BACKGROUND: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. OBJECTIVE: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. METHODS: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). RESULTS: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). INTERPRETATION: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• Klíčová slova
• ZIC1, ZIC4, autopsy-confirmed, genome-wide association study, multiple system atrophy,
• MeSH
• alfa-synuklein metabolismus   MeSH
• autoprotilátky MeSH
• celogenomová asociační studie MeSH
• lidé MeSH
• multisystémová atrofie * genetika   patologie   MeSH
• olivopontocerebelární atrofie * MeSH
• pitva MeSH
• proteiny nervové tkáně genetika   MeSH
• striatonigrální degenerace * MeSH
• transkripční faktory genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• alfa-synuklein MeSH
• autoprotilátky MeSH
• proteiny nervové tkáně MeSH
• transkripční faktory MeSH
• ZIC1 protein, human MeSH Prohlížeč
• ZIC4 protein, human MeSH Prohlížeč

PURPOSE: To determine the molecular genetic cause in previously unreported probands with optic atrophy from the United Kingdom, Czech Republic and Canada. METHODS: OPA1 coding regions and flanking intronic sequences were screened by direct sequencing in 82 probands referred with a diagnosis of bilateral optic atrophy. Detected rare variants were assessed for pathogenicity by in silico analysis. Segregation of the identified variants was performed in available first degree relatives. RESULTS: A total of 29 heterozygous mutations evaluated as pathogenic were identified in 42 probands, of these seven were novel. In two probands, only variants of unknown significance were found. 76% of pathogenic mutations observed in 30 (71%) of 42 probands were evaluated to lead to unstable transcripts resulting in haploinsufficiency. Three probands with the following disease-causing mutations c.1230+1G>A, c.1367G>A and c.2965dup were documented to suffer from hearing loss and/or neurological impairment. CONCLUSIONS: OPA1 gene screening in patients with bilateral optic atrophy is an important part of clinical evaluation as it may establish correct clinical diagnosis. Our study expands the spectrum of OPA1 mutations causing dominant optic atrophy and supports the fact that haploinsufficiency is the most common disease mechanism.

• Klíčová slova
• OPA1, DOA plus syndrome, dominant optic atrophy, haploinsufficiency, novel mutations,
• MeSH
• autozomálně dominantně dědičná optická atrofie genetika   metabolismus   MeSH
• DNA genetika   MeSH
• fenotyp MeSH
• genetické techniky MeSH
• GTP-fosfohydrolasy genetika   metabolismus   MeSH
• heterozygot MeSH
• lidé MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• rodokmen MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Kanada MeSH
• Spojené království MeSH
• Názvy látek
• DNA MeSH
• GTP-fosfohydrolasy MeSH
• OPA1 protein, human MeSH Prohlížeč

INTRODUCTION: Treatment of children with spinal muscular atrophy (SMA) now includes disease modifying drugs such as nusinersen. Real-world data can provide new insight on the efficacy and safety of nusinersen for treatment of children with SMA. AIM: The aim of our study is to evaluate the effect of treatment of children and young adults with SMA type I, II and III at various stages of the disease after 14 months of treatment with nusinersen. METHODS: In this prospective, two-center (in Slovenia and Czech Republic) study, data from all patients with a genetically confirmed diagnosis of SMA before 19 years of age who were treated with nusinersen were collected before initiation of treatment, and after 6 and 14 months of treatment. Various standardized motor scales and a questionnaire that focused on daily-life activities were used. RESULTS: Form both centers, 61 patients from 2 months to 19 years of age were enrolled in the study. Sixteen had SMA type I (median age 5.2 years); 32 had SMA type II (median age 8.9 years); and 13 had SMA type III (median age 8.6 years). Patients had 2-4 copies of the SMN2 gene. One patient died in the study period and one discontinued treatment. After 14 months of treatment, SMA type I (p = 0.002) and type II (p = 0.002) patients had significantly better outcomes, while type III patients showed a trend towards improvement (p = 0.051) on motor scales. Younger age at the initiation of treatment and a higher number of SMN2 copies is related to a better outcome. Younger children also seem to improve faster compared to older children. No serious side effects were reported. CONCLUSION: The results of our study which included patients of various SMA types and stages of the disease suggest that treatment with nusinersen benefits patients, regardless of SMA type. Earlier age at the initiation of treatment and a higher number of SMN2 copies were related to a better outcome, however even some patients of higher age and/or later stage of the disease benefited from the treatment. Our study also suggests that nusinersen is safe to use, as no major side effects, requiring discontinuation of treatment, were reported. There is an unmet need for novel standardized tests and biomarkers, which could help guide clinician's decisions on the selection of best treatment options and monitor treatment success.

