Juvenile Huntington's Disease Research Articles

Clinical Manifestation of Juvenile and Pediatric HD Patients: A Retrospective Case Series.

Background: Studies on the clinical manifestation and course of disease in children suffering from Huntington’s disease (HD) are rare. Case reports of juvenile HD (onset ≤ 20 years) describe heterogeneous motoric and non-motoric symptoms, often accompanied with a delay in diagnosis. We aimed to describe this rare group of patients, especially with regard to socio-medical aspects and individual or common treatment strategies. In addition, we differentiated between juvenile and the recently defined pediatric HD population (onset < 18 years). Methods: Out of 2593 individual HD patients treated within the last 25 years in the Huntington Centre, North Rhine-Westphalia (NRW), 32 subjects were analyzed with an early onset younger than 21 years (1.23%, juvenile) and 18 of them younger than 18 years of age (0.69%, pediatric). Results: Beside a high degree of school problems, irritability or aggressive behavior (62.5% of pediatric and 31.2% of juvenile cases), serious problems concerning the social and family background were reported in 25% of the pediatric cohort. This includes an attempted rape and robbery at the age of 12, as problems caused by the affected children, but also alcohol-dependency in a two-year-old induced by a non-HD affected stepfather. A high degree of suicidal attempts and ideations (31.2% in pediatric and 33.3% in juvenile group) was reported, including drinking of solvents, swallowing razor blades or jumping from the fifth floor with following incomplete paraparesis. Beside dopaminergic drugs for treatment of bradykinesia, benzodiazepines and tetrabenazine for treatment of dystonia, cannabinoids, botulinum toxin injection and deep brain stimulation were used for the improvement of movement disorders, clozapine for the treatment of tremor, and dopa-induced hallucinations and zuclopenthixole for the treatment of severe aggressive behavior. Conclusions: Beside abnormalities in behavior from an early age due to HD pathology, children seem to have higher socio-medical problems related to additional burden caused by early affected parents, instable family backgrounds including drug abuse of a parent or multiple changes of partners. Treatment required individualized strategies in many cases.

Diagnosing Juvenile Huntington's Disease: An Explorative Study among Caregivers of Affected Children.

Objective: To investigate the reasons for the diagnostic delay of juvenile Huntington’s disease patients in the Netherlands. Methods: This study uses interpretative phenomenological analysis. Eligible participants were parents and caregivers of juvenile Huntington’s disease patients. Results: Eight parents were interviewed, who consulted up to four health care professionals. The diagnostic process lasted three to ten years. Parents believe that careful listening and follow-up would have improved the diagnostic process. Although they believe an earlier diagnosis would have benefited their child’s wellbeing, they felt they would not have been able to cope with more grief at that time. Conclusion: The delay in diagnosis is caused by the lack of knowledge among health care professionals on the one hand, and the resistance of the parent on the other. For professionals, the advice is to personalize their advice in which a conscious doctor’s delay is acceptable or even useful.

Drug-Resistant Epilepsy in Children with Juvenile Huntington's Disease: A Challenging Case and Brief Review.

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder with a progressive decline in cognitive, motor, and psychological function. Chorea tends to be the most common associated movement disorder, although other variants of several abnormal movements are also seen. Adult-onset HD is the most common subtype. Juvenile Huntington's disease (JHD) accounts for 5%–10% of all HD cases and presents as a rapidly progressive disorder with a multitude of characteristics. We report on a 9-year-old male with JHD who presented with refractory epilepsy. His EEG findings, seizure type, and antiepileptic drug usage are discussed with a brief review of the currently available relevant literature. The currently reported case sheds light on antiepileptic drugs that proved effective in our patient and the importance of screening for JHD when a child presents with seizures that are difficult to control.

Juvenile Huntington's Disease Skin Fibroblasts Respond with Elevated Parkin Level and Increased Proteasome Activity as a Potential Mechanism to Counterbalance the Pathological Consequences of Mutant Huntingtin Protein.

Huntington’s disease (HD) is an inherited neurodegenerative disorder, caused by an abnormal polyglutamine (polyQ) expansion in the huntingtin protein (Htt). Mitochondrial dysfunction and impairment of the ubiquitin-proteasome system (UPS) are hallmarks of HD neurons. The extraneural manifestations of HD are still unclear. We investigated the crosstalk between mitochondria and proteolytic function in skin fibroblasts from juvenile HD patients. We found reduced mitosis, increased cell size, elevated ROS and increased mitochondrial membrane potential in juvenile HD fibroblasts, while cellular viability was maintained. Mitochondrial OXPHOS analysis did not reveal significant differences compared to control. However, the level of mitochondrial fusion and fission proteins was significantly lower and branching in the mitochondria network was reduced. We hypothesized that juvenile HD fibroblasts counterbalance cellular damage and mitochondrial network deficit with altered proteasome activity to promote cell survival. Our data reveal that juvenile HD fibroblasts exhibit higher proteasome activity, which was associated with elevated gene and protein expression of parkin. Moreover, we demonstrate elevated proteasomal degradation of the mitochondrial fusion protein Mfn1 in diseased cells compared to control cells. Our data suggest that juvenile HD fibroblasts respond to mutant polyQ expansion of Htt with enhanced proteasome activity and faster turnover of specific UPS substrates to protect cells.

Developmental origins of cortical hyperexcitability in Huntington's disease: Review and new observations.

Huntington's disease (HD), an inherited neurodegenerative disorder that principally affects striatum and cerebral cortex, is generally thought to have an adult onset. However, a small percentage of cases develop symptoms before 20years of age. This juvenile variant suggests that brain development may be altered in HD. Indeed, recent evidence supports an important role of normal huntingtin during embryonic brain development and mutations in this protein cause cortical abnormalities. Functional studies also demonstrated that the cerebral cortex becomes hyperexcitable with disease progression. In this review, we examine clinical and experimental evidence that cortical development is altered in HD. We also provide preliminary evidence that cortical pyramidal neurons from R6/2 mice, a model of juvenile HD, are hyperexcitable and display dysmorphic processes as early as postnatal day 7. Further, some symptomatic mice present with anatomical abnormalities reminiscent of human focal cortical dysplasia, which could explain the occurrence of epileptic seizures in this genetic mouse model and in children with juvenile HD. Finally, we discuss recent treatments aimed at correcting abnormal brain development.

Assessment of the Performance of a Modified Motor Scale as Applied to Juvenile Onset Huntington's Disease.

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. To identify a motor scale more suitable for JOHD patients. 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. 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 differences = 13%). 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. 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.

Brain structure in juvenile-onset Huntington disease.

ObjectiveTo assess brain morphometry in a sample of patients with juvenile-onset Huntington disease (JOHD) and several mouse models of Huntington disease (HD) that likely represent the human JOHD phenotype.MethodsDespite sharing the mutation in the Huntingtin gene, adult-onset HD characteristically presents as a hyperkinetic motor disorder, while JOHD typically presents as a hypokinetic motor disease. The University of Iowa Kids-JHD program enrolls individuals 5 to 25 years of age who have already received the clinical diagnosis. A total of 19 children with juvenile HD (JHD) (mean CAG = 72) were studied. Patients with JHD were compared to healthy controls (n = 234) using a cross-sectional study design. Volumetric data from structural MRI was compared between groups. In addition, we used the same procedure to evaluate brain morphology of R6/2, zQ175, HdhQ250 HD mice models.ResultsParticipants with JHD had substantially reduced intracranial volumes. After controlling for the small intracranial volume size, the volumes of subcortical regions (caudate, putamen, globus pallidus, and thalamus) and of cortical white matter were significantly decreased in patients with JHD. However, the cerebellum was proportionately enlarged in the JHD sample. The cerebral cortex was largely unaffected. Likewise, HD mice had a lower volume of striatum and a higher volume of cerebellum, mirroring the human MRI results.ConclusionsThe primary pathology of JOHD extends beyond changes in the striatal volume. Brain morphology in both mice and human patients with JHD shows proportional cerebellar enlargement. This pattern of brain changes may explain the unique picture of hypokinetic motor symptoms in JHD, which is not seen in the hyperkinetic chorea-like phenotype of adult-onset HD.

Design and characterization of mutant and wildtype huntingtin proteins produced from a toolkit of scalable eukaryotic expression systems

The gene mutated in individuals with Huntington's disease (HD) encodes the 348-kDa huntingtin (HTT) protein. Pathogenic HD CAG-expansion mutations create a polyglutamine (polyQ) tract at the N terminus of HTT that expands above a critical threshold of ∼35 glutamine residues. The effect of these HD mutations on HTT is not well understood, in part because it is difficult to carry out biochemical, biophysical, and structural studies of this large protein. To facilitate such studies, here we have generated expression constructs for the scalable production of HTT in multiple eukaryotic expression systems. Our set of HTT expression clones comprised both N- and C-terminally FLAG-tagged HTT constructs with polyQ lengths representative of the general population, HD patients, and juvenile HD patients, as well as the more extreme polyQ expansions used in some HD tissue and animal models. Our expression system yielded milligram quantities of pure recombinant HTT protein, including many of the previously mapped post-translational modifications. We characterized both apo and HTT-HTT-associated protein 40 (HAP40) complex samples produced with this HD resource, demonstrating that this toolkit can be used to generate physiologically meaningful HTT complexes. We further demonstrate that these resources can produce sufficient material for protein-intensive experiments, such as small-angle X-ray scattering, providing biochemical insight into full-length HTT protein structure. The work outlined and the tools generated here lay a foundation for further biochemical and structural work on the HTT protein and for studying its functional interactions with other biomolecules.

Effect of Apolipoprotein E Genotypes on Huntington's Disease Phenotypes in a Han Chinese Population.

Huntington's disease (HD) is an autosomal dominant degenerative disease that mainly encompasses movement, cognition, and behavioral symptoms. The apolipoprotein E (APOE) gene is thought to be associated with many neurodegenerative diseases. Here, we enrolled a cohort of 223 unrelated Han Chinese patients with HD and 1241 unrelated healthy controls in Southeastern China and analyzed the correlation between APOE genotypes and HD phenotypes. The results showed that the frequency of the E4 allele (7.1%) in HD patients was statistically less than that in controls (12.0%) (P =0.004). In addition, we divided patients into motor-onset and non-motor-onset groups, and analyzed the relationship with APOE genotypes. The results, however, were negative. Furthermore, the age at onset (AAO), defined as the age at the onset of motor symptoms, was compared in each APOE genotype subgroup and multivariate regression analysis was used to exclude the interference of CAG repeat length on AAO, but no association was found between APOE genotypes and AAO. Finally, we analyzed adult-onset HD to exclude the interference caused by juvenile HD (n = 13), and the results were negative. Therefore, our study suggests that APOE may not be a genetic modifier for HD, especially for adult-onset HD among Chinese of Han ethnicity. To the best of our knowledge, this is the first study of the correlation between APOE genotypes and HD phenotypes in a Han Chinese population.

Identification of Altered Developmental Pathways in Human Juvenile HD iPSC With 71Q and 109Q Using Transcriptome Profiling.

In Huntington disease (HD) subtle symptoms in patients may occur years or even decades prior to diagnosis. HD changes at a molecular level may begin as early as in cells that are non-lineage committed such as stem cells or HD patients induced pluripotent stem cells (iPSCs) offering opportunity to enhance the understanding of the HD pathogenesis. In addition, juvenile HD non-linage committed cells were previously not directly investigated in detail by RNA-seq. In the present manuscript, we define the early HD and juvenile HD transcriptional alterations using 6 human HD iPS cell lines from two patients, one with 71 CAGs and one with 109 CAG repeats. We identified 107 (6 HD lines), 198 (3 HD71Q lines) and 217 (3 HD109Q lines) significantly dysregulated mRNAs in each comparison group. The analyses showed that many of dysregulated transcripts in HD109Q iPSC lines are involved in DNA damage response and apoptosis, such as CCND1, CDKN1A, TP53, BAX, TNFRSF10B, TNFRSF10C, TNFRSF10D, DDB2, PLCB1, PRKCQ, HSH2D, ZMAT3, PLK2, and RPS27L. Most of them were identified as downregulated and their proteins are direct interactors with TP53. HTT probably alters the level of several TP53 interactors influencing apoptosis. This may lead to accumulation of an excessive number of progenitor cells and potential disruption of cell differentiation and production of mature neurons. In addition, HTT effects on cell polarization also demonstrated in the analysis may result in a generation of incorrect progenitors. Bioinformatics analysis of transcripts dysregulated in HD71Q iPSC lines showed that several of them act as transcription regulators during the early multicellular stages of development, such as ZFP57, PIWIL2, HIST1H3C, and HIST1H2BB. Significant upregulation of most of these transcripts may lead to a global increase in expression level of genes involved in pathways critical for embryogenesis and early neural development. In addition, MS analysis revealed altered levels of TP53 and ZFP30 proteins reflecting the functional significance of dysregulated mRNA levels of these proteins which were associated with apoptosis and DNA binding. Our finding very well corresponds to the fact that mutation in the HTT gene may cause precocious neurogenesis and identifies pathways likely disrupted during development.

The prevalence and the burden of pain in patients with Huntington disease: a systematic review and meta-analysis.

It is remarkable that studies focusing on the prevalence and the burden of pain in patients with Huntington disease (HD) are scarce. This may lead to inadequate recognition of pain and hence lack of treatment, eventually affecting the quality of life. The aim of this review is to investigate the prevalence of pain and its burden in HD by performing a systematic literature search. In February 2018, a systematic search was performed in the electronic databases of Pubmed, Embase, Cinahl, Cochrane, and PsycINFO. Studies focusing on patients with juvenile HD were excluded. All other types of study were included without language restrictions. In total, 2234 articles were identified, 15 of which met the inclusion criteria and provided information on 2578 patients with HD. The sample-weighted prevalence of pain was 41.3% (95% confidence interval: 36%-46%). The pain burden, which was measured with the SF-36, is significantly less compared with that in the general population. The sample-weighted mean score on the SF-36 was 84 (95% confidence interval: 81-86), where a score of 100 represents the lowest symptom burden. The results demonstrate that pain could be an important nonmotor symptom in patients with HD, and there are indications that the pain burden could be diminished because of HD. Larger and high-quality prospective cohort and clinical studies are required to confirm these findings. In the meantime, awareness about pain and its burden in patients with HD is warranted in clinical practice.

Biological and clinical manifestations of juvenile Huntington's disease: a retrospective analysis

Huntington's disease is a rare, neurodegenerative disease caused by an expanded CAG repeat mutation in the huntingtin gene. Compared with adult-onset Huntington's disease, juvenile Huntington's disease (onset ≤20 years) is even rarer and has not been studied extensively. We aimed to further characterise juvenile Huntington's disease by examining the effect of CAG repeat size on disease presentation, progression, and survival. We did a retrospective analysis of patients with juvenile Huntington's disease aged 20 years or younger, according to the length of their CAG repeat and who had disabling psychiatric symptoms (with motor symptoms) or motor symptoms alone, and of patients with adult-onset Huntington's disease manifesting aged 30-60 years with 40 or more CAG repeats, from the REGISTRY and ENROLL-HD platforms and from two institutional databases (Lega Italiana Ricerca Huntington Foundation and the Instituto Neurociencias de Buenos Aires and the Sanatorio de la Trinidad Mitre). Patients with psychiatric but no motor symptoms were excluded. We compared symptoms at onset and longitudinally in patients with juvenile Huntington's disease with highly expanded (HE subgroup) or low expansion (LE subgroup) mutations, grouped by hierarchical clustering analysis. We also compared disease progression (longitudinal change in Unified Huntington's Disease Rating Scale-Total Motor Score) and survival of patients with juvenile and adult-onset Huntington's disease. We extracted medical records from 580 patients entered into the studies or databases between June 23, 2004, and March 31, 2018, of whom 36 patients met our definition of juvenile Huntington's disease and 197 for adult-onset Huntington's disease. According to caregiver reports, gait disturbance was more often a first presenting symptom in the HE subgroup (eight [80%] of 10 patients) than in the LE subgroup (seven [27%] of 26 patients; p=0·0071), whereas loss of hand dexterity was more common in the LE subgroup (11 [42%] of 26 patients) than in the HE subgroup (0 [0%] of 10 patients; p=0·0160). Compared with the LE subgroup, development delay (0 [0%] in the LE subgroup vs nine [90%] in the HE subgroup; p<0·0001), severe gait impairment (nine [35%] in the LE subgroup vs nine [90%] in the HE subgroup; p=0·0072), and seizures (three [11%] in the LE subgroup vs eight [80%] in the HE subgroup; p<0·0001) prevailed over time in the HE subgroup. Disease progression was more rapid in juvenile Huntington's disease (n=14) than in adult-onset Huntington's disease (n=52; generalised estimating equation model, p=0·0003). Of 121 deceased patients, median survival was shorter in the juvenile Huntington's disease (n=17) cohort than in adult-onset Huntington's disease (n=104) cohort (hazard ratio 2·18 [95% CI 1·08-4·40]; p=0·002). Patients with HE juvenile Huntington's disease differ clinically from patients with LE juvenile Huntington's disease or adult-onset Huntington's disease, suggesting reclassification of this particularly aggressive form of Huntington's disease might be required. Lega Italiana Ricerca Huntington Foundation and IRCCS Ospedale Casa Sollievo della Sofferenza.

Juvenile Huntington's disease: left behind?

Juvenile Huntington's disease: left behind?

Pallidal deep brain stimulation in juvenile Huntington's disease: local field potential oscillations and clinical data.

Recently, therapeutic attempts to control motor choreatic hyperkinesia of Huntington's disease (HD) by means of pallidal deep brain stimulation (Gp-DBS) were successful. With respect to the clinical effects of Gp-DBS in juvenile hypokinetic-rigid HD (jHD; Westphal variant), only one single-case has been reported up to date. Oscillatory patterns of the Gp in jHD are not known. This work aimed to analyse pallidal local field potential oscillations (LFP) in two patients with jHD treated with Gp-DBS. Safety data and clinical scores up to 12months after DBS-electrode implantation were collected in the framework of a prospective trial (ClinicalTrials.gov; NCT00902889). Intraoperative LFP revealed local alpha and beta oscillations similar to those found in other movement disorders with akinetic rigid and dystonic presentation. Significant motor improvement was not found. There were no treatment-related complications or unresolved long-term adverse events. In spite of similar intraoperative LFP patterns of jHD with those of movement disorders benefitting from DBS, clinical results were not convincing in our patients, so that Gp-DBS in jHD cannot be generally recommended.

Generation of the induced pluripotent stem cell line CSSi006-A (3681) from a patient affected by advanced-stage Juvenile Onset Huntington's Disease

Juvenile Onset Huntington's Disease (JOHD) is a rare variant of HD withage of onset ≤20 years, accounting for 3–10% of all HD patients. The rarity occurrence of JOHD cases, who severely progress towards mental and physical disability with atypical clinical manifestations compared to classical HD, are responsible of general lack of knowledge about this variant. We obtained a fully reprogrammed iPS cell line from fibroblasts of a JOHD patient carrying 65 CAG repeats and age at onset at age 15. At the biopsy time, the patient showed an advanced stage after 10 years of disease.

