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

Shapiro-szindróma, azaz a termoregulációs zavar ritka esete

Absztrakt A corpus callosum anomáliái a központi idegrendszer leggyakoribb fejlődési rendellenességei. A corpus callosum agenesiához társuló spontán periodikus hypothermia és hyperhidrosis triászt Shapiro-szindrómának nevezték el. A Shapiro-szindróma ritka kórkép, amely bármilyen életkorban megjelenhet. A corpus callosum agenesia nem megkülönböztető jegye a szindrómának, mint azt korábban feltételezték, a paroxysmalis hypothermia bizonyult a fő betegségjegynek. A rekurrens hypothermia hátterében a maghőmérséklet beállításáért felelős hypothalamus működési zavarát feltételezik, de a pontos patofiziológia még nem ismert. Definitív terápia nem létezik, az életminőséget viszont kedvezően befolyásoló szupportív terápiás alternatívák állnak rendelkezésre. A szerzők az esetismertetésben az első, hazánkban diagnosztizált Shapiro-szindrómás beteget mutatják be. A 21 éves férfi beteg fő tünete a rekurrens hyperhidrosis és hypothermia, következményes elesett általános állapot volt. A koponya mágneses rezonanciás vizsgálata corpus callosum agenesiát igazolt. A betegnél az empirikusan indított clonidinterápia hatásosnak bizonyult, s mint számos korábban közölt esetben, a klinikai tünetek remissziója jelentkezett. Orv. Hetil., 2016, 157(7), 275–278

Characterisation of the nucleic acid binding features of the PRRSV 7ap and its ability to induce antinuclear antibodies

A short alternative open reading frame named ORF7a has recently been discovered within the nucleocapsid gene of the porcine reproductive and respiratory syndrome virus (PRRSV) genome. Proteins (7ap) translated from the ORF7a of two divergent strains — a type I and a type II — are able to completely reduce the motility of nucleic acids at relatively high molar charge ratios in gel retardation assays indicating strong dsDNA- and ssRNA-binding capability. Conserved RNA- and DNA-binding properties suggest that nucleic acid binding is a functional property of the divergent 7aps, and not an arbitrary consequence of their net positive charge. Sera from Hu7ap-immunised pigs and mice did not react with Hu7ap or Hu7ap-GFP; however, antinuclear antibodies were detected in the sera of the immunised animals, suggesting an ability of Hu7ap to interact with or mimic autoantigenic macromolecules

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