The Prevalence of Juvenile Huntington’s Disease: A Review of the Literature and Meta-Analysis

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Juvenile Huntington’s disease (JHD) is usually defined as Huntington’s disease with an onset ≤ 20 years. The proportion of JHD cases reported in studies of Huntington’s disease (HD) varies. A review of the literature found 62 studies that reported the proportion of JHD cases amongst all HD cases. The proportion of JHD cases in these studies ranged from 1% to 15%, and in a meta-analysis the pooled proportion of JHD cases was 4.92% (95% confidence interval of 4.07% to 5.84%). Limiting the analysis to the 25 studies which used multiple methods of ascertainment resulted in a similar pooled proportion of 5.32%, (95% confidence interval 4.18% to 6.60%).

A small difference was observed when the meta-analysis was restricted to studies from countries defined by the World Bank as high income, that used multiple methods of ascertainment, and that were conducted since 1980 (4.81%, 95% confidence interval 3.31% to 6.58%, n=11). This contrasts with the pooled result from three post 1980 studies using multiple methods of ascertainment from South Africa and Venezuela, defined by the World Bank as upper middle income, where the estimated mean proportion was 9.95%, (95% confidence interval 6.37% to 14.22%).

These results, which are expected to be more robust than those from a single study alone, may be helpful in estimating the proportion of JHD cases in a given population.

Key Words: Juvenile Huntington’s disease, prevalence, epidemiology

Huntington’s like conditions in China, A review of published Chinese cases

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Background: Knowledge about HD in China is lacking in the international literature. We have therefore analyzed the Chinese literature to thoroughly explore the clinical characteristics of Huntington disease in China.

Methods: A computer-based online search of China National Knowledge Infrastructure was performed to review case reports concerning HD published between January 1980 and April of 2011, and the clinical characteristics were extracted.

Results: A total of 92 studies involving 279 patients (157 males and 122 females) were collected, 82.0% of which were from provinces of North China. Most of the cases (97.8%) had a family history of HD, and paternal inheritance (65.5%) was higher than maternal inheritance (34.5%). Onset age was 35.8 (± 11.8) years, death occurred with 45.6 (± 13.5) years after a course of 11.6 (± 5.6) years. Involuntary movements were the most frequent reported presentation (found in 52.3%, including 64.4% in the entire body, 19.8% in the upper limbs, and 13.7% in the head and face). Psychiatric symptoms at onset were reported in 16.1%, and cognitive impairment in 1.8%. With disease progression, 99.6% of patients had abnormal movements, 67.9% cognitive impairment, and 35.0% suffered psychiatric symptoms. Of the reported patients, only 22 underwent IT15 gene testing with positive results.

Conclusion: HD is a well-reported entity in Chinese medical literature, however, only a small number of instances have been proven by molecular diagnosis. Most of the features resemble what is known in other countries. The highly predominant motor presentation, and the higher male prevalence as well as the apparent concentration in Northern China may be due to observational bias. There is therefore a need to prospectively examine cohorts of patients with appropriate comprehensive assessment tools including genetic testing.

Current Pharmacological Management in Juvenile Huntington’s Disease

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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.

Aspiration pneumonia and death in Huntington’s disease

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Huntington’s disease (HD) is a progressive neurodegenerative autosomal dominant disease characterized by choreatic and hypokinetic movements, disturbed behaviour, and cognitive decline. Pneumonia is the most common cause of death, followed by cardiovasculair diseases. It has been suggested that choking is the causative underlying factor for pneumonia in HD. As a detailed specification of the type of pneumonia has never been performed, we analyzed the records of our Brain Bank containing 224 cases to determine the exact cause of death and type of pneumonia. The conclusion is that the majority (86.8%) of our HD patients where the cause of death could be identified died from aspiration pneumonia.

Seven-year clinical follow-up of premanifest carriers of Huntington’s disease

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Detecting subtle clinical abnormalities in the ‘premanifest’ phase of Huntington’s disease (HD) is of importance in the development of instruments to monitor early therapeutic intervention trials. The current study examined changes in motor function, cognition and behaviour over a period of seven years in premanifest carriers of the HD gene mutation. Twenty-nine carriers without unequivocal motor signs of HD and 43 non-carrier controls were prospectively examined four times. The assessments consisted of the Unified Huntington’s Disease Rating Scale (UHDRS) and an extensive neuropsychological test battery addressing global cognitive function, memory, language and executive function. Rate of Change (RoC) analysis was performed to measure longitudinal differences between carriers and non-carriers. Carriers performed consistently worse on executive function (Symbol Digit Modalities Test (SDMT), Stroop, Trail Making Test (TMT) and WAIS-R arithmetic). Over the years, carriers showed a decline in memory and concentration function (Wechsler Memory Scale (WMS)) and in motor function (UHDRS motor scale). Changes over time could be particularly ascribed to carriers converting to manifest HD. These results demonstrate that standardized motor assessments and objective memory and concentration tasks are sensitive to change over a period of 7 years, specifically in carriers converting to manifest HD. Executive tasks also showed subtle cognitive abnormalities in premanifest HD, but a decline over time could not be demonstrated.

