirmed the diagnosis of HD and no cause of secondary postural tremor was found. Propanolol was introduced with success.

Conclusion

This kind of presentation is unusual and has mostly been reported in the juvenile form of HD.     

Perospirone in treatment of Huntington's disease: a first case report

Huntington's disease (HD) is a hereditary disorder clinically characterized by involuntary movements, cognitive decline and psychiatric symptoms. We report on a patient with HD, whose involuntary movements and psychiatric symptoms were clinically improved with perospirone, a second-generation antipsychotic agent with antagonistic effects on serotonin 5-HT(2A) and dopamine D(2) (D(2)) receptors, as well as a unique agonistic effect on serotonin 5-HT(1A) (5-HT(1A)) receptors. The fact that perospirone antagonizes D(2) receptors could explain its effects on the hyperkinetic syndrome, while its agonistic effects on 5-HT(1A) receptors may explain the amelioration of psychiatric symptoms (fear and anxiety) in this patient. Future studies would be valuable to elucidate the utility of perospirone for the treatment of involuntary movements and psychiatric symptoms in HD.     

Presymptomatic testing in Huntington's disease and autosomal dominant cerebellar ataxias

OBJECTIVE: To report a 7-year experience of presymptomatic testing in persons at risk for Huntington disease (HD) and to compare their characteristics and outcomes with those of persons at risk for a less disabling condition, autosomal dominant cerebellar ataxias (ADCA). METHODS: The authors collected data on presymptomatic testing for HD (n = 712) and ADCA (n = 46) in 10 French centers. RESULTS: The characteristics of applicants were similar in HD and ADCA, revealing a predominance of women, a low rate of completing the presymptomatic testing program, and a high rate of follow-up. The frequency of serious events was low (2% for HD, 5% for ADCA), but such events were also found after favorable results. Family planning was a more frequent reason for seeking presymptomatic testing in ADCA than in HD. Prenatal diagnosis was performed in only half of the pregnancies in HD carriers (n = 35) but in all of those in ADCA carriers (n = 4). CONCLUSION: Counseling in multistep and multidisciplinary teams is important not only for presymptomatic testing in HD but also for less disabling diseases.     

Riluzole in Huntington's disease (HD): an open label study with one year follow up

In an open label study, we administered riluzole (50 mg twice a day) to nine patients with genetically confirmed Huntington's disease (HD) (clinical stages 1–3; mean age 46.4 (SD 9.3) years; mean disease duration 8 (SD 3.3) years). The study was designed to evaluate (1) safety and tolerability of riluzole and (2) effects of riluzole on motor impairment, functional disability, cognitive impairment, and behavioral abnormalities using the Unified HD Rating Scale. Patients were evaluated at baseline and after three and twelve months of riluzole therapy. Laboratory tests (hematology and liver enzymes) were repeated monthly. All adverse experiences, reported spontaneously or observed directly by the investigator, were recorded. Riluzole was well tolerated. No increase of serum liver enzymes was seen throughout the study in all but one patient showing a mild elevation. At three months, mean total motor scale (TMS), mean TMS chorea subscore, and mean total functional capacity scale were significantly improved compared with baseline. At twelve months, however, this beneficial effect on motor status and overall function was not sustained. In contrast, severity and frequency of behavioral dysfunction as well as psychomotor speed assessed by the symbol digit modalities test were improved compared with baseline. Our data suggest that there are transient antichoreatic effects and more sustained effects of riluzole on psychomotor speed and behavior in patients with HD. A double-blind, placebo-controlled trial appears highly warranted to establish definitely the symptomatic versus neuroprotective actions of riluzole in HD. Received: 2 February 2001, Received in revised form: 2 April 2001, Accepted: 9 April 2001     

Hirayama disease with juvenile myoclonic epilepsy: A case report

Hirayama disease (HD) is rare, but benign anterior horn cell disease, predominantly affecting young men. One of the symptoms, besides weakness, is abnormal movement in the hand. Juvenile myoclonic epilepsy (JME) is one of the most common types of generalized epilepsies and can be recognized by a myoclonic jerk and electroencephalography (EEG) features. We report the case of a 19-year-old male who had HD, with unilateral abnormal movement in the hand, which was diagnosed as JME. We should consider performing an EEG in patients with HD, who present with atypical hand movements, in order to differentiate it from seizure.     

Huntington's disease as caused by 34 CAG repeats

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by an abnormal expansion of a polymorphic stretch of CAG repeats in the coding 5′ part of the HD gene on chromosome 4p. Expansions of CAG blocks beyond 35 repeats are associated with the clinical presentation of HD. There is an intermediate range of rare alleles between 27 and 35 CAG repeats with a higher risk for further expansion in subsequent generations. Here, we report a 75‐year‐old male with clinical features of HD and 34 CAG repeat units. © 2008 Movement Disorder Society     

Genetic association of Huntington's disease and restless legs syndrome? A family report

We report on a family with comorbidity of Huntington's disease (HD) and idiopathic restless legs syndrome (RLS). All family members investigated and affected by RLS are also affected by HD, but not vice versa. The association of HD and RLS is discussed with respect to dopaminergic dysfunction.     