• Klíčová slova
• Adult, Child, Follow-up, Nusinersen, Spinal muscular atrophy,
• MeSH
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• oligonukleotidy terapeutické užití   MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• spinální svalová atrofie farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Slovinsko MeSH
• Názvy látek
• nusinersen MeSH Prohlížeč
• oligonukleotidy MeSH

Spinal muscular atrophy (SMA) is one of the most common genetic diseases and was, until recently, a leading genetic cause of infant mortality. Three disease-modifying treatments have dramatically changed the disease trajectories and outcome for severely affected infants (SMA type 1), especially when initiated in the presymptomatic phase. One of these treatments is the adeno-associated viral vector 9 (AAV9) based gene therapy onasemnogene abeparvovec (Zolgensma®), which is delivered systemically and has been approved by the European Medicine Agency for SMA patients with up to three copies of the SMN2 gene or with the clinical presentation of SMA type 1. While this broad indication provides flexibility in patient selection, it also raises concerns about the risk-benefit ratio for patients with limited or no evidence supporting treatment. In 2020, we convened a European neuromuscular expert working group to support the rational use of onasemnogene abeparvovec, employing a modified Delphi methodology. After three years, we have assembled a similar yet larger group of European experts who assessed the emerging evidence of onasemnogene abeparvovec's role in treating older and heavier SMA patients, integrating insights from recent clinical trials and real-world evidence. This effort resulted in 12 consensus statements, with strong consensus achieved on 9 and consensus on the remaining 3, reflecting the evolving role of onasemnogene abeparvovec in treating SMA.

• Klíčová slova
• Adeno-associated viral vector, Disease modifying treatment, Effectiveness, Gene therapy, Newborn screening, Onasemnogene abeparvovec, Safety, Spinal muscular atrophy, Survival motor neuron gene, Zolgensma®,
• MeSH
• biologické přípravky terapeutické užití   MeSH
• genetická terapie * metody   MeSH
• konsensus MeSH
• lidé MeSH
• rekombinantní fúzní proteiny MeSH
• spinální svalová atrofie * terapie   genetika   MeSH
• spinální svalové atrofie v dětství terapie   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• biologické přípravky MeSH
• rekombinantní fúzní proteiny MeSH
• Zolgensma MeSH Prohlížeč

Denosumab is a fully human recombinant monoclonal antibody to the receptor activator of nuclear factor-κB ligand. Denosumab is used in the treatment of postmenopausal osteoporosis and cancer-related bone disorders. There are only very scarce data on denosumab treatment in children. 14-year-old boy with spinal muscular atrophy (SMA) and severe disuse osteoporosis (spinal bone mineral density L1-L4 BMD-6.2SD Z-score) and two prevalent fragility fractures was treated with denosumab. He received 60 mg subcutaneous injection at the baseline and seven months later. Six months after the initial injection there was a 19% increase in L1-L4 BMD. The injections were well tolerated without any adverse reactions. Calcemia remained stable (2.3-2.4 mmol/L). He was scheduled for the third denosumab injection six months later. Prior to this date, he acquired pneumonia and died due to respiratory failure, which is a frequent cause of death in patients with SMA. There was no relation to the denosumab treatment. In conclusion, one dose of denosumab significantly increased BMD in a child with severe osteoporosis.