No evidence of impaired gastric emptying in early Huntington‘s Disease

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Background: Several factors, such as dysphagia, an increased motor activity, increased metabolic rate and a hypermetabolic state have been discussed as contributing to weight loss even at the early stages of Huntington’s Disease (HD). Aim of this pilot study was to investigate gastric emptying as a possible reason for weight loss in HD.

Methods: 11 HD participants at early stages of the disease and matched controls were investigated by using the well-established and non-invasive 13C-octanoate breath test. The “Gastroparesis Cardinal Symptom Index” and the “Short-Form Leeds Dyspepsia Questionnaire” were used for clinical evaluation of gastroparesis or dyspepsia.

Results: When compared to standard values ​​given in literature and controls all HD patients had normal breath test results. There was no evidence of gastroparesis or dyspepsia. There was a correlation of breath test results with the cognitive and functional performance of HD participants.

Conclusion: According to our data, there is no evidence of impaired gastric emptying in early HD. We can not exclude that gastric emptying contributes to weight loss at more advanced stages of the disease.

Corresponding author: PD Dr. med. Carsten Saft, Department of Neurology, Huntington-Center NRW, St. Josef Hospital, Gudrunstrasse 56, 44791 Bochum, Germany, E-mail: carsten.saft@ruhr-uni-bochum.de

§ Carsten Saft and Jürgen Andrich contributed equally to this work

An International Survey-based Algorithm for the Pharmacologic Treatment of Irritability in Huntington’s Disease

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It is generally believed that treatments are available to manage irritability in Huntington’s disease (HD). However, lack of an evidence base prevents the establishment of treatment guidelines for this symptom. The research literature fails to address behavioral intervention strategies, drug selection, drug dosing, management of inadequate response to a single drug, or preferred drugs when additional behavioral symptoms comorbid to irritability are present. In an effort to inform clinical decision-making we surveyed an international group of experts to address these points. The experts consistently endorsed an antipsychotic drug (APD) as first choice for treatment of urgent and aggressive irritability behaviors. However, there was variation in practice patterns for treating less severe symptoms. Serotonin reuptake inhibitors (SSRIs) were first choice drug treatments by most respondents across all geographic regions. However, APDs were also endorsed as first choice for mild or moderate irritability, more frequently in Europe than in North America and Australia. Antiepileptic mood stabilizers (AEDs) were used by fewer respondents as first choice drug. Perceived efficacy for control of mild or moderate irritability was judged somewhat higher for APDs than SSRIs or AEDs. Benzodiazepines were not used as monotherapy, but frequently as an adjunctive drug in the setting of comorbid anxiety. Though many cited lack of experience with mirtazapine, others familiar with its use in HD chose it as an alternative monotherapy, or as adjunctive therapy if insomnia was a comorbid factor. This report presents survey results, reviews available irritability studies, and lastly proposes an algorithm for the treatment of irritability in HD derived from expert preferences obtained through this survey.

An International Survey-based Algorithm for the Pharmacologic Treatment of Chorea in Huntington’s Disease

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It is generally believed that treatments are available to manage chorea in Huntington’s disease (HD). However, lack of evidence prevents the establishment of treatment guidelines. The HD chorea research literature fails to address the indications for drug treatment, drug selection, drug dosing and side effect profiles, management of inadequate response to a single drug, and preferred drug when behavioral symptoms comorbid to chorea are present. Because there is lack of an evidence base to inform clinical decision-making, we surveyed an international group of experts to address these points. Survey results showed that patient stigma, physical injury, gait instability, work interference, and disturbed sleep were indications for a drug treatment trial. However, the experts did not agree on first choice of chorea drug, with the majority of experts in Europe favoring an antipsychotic drug (APD), and a near equal split in first choice between an APD and tetrabenazine (TBZ) among experts from North America and Australia. All experts chose an APD when comorbid psychotic or aggressive behaviors were present, or when active depression prevented the use of TBZ. However, there was agreement from all geographic regions that both APDs and TBZ were acceptable as monotherapy in other situations. Perceived efficacy and side effect profiles were similar for APDs and TBZ, except for depression as a significant side effect of TBZ. Experts used a combination of an APD and TBZ when treatment required both drugs for control of chorea and a concurrent comorbid symptom, or when severe chorea was inadequately controlled by either drug alone. The benzodiazepines (BZDs) were judged ineffective as monotherapy but useful as adjunctive therapy, particularly when chorea was exacerbated by anxiety. There was broad disagreement about the use of amantadine for chorea. Experts who had used amantadine described its benefit as small and transient. In addition to survey results, this report reviews available chorea studies, and lastly presents an algorithm for the treatment of chorea in HD which is based on expert preferences obtained through this international survey.

