The Application of Goal Attainment Scaling in Cervical Dystonia - An Exploratory Observational Pilot Study.

BACKGROUND: Due to its heterogeneous manifestation an individualized approach to reach therapeutic goals in cervical dystonia (CD) is advantageous. OBJECTIVES: The aim of the current study was to adapt goal attainment scaling (GAS) to drive the management of CD. METHODS: 38 patients with CD, regularly treated with botulinum neurotoxin (BoNT), were involved in the current exploratory observational pilot study. GAS, including domains of motor, pain, disability, and psychiatric features, was applied to set up individualized goals with the calculation of initial GAS T-scores. Following at least 4 BoNT injection cycles, patients were reassessed whether they reached the pre-set goals. RESULTS: The initial GAS T-scores (median: 36.9, range: 22.8-40) significantly improved (P < 0.001) to the end of the study (the median of final GAS T-scores: 50, range: 25.5-63.6). CONCLUSIONS: The applicability of GAS in CD patients was confirmed, but further large-scale studies are needed refining this innovative approach.

Genetic Screening of a Hungarian Cohort with Focal Dystonia Identified Several Novel Putative Pathogenic Gene Variants.

Dystonia is a rare movement disorder which is characterized by sustained or intermittent muscle contractions causing abnormal and often repetitive movements, postures, or both. The two most common forms of adult-onset focal dystonia are cervical dystonia (CD) and benign essential blepharospasm (BSP). A total of 121 patients (CD, 74; BSP, 47) were included in the study. The average age of the patients was 64 years. For the next-generation sequencing (NGS) approach, 30 genes were selected on the basis of a thorough search of the scientific literature. Assessment of 30 CD- and BSP-associated genes from 121 patients revealed a total of 209 different heterozygous variants in 24 genes. Established clinical and genetic validity was determined for nine heterozygous variations (three likely pathogenic and six variants of uncertain significance). Detailed genetic examination is an important part of the work-up for focal dystonia forms. To our knowledge, our investigation is the first such study to be carried out in the Middle-European region.

Clinical features of cervical dystonia patients classified by the COL-CAP concept and treated with ultrasound-guided botulinum neurotoxin.

Background and purpose:

Cervical dys­tonia (CD) is the most common form of focal dystonias, where the identification of the involved muscles, the determination of optimal botulinum neurotoxin A (BoNT-A) dose per muscle injection, and precise tar­ge­ting may be challenging. The aim of the current study is to compare local centre data with international data, enabling the iden­tification of population and me­tho­do­­lo­gical factors behind the differences, there­by further improvement of the care of Hun­ga­rian patients with CD.

The data of all consecutive CD patients, who were injected with BoNT-A at the botulinum neurotoxin outpatient clinic at the Department of Neurology, University of Szeged between 11 August and 21 Sep­tember 2021, were retrospectively col­lected and analysed in a cross-sectional manner. The frequency of the involved muscles, determined by the application of the collum-caput (COL-CAP) concept, and the parameters for the BoNT-A formulations, injected via ultrasound (US)-guidance, were calculated and compared with available international data.

In the current study, 58 patients (19 males and 39 females) were involved with mean age of 58.4 (± SD 13.6, range 24-81) years. The most common subtype was torticaput (29.3%). Tremor affected 24.1% of patients. The most injected muscles were trapezius (56.9% of all cases), followed by the levator scapulae (51.7%), splenius capitis (48.3%), sternocleidomastoid (32.8%), and semispinalis capitis (22.4%). The injected mean doses per patient were 117 ± SD 38.5 (range: 50-180) units for onaBoNT-A, 118 ± SD 29.8 (range: 80-180) units for incoBoNT-A, and 405 ± SD 162 (range: 100-750 units) for aboBoNT-A.

Although there were several similarities between the results of the current and the multicentre studies, all were carried out using the COL-CAP concept and US-guided BoNT-A injections, authors should pay attention to better distinction of torti-forms and the more frequent injection of especially the obliquus capitis inferior, mainly in cases with no-no tremor.

Genetic epidemiological characteristics of a Hungarian subpopulation of patients with Huntington's disease.

BACKGROUND: Recent advances in therapeutic options may prevent deterioration related to Huntington's disease (HD), even at the pre-symptomatic stage. Be that as it may, a well-characterized patient population is essential for screening and monitoring outcome. Accordingly, the aim of this study was to describe the characteristics of a Hungarian subpopulation of HD patients and mutation carriers diagnosed at the University of Szeged. METHODS: We conducted a search for International Classification of Diseases (ICD) code G10H0 in the local medical database for the period of 1 January 1998 to 31 December 2018. RESULTS: We identified 90 HD cases (male: 45, female: 45) and 34 asymptomatic carriers (male: 15, female: 19). The median age of onset was 45 years (range: 16-79). There were 3 cases of juvenile onset (3.3%), and 7 of late disease onset (7.8%). The median repeat length was 43 (range: 36-70) for the pathological and 19 for the non-pathological alleles (range: 9-35). 17.5% of the pathological alleles were in the decreased penetrance range, while 7% of non-pathological alleles were intermediate. CONCLUSIONS: The genetic and clinical features of the population examined in the present study were in line with the previous Hungarian study, as well as with international literature. The exceptions were the higher ratio of reduced penetrance and intermediate alleles.