• Klíčová slova
• Bone, Bone mineral density, Denosumab, Fractures, Osteoporosis, Spinal muscular atrophy,
• MeSH
• denosumab terapeutické užití   MeSH
• fraktury kostí farmakoterapie   MeSH
• inhibitory kostní resorpce terapeutické užití   MeSH
• injekce subkutánní MeSH
• kostní denzita účinky léků   MeSH
• lidé MeSH
• mladiství MeSH
• osteoporóza farmakoterapie   MeSH
• spinální svalová atrofie komplikace   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• denosumab MeSH
• inhibitory kostní resorpce MeSH

Spinal muscular atrophy (SMA) used to be one of the most common genetic causes of infant mortality. New disease modifying treatments have changed the disease trajectories and most impressive results are seen if treatment is initiated in the presymptomatic phase of the disease. Very recently, the European Medicine Agency approved Onasemnogene abeparvovec (Zolgensma®) for the treatment of patients with SMA with up to three copies of the SMN2 gene or the clinical presentation of SMA type 1. While this broad indication provides new opportunities, it also triggers discussions on the appropriate selection of patients in the context of limited available evidence. To aid the rational use of Onasemnogene abeparvovec for the treatment of SMA, a group of European neuromuscular experts presents in this paper eleven consensus statements covering qualification, patient selection, safety considerations and long-term monitoring.

• Klíčová slova
• Gene therapy, Nusinersen, Onasemnogene abeparvovec, SMN1, SMN2, Spinal muscular atrophy, Zolgensma,
• MeSH
• biologické přípravky terapeutické užití   MeSH
• genetická terapie metody   MeSH
• kojenec MeSH
• konsensus MeSH
• lidé MeSH
• rekombinantní fúzní proteiny terapeutické užití   MeSH
• spinální svalová atrofie genetika   terapie   MeSH
• výběr pacientů MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• konsensus - konference MeSH
• Názvy látek
• biologické přípravky MeSH
• rekombinantní fúzní proteiny MeSH
• Zolgensma MeSH Prohlížeč

Spinal muscular atrophy (SMA) is a rare and devastating disease. New disease-modifying treatments have recently been approved and early treatment has been related to a better outcome. In this context, several newborn screening (NBS) programs have been implemented. The aim of the study was to obtain a global overview on the current situation and perspectives on SMA NBS. We conducted a survey and contacted experts from 152 countries, from which we gathered 87 responses. We identified 9 SMA NBS programs that have so far detected 288 newborns with SMA out of 3,674,277 newborns screened. Funding, screening methods, organisation, and consent process were variable between SMA NBS programs. Many respondents pointed the lack of cost/benefit data as a major obstacle to SMA NBS implementation. In the next four years, our data suggest a 24% coverage of newborns from countries where a disease-modifying drug is available and 8,5% coverage in countries with no diseases-modifying drugs. The annual proportion of newborns to be screened in the coming years is expected to increase steadily. The experts expressed a strong need for the implementation of SMA NBS as means to improve care for patients with SMA.