Autopsy-proven Huntington's disease with 29 trinucleotide repeats.

Huntington's disease (HD) is a neurodegenerative disorder associated with expansion of CAG trinucleotide repeats in the huntingtin gene. A minimum of 36 CAG repeats is usually reported in patients with clinical features of HD; 30 to 35 repeats represent an intermediate range. Here we report a 65-year-old male with autopsy-proven HD and 29 CAG repeats.     

Positron emission tomography after fetal transplantation in Huntington's disease

Huntington's disease (HD) is a progressive disorder with no known cure. We report two-year postoperative positron emission tomography (PET) data from 7 HD patients who underwent intrastriatal fetal transplantation. Patients showed widespread reductions in glucose uptake with no significant change over 2 years. Dopamine receptor binding was significantly reduced in HD striatum. D1 binding did not change significantly following transplantation, but there was a significant loss of D2 binding. These findings may reflect loss of graft viability and/or disease progression. There was no significant relationship between changes in PET and clinical function. In summary, there was no benefit from transplantation.     

Distribution of inclusions in neuronal nuclei and dystrophic neurites in Huntington disease brain

Recently, an N-terminal fragment of huntingtin was localized to neuronal intranuclear inclusions (NII), presumed to cause cellular dysfunction, and to inclusions in dystrophic neurites (IDN) in the neostriatum and neocortex of Huntington disease (HD) patients. In the present immunohistochemical study of autopsy brain of 2 juvenile-onset HD patients, 5 HD patients with adult-onset, and 5 controls, NII and IDN as stained with both N-terminal antiserum to huntingtin and ubiquitin antiserum were detected in the HD neostriatum, neocortex, and allocortex, but not in the HD pallidum, cerebellum, and substantia nigra nor in control brain. The frequency of NII in the HD neocortex was highest in the juvenile patients. Within the allocortex, NII and IDN were found in the entorhinal region, subiculum, and pyramidal cell layer of Ammon's horn. N-terminal huntingtin antiserum also labeled intranuclear granular structures adjacent to the neuronal nuclear membrane in 5 HD patients, one control with idiopathic epilepsy, and one with Alzheimer disease. Our results show that NII formation in HD involves the allocortex in addition to the neostriatum and neocortex. The development of NII in the neocortex and allocortex in HD brain might contribute to the emergence of the cognitive and behavioral symptoms of the disease.     

Comparison of mid-age-onset and late-onset Huntington’s disease in Finnish patients

The phenotype of juvenile Huntington’s disease (HD) differs clearly from that of adult-onset HD, but information about differences between mid-age-onset HD and late-onset HD (LOHD) is scarce. A national cohort of 206 patients with adult-onset HD was identified using national registries and patient records. LOHD was defined as age ≥60 years at HD diagnosis. Genetic disease burden was assessed using CAG age product (CAP) score. LOHD comprised 25% of the adult-onset HD cohort giving a point prevalence of 2.38/100,000 in the Finnish population at least 60 years of age. The proportion of LOHD out of new HD diagnoses increased from 21% in 1991–2000 to 33% in 2001–2010. At the time of diagnosis, patients with LOHD had 10.4 units (95% CI 4.8–15.9; p = 0.0003) higher CAP scores, more severe motor impairment and slightly more severe functional impairment than that in patients with mid-age-onset HD. There was no difference in the rate of disease progression or survival between LOHD and mid-age-onset patients. The lifespans of deceased patients were shorter in mid-age-onset HD (p < 0.001) and LOHD (p = 0.002) than their life expectancies. Causes of death differed between the two patient groups (p = 0.025). LOHD comprises a quarter of Finnish HD patients and the proportion appears to be increasing. Our results did not reveal differences in the phenotype between mid-age-onset HD and LOHD, but prospective studies are needed.     

Monozygotic twins discordant for Huntington disease after 7 years

BACKGROUND: Huntington disease (HD) has only rarely been identified in identical twins. All described twins have had disease onset within 1 year of each other, suggesting that disease onset is determined solely by genetic influences. OBJECTIVE: To describe a unique set of monozygotic twins in whom clinical HD onset is at least 7 years apart. DESIGN: A 71-year-old woman was diagnosed as having HD based on medical history, physical examination results consistent with HD, and a CAG trinucleotide repeat number of 39 in the HD gene on chromosome 4. Her onset was 6 years earlier. Her genetically confirmed identical twin, carrying the same number of CAG repeats, was neurologically healthy when examined the next year. Only the HD-manifest twin had chronic bronchitis, rheumatoid arthritis, type 2 diabetes mellitus, and chronic anemia. Both had hypertension. CONCLUSIONS: To our knowledge, this is the first report of monozygotic twins discordant for HD by more than 2 years. The onset of HD symptoms in a patient with 39 triplet repeats at least 7 years earlier than her identical twin suggests the possibility that the disease may be initiated (or delayed) by environmental factors. We have identified increased cigarette use and longer exposure to various industrial toxins as potential explanations for the earlier onset in one twin.     