Increased glucose metabolism and ATP level in brain tissue of Huntington's disease transgenic mice.

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by multifarious dysfunctional alterations including mitochondrial impairment. In the present study, the formation of inclusions caused by the mutation of huntingtin protein and its relationship with changes in energy metabolism and with pathological alterations were investigated both in transgenic and 3-nitropropionic acid-treated mouse models for HD. The HD and normal mice were characterized clinically; the affected brain regions were identified by immunohistochemistry and used for biochemical analysis of the ATP-producing systems in the cytosolic and the mitochondrial compartments. In both HD models, the activities of some glycolytic enzymes were somewhat higher. By contrast, the activity of glyceraldehyde-3-phosphate dehydrogenase was much lower in the affected region of the brain compared to that of the control. Paradoxically, at the system level, glucose conversion into lactate was enhanced in cytosolic extracts from the HD brain tissue, and the level of ATP was higher in the tissue itself. The paradox could be resolved by taking all the observed changes in glycolytic enzymes into account, ensuing an experiment-based detailed mathematical model of the glycolytic pathway. The mathematical modelling using the experimentally determined kinetic parameters of the individual enzymes and the well-established rate equations predicted the measured flux and concentrations in the case of the control. The same mathematical model with the experimentally determined altered V(max) values of the enzymes did account for an increase of glycolytic flux in the HD sample, although the extent of the increase was not predicted quantitatively. This suggested a somewhat altered regulation of this major metabolic pathway in HD tissue. We then used the mathematical model to develop a hypothesis for a new regulatory interaction that might account for the observed changes; in HD, glyceraldehyde-3-phosphate dehydrogenase may be in closer proximity (perhaps because of the binding of glyceraldehyde-3-phosphate dehydrogenase to huntingtin) with aldolase and engage in channelling for glyceraldehyde-3-phosphate. By contrast to most of the speculation in the literature, our results suggest that the neuronal damage in HD tissue may be associated with increased energy metabolism at the tissue level leading to modified levels of various intermediary metabolites with pathological consequences.

Animal models of Huntington's disease.

Huntington's disease is an autosomal dominantly inherited progressive neurodegenerative disorder. The main symptoms are choreiform, involuntary movements, personality changes and dementia. Huntington's disease is a member of a group of diseases caused by CAG repeat expansions. One research aim is to determine the earliest molecular changes associated with Huntington's disease. There is no possibility for this in humans, but various early changes have been identified in an animal model of Huntington's disease. They are constructed by excitotoxin causing striatal lesion, or mitochondrial toxins inducing energy impairment, or by generating transgenic mice.

Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is caused by an expansion of exonic CAG triplet repeats in the gene encoding the huntingtin protein (Htt), however, the means by which neurodegeneration occurs remains obscure. There is evidence that mutant Htt interacts with transcription factors leading to reduced histone acetylation. We report that administration of the histone deacetylase inhibitor phenylbutyrate after onset of symptoms in a transgenic mouse model of HD significantly extends survival and attenuates both gross brain and neuronal atrophy. Administration of phenylbutyrate increased brain histone acetylation and decreased histone methylation levels as assessed by both immunocytochemistry and Western blots. Phenylbutyrate increased mRNA for components of the ubiquitin-proteosomal pathway and down-regulated caspases implicated in apoptotic cell death, and active caspase 3 immunoreactivity in the striatum. These results show that administration of phenylbutyrate, at doses that are well tolerated in man, exerts significant neuroprotective effects in a transgenic mouse model of HD, and therefore represents a very promising therapeutic approach for HD.

Neuroprotective effects of phenylbutyrate against MPTP neurotoxicity.

There is increasing evidence that administration of histone deacetylase (HDAC) inhibitors can exert neuroprotective effects by a variety of mechanisms. Phenylbutyrate is a well-known HDAC inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. These include several antioxidant enzymes, chaperones, and genes involved in cell survival. We examined whether administration of phenylbutyrate could exert significant neuroprotective effects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which has been used to model Parkinson's disease. Administration of phenylbutyrate significantly attenuated MPTP-induced depletion of striatal dopamine and loss of tyrosine hydroxylase-positive neurons in the substantia nigra. These findings provide further evidence that administration of phenylbutyrate may be a useful approach for the treatment of neurodegenerative diseases.