• Klíčová slova
• Newborn screening, Nusinersen, Onasemnogene abeparvovec, Pre-symptomatic, Risdiplam, Spinal muscular atrophy,
• MeSH
• lidé MeSH
• novorozenec MeSH
• novorozenecký screening trendy   MeSH
• průzkumy a dotazníky MeSH
• spinální svalová atrofie diagnóza   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Spinal muscular atrophy is a rare hereditary neuromuscular disorder (with a prevalence of 1 per 30,000) that greatly debilitates patients and, in most cases, shortens their life expectancy. Although there is no causal therapy, improvements in symptomatic therapy have extended patients' life expectancy and increased their quality of life. Unfortunately, the advancements in care vary from country to country. To improve the care for children with spinal muscular atrophy in the Czech Republic, we created a survey to obtain the baseline information about their quality of life and compared the data with equivalent data from the United States. METHODS: We used the Pediatric Quality of Life Inventory 3.0 Neuromuscular Measurement Model, which is a health-related quality of life questionnaire specific to children with neuromuscular disorders. The survey was conducted on 35 children with genetically proven spinal muscular atrophy and their parents. RESULTS: Compared with the US data, the Czech data generally show a lower quality of life, mainly in the family resources part. The greatest score was achieved in the section about communication. Altogether, the parents' scores are lower than those of the children. CONCLUSION: In the Czech Republic, patients with spinal muscular atrophy and, especially their parents, have a significantly lower quality of life compared with US patients, mostly because of economic factors and a lack of social support. Our results reveal areas toward which improvement should be directed. The need for family support through social care as well as civic, patient, or organizational support is accentuated.

• Klíčová slova
• Czech Republic, health-related quality of life, neuromuscular disorders, spinal muscular atrophy,
• MeSH
• dítě MeSH
• kvalita života * MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• průzkumy a dotazníky MeSH
• rodiče psychologie   MeSH
• sociální opora MeSH
• spinální svalová atrofie ekonomika   psychologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Geografické názvy
• Česká republika MeSH
• Spojené státy americké MeSH

• Klíčová slova
• CLOSTRIDIUM BOTULINUM *, EXPERIMENTAL LAB STUDY *, MUSCULAR ATROPHY *, PATHOLOGY *, RATS *, TOXICOLOGIC REPORT *, TOXINS AND ANTITOXINS *,
• MeSH
• antitoxiny * MeSH
• atrofie * MeSH
• biologické toxiny * MeSH
• botulotoxiny * MeSH
• Clostridium botulinum * MeSH
• kosterní svaly * MeSH
• krysa rodu Rattus MeSH
• patologie * MeSH
• svalová atrofie * MeSH
• toxikologie * MeSH
• výzkum * MeSH
• Check Tag
• krysa rodu Rattus MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitoxiny * MeSH
• biologické toxiny * MeSH
• botulotoxiny * MeSH

Longlasting nociceptive stimulation is known to cause atrophy of adjacent muscles. The aim of this study was to determine further the possible mechanisms of this pathological phenomenon. Unilateral fracture of the paw was performed under pentobarbital anaesthesia in several experimental groups (n = 8-11) of female and male rats. Dry muscle weights of the soleus (SOL), extensor digitorum longus (EDL), gastrocnemius (GA) and tibialis anterior (TA) were determined 7 days following the bone fracture and compared to the weight of contralateral control muscles. To demonstrate the reflex origin of this atrophy, deafferentation of the paw by dorsal root section (L4-6) was performed before or after unilateral fracture of hindlimb metatarsal bones. In female rats, the fracture resulted in a significant loss of muscle weight in all the four muscles examined. When the hindlimb was deafferented prior to the fracture, no muscle atrophy developed, and neither did deafferentation itself cause any appreciable change in muscle weight except in male rats. This supports the concept that this type of atrophy is reflex in origin. Deafferentation, when performed after the fracture, did not prevent the weight loss in extensor muscles (SOL, GA), while the flexors (EDL, TA) did not in general lose any weight. The results in male rats had a similar trend as in female rats, although the weight loss was significantly smaller. Our results showed that the mechanism of reflex muscle atrophy following metatarsal bone fracture involves a component which is dependent on afferent information from the injured paw.(ABSTRACT TRUNCATED AT 250 WORDS)

• MeSH
• aferentní nervové dráhy fyziologie   MeSH
• bolest komplikace   MeSH
• fraktury kostí komplikace   MeSH
• krysa rodu Rattus MeSH
• potkani Wistar MeSH
• sexuální faktory MeSH
• svalová atrofie etiologie   MeSH
• svaly patologie   MeSH
• velikost orgánu MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH