Clinical characteristics and possible drug targets in autosomal dominant spinocerebellar ataxias

The autosomal dominant spinocerebellar ataxias (SCAs) belong to a large and expanding group of neurodegenerative disorders. SCAs comprise more than 40 subtypes characterized by progressive ataxia as a common feature. The most prevalent diseases among SCAs are caused by CAG repeat expansions in the coding-region of the causative gene resulting in polyglutamine (polyQ) tract formation in the encoded protein. Unfortunately, there is no approved therapy to treat cerebellar motor dysfunction in SCA patients. In recent years, several studies have been conducted to recognize the clinical and pathophysiological aspects of the polyQ SCAs more accurately. This scientific progress has provided new opportunities to develop promising gene therapies, including RNA interference and antisense oligonucleotides.The aim of the current work is to give a brief summary of the clinical features of SCAs and to review the cardinal points of pathomechanisms of the most common polyQ SCAs. In addition, we review the last few years promising gene suppression therapies of the most frequent polyQ SCAs in animal models, on the basis of which human trials may be initiated in the near future

The genetic background of Parkinson's disease and novel therapeutic targets

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. The median age of disease onset is around 60 years. From a genetic point of view, PD is basically considered a sporadic, idiopathic disease, however, hereditary components can be detected in 5-10% of patients. Expanding data are available regarding the targeted molecular therapy of the disease.The aim of this current review article is to provide brief clinical and molecular insight into three important genetic forms (LRRK2, SNCA, GBA) of hereditary PD subtypes and to present the human clinical trials in relation to these forms of the disease.These small hereditary subgroups are crucially important in drug development, because the general trend is that clinical trials that treat PD patients as a large group, without any separation, do not meet expectations. As a result, no long term conclusions can currently be drawn regarding the effectiveness of the molecules tested in these phase 1 and 2 studies. Further precise studies are needed in the near future

Clinical characteristics and possible drug targets in autosomal dominant spinocerebellar ataxias

The autosomal dominant spinocerebellar ataxias (SCAs) belong to a large and expanding group of neurodegenerative disorders. SCAs comprise more than 40 subtypes characterized by progressive ataxia as a common feature. The most prevalent diseases among SCAs are caused by CAG repeat expansions in the coding-region of the causative gene resulting in polyglutamine (polyQ) tract formation in the encoded protein. Unfortunately, there is no approved therapy to treat cerebellar motor dysfunction in SCA patients. In recent years, several studies have been conducted to recognize the clinical and pathophysiological aspects of the polyQ SCAs more accurately. This scientific progress has provided new opportunities to develop promising gene therapies, including RNA interference and antisense oligonucleotides.The aim of the current work is to give a brief summary of the clinical features of SCAs and to review the cardinal points of pathomechanisms of the most common polyQ SCAs. In addition, we review the last few years promising gene suppression therapies of the most frequent polyQ SCAs in animal models, on the basis of which human trials may be initiated in the near future

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

Háttér és cél – A cervicalis dystonia (CD) a leggyakoribb fokális dystonia, amelynek esetén az érintett izmok azonosítása, az izmonkénti botulinum neurotoxin A- (BoNT-A-) dózis meghatározása és a precíz injekció kivitelezése egyaránt kihívást jelenthet. A jelen tanulmány célja, hogy a lokáliscentrumadatokat a nemzetközi adatokkal összehasonlítva azonosítani tudjuk a különbségek hátterében álló populációbeli és metodikai faktorokat, ezáltal javítani tudjuk a CD-ben szenvedő magyar betegek ellátását. Módszerek – Elvégeztük az összes olyan CD-s beteg retrospektív keresztmetszeti adatfeldolgozását, aki a Szegedi Tudományegyetem Neurológiai Klinikáján 2021. augusztus 11. és szeptember 21. között BoNT-A-oltásban részesült. A collum-caput (COL-CAP) módszerrel meghatározott érintett izmok gyakorisága és az ultrahang- (UH-) vezérelt módon alkalmazott BoNT-A-oltások paraméterei meghatározásra kerültek, majd összehasonlítottuk ezeket a nemzetközi adatokkal. Eredmények – Ötvennyolc beteget (19 férfi és 39 nő) vontunk be a tanulmányba, átlagéletkoruk 58,4 (± SD 13,6, terjedelem 24–81) év volt. A CD leggyakoribb fő altípusa a torticaput (29,3%) volt. Tremor a betegek 24,1%-át érintette. A leggyakrabban oltott izmok a trapezius (az összes eset 56,9%-a), a levator scapulae (51,7%), a splenius capitis (48,3%), a sternocleidomastoidus (32,8%) és a semispinalis capitis (22,4%) voltak. A betegenként átlagosan injektált dózis onaBoNT-A esetén 117 ± SD 38,5 egység (terjedelem: 50–180) volt, incoBoNT-A esetén 118 ± SD 29,8 egység (terjedelem: 80–180) és aboBoNT-A esetén 405 ± SD 162 egység (terjedelem: 100–750). Következtetés – Bár a jelenlegi és a multicentrikus tanulmány (mindkettő a COL-CAP koncepciót és UH-vezérelt oltást használt) eredményei között számos hasonlóság adódott, a szerzőknek a jövőben kiemelt figyelmet kell fordítaniuk a torti-formák minél precízebb differenciálására, valamint leginkább az obliquus capitis inferior oltásának gyakoribb alkalmazására, főként a no-no tremorral társuló esetekben

Humán szérum tokoferol- és ubikinonszintek bioanalitikai vizsgálata

The vitamin E group of compounds and ubiquinone are widely known substances with antioxidant properties. However, the setup of high-performance liquid chromatography (HPLC) methods for the detection of these molecules in human serum are often difficult. We report here a reversed-phase HPLC method using diode array detection and a single C18 column separation kept at 25 °C with an isocratic system of acetonitrile, tetrahydrofuran, methanol, ammonium acetate and water at a flow-rate of 2.1 mL/min. This method resolves 3 tocopherols (α, γ, δ) and ubiquinone from human serum within 17 minutes with the application of tocol as an internal standard. We conclude that our procedure provides an adequate sample preparation and separation of the 3 examined tocopherols (α, γ, δ). Although the developed method has been proven to be efficient, accurate and inexpensive, further improvements in the quantitative assessment of ubiquinone are necessary

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. © 2023 by the authors

Novel heterozygous STUB1 gene mutation causes SCA48 in a Hungarian patient

Spinocerebellar ataxia type 48 (SCA48) is an autosomal dominantly inherited disease characterized by gait and limb ataxia, cerebellar dysarthria, cognitive impairment, psychiatric abnormalities and variable types of movement disorders. To date, more than 30 STUB1 gene (NM_005861.4) mutations have been described in the genetic background of SCA48.The aim of this short report was to demonstrate the first Hungarian SCA48 patient caused by a novel STUB1 missense mutation (c.788G>C, p.Arg263Pro). The characteristics of detailed neurological phenotype, brain MRI and genetic assessment are presented and compared to previously published cases. The most important neurological findings of the patient were gait ataxia, dysarthria, cognitive decline and psychiatric problems including depression, anxiety and mild impulsivity. The brain MRI demonstrated cerebellar atrophy with posterolateral predominance and frontal lobe cortical atrophy. Clinical exome sequencing examination identified the above-mentioned missense variant located in the significant ubiquitinase domain of the CHIP protein.In this paper the first Hungarian SCA48 patient was described with characteristic neuropsychiatric signs and brain MRI abnormalities, due to a novel STUB1 gene missense mutation