Daniel Zielonka

Update on Huntington's disease: Advances in care and emerging therapeutic options

INTRODUCTION Huntingtons disease (HD) is the most common hereditary neurodegenerative disorder. Despite the fact that both the gene and the mutation causing this monogenetic disorder were identified more than 20 years ago, disease-modifying therapies for HD have not yet been established. REVIEW While intense preclinical research and large cohort studies in HD have laid foundations for tangible improvements in understanding HD and caring for HD patients, identifying targets for therapeutic interventions and developing novel therapeutic modalities (new chemical entities and advanced therapies using DNA and RNA molecules as therapeutic agents) continues to be an ongoing process. The authors review recent achievements in HD research and focus on approaches towards disease-modifying therapies, ranging from huntingtin-lowering strategies to improving huntingtin clearance that may be promoted by posttranslational HTT modifications. CONCLUSION The nature and number of upcoming clinical studies/trials in HD is a reason for hope for HD patients and their families.

Skeletal muscle pathology in Huntington's disease

Huntingtons disease (HD) is a hereditary neurodegenerative disorder caused by the expansion of a polyglutamine stretch within the huntingtin protein (HTT). The neurological symptoms, that involve motor, cognitive and psychiatric disturbances, are caused by neurodegeneration that is particularly widespread in the basal ganglia and cereberal cortex. HTT is ubiquitously expressed and in recent years it has become apparent that HD patients experience a wide array of peripheral organ dysfunction including severe metabolic phenotype, weight loss, HD-related cardiomyopathy and skeletal muscle wasting. Although skeletal muscles pathology became a hallmark of HD, the mechanisms underlying muscular atrophy in this disorder are unknown. Skeletal muscles account for approximately 40% of body mass and are highly adaptive to physiological and pathological conditions that may result in muscle hypertrophy (due to increased mechanical load) or atrophy (inactivity, chronic disease states). The atrophy is caused by degeneration of myofibers and their replacement by fibrotic tissue is the major pathological feature in many genetic muscle disorders. Under normal physiological conditions the muscle function is orchestrated by a network of intrinsic hypertrophic and atrophic signals linked to the functional properties of the motor units that are likely to be imbalanced in HD. In this article, we highlight the emerging field of research with particular focus on the recent studies of the skeletal muscle pathology and the identification of new disease-modifying treatments.

The influence of gender on phenotype and disease progression in patients with Huntington's disease

INTRODUCTION Huntingtons disease (HD) is an autosomal dominant neurodegenerative disorder. The aim of this study is to determine whether gender plays a role in the phenotypic expression and progression of HD. METHODS 1267 patients with HD (636 women) from the Registry project of the EHDN were included. A cross-sectional analysis (ANCOVA) controlling for differences in age at onset, disease burden, disease duration, smoking status, alcohol abuse, depression and the number of years of education, was performed to evaluate if there were differences between men and women in UHDRS motor, function and cognitive scores. Additionally, analyses on follow-up data using linear mixed models with the same covariates were performed to test for gender-related differences in progression. RESULTS Baseline features did not differ between genders, with the exception of a higher frequency of past and current depression among women, and a higher number of years of education as well as more frequent alcohol abuse and smoking among men. In the cross-sectional ANCOVA analyses of patients with a mid-age HD onset, women showed worse scores than men in the functional domain (TFC, P = 0.001; UHDRS functional, P = 0.033), UHDRS motor (P = 0.033). The longitudinal analyses showed a faster rate of progression in women in the functional assessment (P = 0.025), the motor assessment (P = 0.032) and the independence scale (P = 0.008). CONCLUSIONS These results suggest a complex gender effect on the phenotypical presentation and the rate of disease progression in HD, with slightly more severe phenotype and faster rate of progression in women in especially the motor and functional domains.