Acute psychosis in a verified Huntington disease gene carrier with subtle motor signs: psychiatric criteria should be considered for the diagnosis

Huntington disease (HD) is an inherited, progressive, autosomal dominant disorder. Some patients develop severe chorea or cognitive symptoms. The genetic defect causes progressive atrophy of the striatum, the cortex and extrastriatal structures (Sheperd GM. Corticostriatal connectivity and its role in disease. Nat Rev Neurosci 2013;14:278-91). The precise timing of clinical diagnosis of HD is poorly characterized and is mainly based on motor symptoms (Huntington, Study and Group. Unified Huntington's Disease Rating Scale: reliability and consistency. Huntington Study Group. Mov Discord 1996:136-42). Patients suffering from HD frequently show cognitive or affective symptoms even before manifesting motor signs. Psychiatric symptoms like depression, apathy, aggression, and disinhibition are common, and suicide rates are over four times higher than in the general population (Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM. Suicide risk in Huntington's disease. J Med Genet 1993;30:293-5). This case report of a female patient with genetically proven HD is of special interest because motor or cognitive impairment were absent whereas she suffered from symptoms of an acute and severe psychosis likely to be symptomatic signs of HD.     

Perspectives towards predictive testing in Huntington disease

OBJECTIVE: Genetic counseling for individuals undergoing presymptomatic testing is lacking in India although testing is easily available. This has an impact on family members of Huntington's disease (HD), an autosomal dominant disease, wherein the age at onset of symptoms varies. AIM: We examine if attitudes differ towards presymptomatic testing for HD amongst HD family members, physicians and laypersons. MATERIALS AND METHODS: A modified questionnaire enquiring about opinions on various personal, family, social and future health care with regards to presymptomatic testing of HD was designed. A physician explained briefly about HD and presymptomatic testing of HD and recorded responses of unaffected family members of HD (n=25) and laypersons (n=50). Medical doctors (n=50) answered the questionnaire based on their knowledge of HD. RESULTS: HD family members, Medical doctors and laypersons were similar in their opinion to undergo the testing. Majority (60%) of HD family members did not wish to communicate test results with their friends when compared to the other two groups. Medical doctors and HD family members were more concerned about certainty of developing disease when the test results are positive. Majority (80%) of Medical doctors and less than half in the other groups felt that their decision to have a child would strongly depend on test results. Large proportion (80%) of HD family members did not wish to report their test results to their employers. CONCLUSIONS: Individuals with knowledge about HD and the test differ in their decision of sharing test results and reproductive choices.     

Intracranial localization revealing Hodgkin's disease

The central nervous system's (CNS) involvement is uncommon in Hodgkin's disease (HD) and usually occurs in patients with relapsing disease many years after the initial diagnosis. An isolated involvement of the CNS is extremely rare and therefore, difficult to diagnosis. We report the case of a 27-year-old woman with seizure and a left cerebrodural mass on the cerebral imaging; secondarily, she developed cervical lymph node swelling; histological examination of the node revealed HD of the nodular sclerosis type. The dural lesion resolved after chemotherapy for HD.     

Genetically confirmed clinical Huntington's disease with no observable cell loss

Huntington's disease (HD) results from neurodegeneration of the neostriatum. The mutation on chromosome 4 is an expansion in a triplet repeat (CAG)(n) located within the IT15 gene. Only six patients have been reported with clinical features of HD in association with limited neuropathology. Of these, only one has had the diagnosis confirmed by genetic (DNA) testing. We describe a patient with the clinical phenotype and genetically confirmed HD but unexpected limited neuropathology. The patient was seen because of aggressive behaviour and memory problems of two years duration. The differential diagnosis included HD although there was no family history. DNA testing was positive for the HD mutation. Clinical follow up three months later confirmed classic features of HD. Progression of the disease was rapid with death three years later. Neuropathology revealed a largely intact neostriatum with bilateral ischaemic damage and cell loss in the external globus pallidus. Such pathology alone could explain the clinical features of HD. This is only the second report of genetically confirmed clinically manifest HD with little evidence of HD neuropathology. There are several unusual features which could not have been predicted by the clinical picture, in particular the progressive course of bilateral ischaemic changes restricted to the external globus pallidus. The potential to miss other HD cases at post-mortem examination, and the implications of this for family members, are discussed.     

Huntington disease in a nonagenarian mistakenly diagnosed as normal pressure hydrocephalus

In the absence of family history or overt chorea, the protean manifestations (cognitive, motor and behavioral) of Huntington disease (HD) may suggest alternative disease processes, particularly in elderly patients. Herein, we report on a nonagenarian with HD who did not manifest overt chorea until 91 years of age and was mistakenly diagnosed with normal pressure hydrocephalus at 89 years of age. The gait abnormalities seen in early HD should be readily distinguished from those of normal pressure hydrocephalus.