An International Survey-based Algorithm for the Pharmacologic Treatment of Obsessive-Compulsive Behaviors in Huntington’s Disease

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It is generally believed that treatments are available to manage obsessive-compulsive behaviors (OCB’s) in Huntington’s disease (HD). However, lack of an evidence base prevents guideline development. The research literature fails to address the indications for behavioral interventions, drug selection, drug dosing, management of inadequate response to a single drug, and preferred drugs when additional behavioral symptoms comorbid to OCBs are present. In an effort to inform clinical decision-making, we surveyed an international group of experts to address these points. Survey results showed that experts utilized behavioral therapy only for patients with mild cognitive impairment. There was expert agreement that a selective serotonin reuptake inhibitor (SSRI) was the first choice drug, although clomipramine (CMI) was cited as a monotherapy choice by the smaller number of experts familiar with its use. Perceived efficacy for control of OCBs was similar for both SSRIs and CMI. Though less favored choices overall, antipsychotics (APDs) and antiepileptic mood stabilizers (AEDs) were most often used as augmentation strategies. In addition to survey results, this report reviews available studies, and lastly presents an algorithm for the treatment of OCBs in HD based on practice-based preferences obtained from this survey.

Self Reports of Day-to-Day Function in a Small Cohort of People with Prodromal and Early HD

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Day-to-day functioning is a component of health-related quality of life and is an important end point for therapies to treat Huntington Disease (HD). Specific areas of day-to-day function changes have not been reported for prodromal or very early stages of HD. An exploratory self-report telephone interview was conducted with sixteen people with prodromal HD or early HD who met criteria designed to capture research participants most near to motor diagnosis. All completed semi-structured interviews on function in nine aspects of day-to-day life. Out of 16, 14 reported changes in at least one area. All day-to-day function areas were endorsed by at least one participant with driving being the most common area endorsed by 11/16. Changes in ability to perform some day-to-day tasks are experienced by people who are close to the time of clinical diagnosis for HD. Functional ability is likely to be an important component of outcome assessments of clinical trials and in ongoing clinical management.

Music perception and movement deterioration in Huntington’s disease

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Background: There is increasing evidence for functional interactions of the auditory and the motor system in music perception. Based on that we hypothesized that altered music perception in patients with a movement disorder, here Huntington’s disease (HD), compared to controls should be present. Additionally, there should be also a relation between areas associated with the assessment of musical rhythms and measures of movement deterioration in patients.

Methods: Manifest (HD) and premanifest HD (pHD), as well as healthy controls underwent an examination with auditory functional MRI (fMRI) with presentation of music and syllables as stimuli. Additionally, motor performance was assessed in tasks with different complexity and related to fMRI-data.

Results: There was a significant interaction of type of stimuli (music, syllables) and group (HD, phD, controls). During music processing when compared to blocks with syllables only, HDs revealed hyperactivations, especially in cerebellar structures,. In contrast, these structures were stronger activated during syllable presentation in pHD´s and controls, when compared to HD and music processing. Increased cerebellar activations during music processing in HDs were related to more severe voluntary and involuntary movement dysfunction. No correlations were observed with activations after syllable presentation. Generally, no relations were found in pHDs.

Conclusion: The results suggest modulation of auditory music processing in a movement disorder, which seems to relate to severity of movement deterioration.

Age-at-onset in Huntington disease

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Background: In Huntington disease, the accurate determination of age-at-onset is critical to identify modifiers and therapies that aim to delay it.

Methods: Retrospective data from the European Huntington’s Disease Network’s REGISTRY. Data (age, gender, CAG repeat length, parent affected, and Unified Huntington’s Disease Rating Scale motor score, total functional capacity) from at least three visits in 423 REGISTRY participants were included. Data based extrapolations of individual age-at-onset using generalized linear mixed models based on individual slopes of motor score or total functional capacity, and predictions using the Langbehn, or Ranen formula, were compared with clinicians’ estimates.

Results: Concordance was best for the calculated onset using the REGISTRY UHDRS longitudinal motor scores. For total functional capacity, the investigator’s estimate was 4 years before the data derived age-at-onset. The concordance of predictions of probability of age-at-onset was ±20 years (difference in 25%tile).

Conclusions: Estimating or predicting age-at-onset in Huntington disease may be inaccurate. It can be useful to 1) add in the manifest population motor score regression derived age-at-onset as additional motor onset and 2) add total functional capacity regression derived age-at-onset for the onset of functional impact of Huntington disease when patients are in mid- to late-stage.