HDAC4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements

For the past decade protein acetylation has been shown to be a crucial post-transcriptional modification involved in the regulation of protein functions. Histone acetyltransferases (HATs) mediate acetylation of histones which results in the nucleosomal relaxation associated with gene expression. The reverse reaction, histone deacetylation, is mediated by histone deacetylases (HDACs) leading to chromatin condensation followed by transcriptional repression. HDACs are divided into distinct classes: I, IIa, IIb, III, and IV, on the basis of size and sequence homology, as well as formation of distinct repressor complexes. Implications of HDACs in many diseases, such as cancer, heart failure, and neurodegeneration, have identified these molecules as unique and attractive therapeutic targets. The emergence of HDAC4 among the members of class IIa family as a major player in synaptic plasticity raises important questions about its functions in the brain. The characterization of HDAC4 specific substrates and molecular partners in the brain will not only provide a better understanding of HDAC4 biological functions but also might help to develop new therapeutic strategies to target numerous malignancies. In this review we highlight and summarize recent achievements in understanding the biological role of HDAC4 in neurodegenerative processes.

Validation of the first quality-of-life measurement for patients with Huntington's disease: The Huntington quality of life instrument

Health-related quality-of-life instruments are critical for assessing disease burdens. Generic tools allow comparison between diseases but do not discriminate between disease severities. Specific tools also tend to be more sensitive. No specific tool is available to assess quality of life in patients with Huntington’s disease (HD). In the context of the European study on HD burden, a specific tool was created: the Huntington Quality of Life Instrument (H-QoL-I). The aim of this study was to optimize the content and validate the H-QoL-I. After a semistructured interview with patients, caregivers and HD specialists, we conducted a patient focus group. A self-reported questionnaire was then developed in French and Italian. A total of 252 patients were recruited to answer the questionnaire. Face, internal and external validities were examined using a variety of methods. The shortened H-QoL-I that resulted from the successive analyses comprises 11 items, which are divided into three dimensions: motor functioning (four items), psychology (four items) and socializing (three items). These three domains were identified as being essential to cover the full domain of the quality of life for patients affected by HD. The H-QoL-I showed an acceptable reliability (Cronbach’s &agr;>0.84). Factor analyses demonstrated satisfactory construct validity. Moreover, the item internal consistency and item discriminant validity criteria were fulfilled. No differential item functioning was detected. External validity supported the scale’s robustness. These data support the validity of the H-QoL-I in patients with HD.

A study of molecular changes relating to energy metabolism and cellular stress in people with Huntington’s disease: looking for biomarkers

Huntington’s disease (HD) is a neurodegenerative disorder characterized by a progressive motor and cognitive decline and the development of psychiatric symptoms. The origin of molecular and biochemical disturbances in HD is a mutation in the HTT gene, which is autosomally dominantly inherited. The altered huntingtin protein is ubiquitously expressed in the CNS, as well as in peripheral tissues. In this study we measured the metabolism changes in gene transcription in blood of HD gene carriers (premanifest and manifest combined) versus 28 healthy controls. The comparison revealed statistically significant Global Pattern Recognition Fold Change (FC) for 6 mRNA transcripts, reflecting an increase of: MAOB (FC = 3.07; p = 0.0005) which encodes an outer mitochondrial membrane-bound enzyme called monoamine oxidase type B; TGM2 (FC = 1.8; p = 0.02) encoding a transglutaminase 2 that mediates cellular stress; SLC2A4 (FC = 1.64; p = 0.02) solute carrier family 2 (facilitated glucose transporter) member 4; branched chain ketoacid dehydrogenase kinase (BCKDK) (FC = 1.34; p = 0.02); decrease of LDHA (FC = −1.16; p = 0.03) lactate dehydrogenase A; and brain-derived neurotrophic factor (BDNF) (FC = −2,11; p = 0.03). These distinguished changes coincided with HD progress. The analyses of gene transcription levels in sub-cohorts confirmed these changes and also revealed 28 statistically significant FCs of gene transcripts involved in ATP production and BCAA metabolism.

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy.

Huntingtons disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of re-synthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings.