Generation of induced pluripotent stem cell line, CSSi002-A (2851), from a patient with juvenile Huntington Disease

Huntington Disease (HD) is an autosomal dominant disorder characterized by motor, cognitive and behavioral features caused by a CAG expansion in the HTT gene beyond 35 repeats. The juvenile form (JHD) may begin before the age of 20years and is associated with expanded alleles as long as 60 or more CAG repeats. In this study, induced pluripotent stem cells were generated from skin fibroblasts of a 8-year-old child carrying a large size mutation of 84 CAG repeats in the HTT gene. HD appeared at age 3 with mixed psychiatric (i.e. autistic spectrum disorder) and motor (i.e. dystonia) manifestations.

A survey-based study identifies common but unrecognized symptoms in a large series of juvenile Huntington's disease.

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. A symptom survey was constructed using the online tool Qualtrics and dispersed to JHD caregivers through websites. 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%). 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.

A case report of juvenile Huntington disease

Huntington disease (HD) is a progressive neurodegenerative disorder, characterized by autosomal dominant inheritance, movement disorder, dementia, and behavioural disturbances. It is caused by a mutation in IT15 gene on chromosome 4p16.3, which leads to unstable CAG trinucleotide repeat expansion. The onset of juvenile HD occurs before the 2 nd decade of life and comprises approximately 10% of total HD patients. Juvenile HD differs in symptomatology and is usually transmitted from paternal side with genetic anticipation phenomenon. Magnetic resonance imaging (MRI) of the brain shows specific changes of early affection of caudate nucleus and putamen. Multidisciplinary approach with symptomatic treatment of specific symptoms is the current available management. Gene editing and gene silencing treatment are under trial. Hereby, we introduce a case of an 8-year-old boy, who presented with typical symptoms of juvenile HD, positive family history with genetic anticipation phenomenon and characteristic MRI findings.

Hospitalizations of Children with Huntington's Disease in the United States.

Juvenile Huntington's disease (JHD) is a childhood-onset neurodegenerative disorder. Although it is caused by the same pathologic expansion of CGA repeats as adult-onset Huntington's disease, JHD has distinct clinical features. Most clinical research in HD focuses in the adult-onset disease; therefore, little is known about acute care outcomes for patients with JHD. The Kids' Inpatient Database (KID) was used to examine hospitalizations of children with JHD and to determine the diagnoses and procedures associated with inpatient care for JHD. Regression models were built to examine acute care outcomes, including death, length of stay, and disposition at discharge in patients with JHD compared with patients in the general KID data. The proportion of JHD cases among hospitalized children was 1.23 per 100,000 KID inpatient stays. Seizures/convulsions (58.5%) and psychiatric conditions (26.1%) were the most common primary or secondary diagnoses among JHD patient hospitalizations. The most common procedure was percutaneous endoscopic gastrostomy tube placement (8.6%). Compared with hospitalizations of the general population, hospitalizations of patients with JHD had a lower odds of discharge to home (adjusted odds ratio [AOR], 0.23; 95% confidence interval [CI], 0.14-0.37) and an increased likelihood of death (AOR, 8.03; 95% CI, 2.98-21.60) or discharge to a short-term care facility (AOR, 4.44; 95% CI, 2.59-7.61). A diagnosis of JHD was associated with increased length of stay (7.04 vs. 3.75 days; P < 0.01). Children with JHD have unique acute care patterns. Future studies are needed to determine the extent to which coordinated care may impact inpatient and disposition needs.

A-50Neuropsychiatric and Behavior Complexities of Monitoring Progression of Juvenile Huntington's Disease Symptoms: A Case Study of Two Siblings

A-50Neuropsychiatric and Behavior Complexities of Monitoring Progression of Juvenile Huntington's Disease Symptoms: A Case Study of Two Siblings