A Becker myotonia patient with compound heterozygosity for CLCN1 mutations and Prinzmetal angina pectoris

Becker myotonia is a recessive muscle disease with prevalence of > 1:50,000. It is caused by markedly reduced function of the chloride channel encoded by CLCN1. We describe a Polish patient with severe myotonia, transient weakness, and muscle cramps who only responds to lidocaine. In addition, the patient has Prinzmetal angina pectoris and multiple lipomatosis. He is compound heterozygeous for a novel p.W303X and a frequent p.R894X CLCN1 mutation. CLCN1 exon number variation was excluded by MLPA. His son with latent myotonia was heterozygeous for p.R894X. We discuss the potential relations of the three rare diseases and the inheritance of p.R894X.

F07 A frequency of concomitant disorders in presymptomatic huntington’s disease patients

There is growing evidence that Huntington’s disease (HD) is a multi-system disorder. Although HD is predominantly recognized as a neurodegenerative disease, there is a mounting evidence that peripheral component to its pathology may also contribute to the disease progression. A number of pre-clinical studies in recent years revealed that murine models of HD develop a wide range of peripheral tissue abnormalities including eyes, cardiac and skeletal muscles, even at the pre-symptomatic stage. Hence, the aim of this study was to unravel concomitant disorders in the pre-symptomatic HD subjects. Our study was performed based on two EHDN Study sites in Poznan and Warsaw (Poland) and we collected data about: a frequency of concomitant disorders, age and number of CAG repeats from the REGISTRY and ENROLL-HD programs. In total, we identified 97 presymptomatic individuals using UHDRS as a criterion out of 542 patients between those two EHDN centers. The mean of age for the presymptomatic patients was 32.5 (±SD 8.9) years while the mean of the number of CAG repeats was 42.6 (±SD 3.1). We found that nearly a third of the group (28.9%) did not report any concomitant disorders. However, there was a number of patients that already developed psychiatric diseases (26.8%), predominantly depression was present in 18 cases. Moreover, we found the following comorbid conditions: musculoskeletal disorders and injuries (19.6%), allergies (18.6%), cardiovascular disorders (14.4%), neurological disorders (13.4%), gastrointestinal disorders (9.3%) and thyroid abnormalities (8.2%). A comparative analysis showed that the same comorbidities were observed in the symptomatic and presymptomatic HD subjects, only with a lower frequency in the latter. Our current study revealed for the first time that the peripheral component of HD pathology is already present in the group of presymptomatic HD patients at a similar level to the previously reported study on the group of symptomatic HD patients. The presence of concomitant disorders in over 70% presymptomatic patients might suggest an intrinsic role of mutated HTT across different human organs. These findings need further investigation in clinical settings, however they are in line with a number of preclinical studies that have previously identified a peripheral component in presymptomatic HD mouse models.

How motor, behavioral and cognitive symptoms affect functional abilities in Huntington’s disease?

Conclusions Introduction Results How motor, behavioral and cognitive symptoms affect functional abilities in Huntington’s disease? Daniel Zielonka1, Michał Ren2, Raymund AC Roos3, Giuseppe De Michele4, Jerzy T. Marcinkowski1, Ferdinando Squitieri5, Anna Rita Bentivoglio6, and G. Bernhard Landwehrmeyer7 1–Poznan University of Medical Sciences, Poland, Department of Social Medicine, Poznan, Poland. 2–Adam Mickiewicz University in Poznan, Poland. 3–Leiden University Medical Center (LUMC), Department of Neurology K5, Leiden, Netherlands. 4-Department of Neurosciences, Università Federico II, Napoli, Italy. 5–Huntington and Rare Diseases Unit, IRCCS Casa Sollievo della Sofferenza Research Hospital, San Giovanni Rotondo, Italy. 6–Institute of Neurology U.C.S.C Policlinico “A.Gemelli” Rome, Italy. 7–Universitätsklinik Ulm, Abteilung Neurologie, Ulm, Germany.