CANVAS: case report on a novel repeat expansion disorder with late-onset ataxia

This article presents the case of a 74-year-old female patient who first developed a progressive disease with sensory neuropathy, cerebellar ataxia and bilateral vestibulopathy at the age of 60 years. The family history was unremarkable. Magnetic resonance imaging (MRI) showed atrophy of the cerebellum predominantly in the vermis and atrophy of the spinal cord. The patient was given the syndromic diagnosis of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). In 2019 the underlying genetic cause of CANVAS was discovered to be an intronic repeat expansion in the RFC1 gene with autosomal recessive inheritance. The patient exhibited the full clinical picture of CANVAS and was tested positive for this repeat expansion on both alleles. The CANVAS is a relatively frequent cause of late-onset hereditary ataxia (estimated prevalence 5‑13/100,000). In contrast to the present patient, the full clinical picture is not always present. Therefore, testing for the RFC1 gene expansion is recommended in the work-up of patients with otherwise unexplained late-onset sporadic ataxia. As intronic repeat expansions cannot be identified by next generation sequencing methods, specific testing is necessary

A patient with typical clinical features of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) but without an obvious genetic cause: a case report

<p>Abstract</p> <p>Introduction</p> <p>There are currently 23 missense point mutations and one 4 basepair deletion spanning different mitochondrial genes associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). The spectrum of mitochondrial DNA mutations in Arab patients with MELAS is largely unknown.</p> <p>Case presentation</p> <p>A standard clinical examination was carried out on a 34-year-old Saudi woman showing clinical features of MELAS. Fresh frozen muscle tissue was subjected to enzyme histochemical analysis. DNA was extracted from her leukocytes and muscle tissue, and the full mitochondrial genome was screened for base substitution mutations and deletions. Additionally, we screened the polymerase gamma-1 nuclear gene for mutations. The patient was negative for the most common m.3243 A>G MELAS mutation. Sequencing the full mitochondrial genome did not reveal any known or potentially pathogenic sequence changes. The polymerase gamma-1 gene was also free from mutations.</p> <p>Conclusion</p> <p>The clinical picture described here typically fits that observed in patients with MELAS or mitochondrial stroke-like events, but mutations in recognized genes (mitochondrial DNA and polymerase gamma-1 gene) were absent. We report the case of a patient with typical clinical features of MELAS, but without an obvious genetic cause.</p

Ди-мюонное фоторождение в эксперименте NA64

В работе проанализированы основные процессы, вносящие мюонный вклад в статистику эксперимента NA64. Рассмотрены методы моделирования случайных величин. Разработан Монте-Карло генератор процесса ди-мюонного фоторождения, позволяющий получить энергетические и угловые распределения мюонов.The main processes involved in the muon contribution to the NA64 experiment statistics are analyzed. Methods for modeling random variables are considered. A Monte-Carlo generator was developed for the process of di-muon photoproduction, which makes it possible to obtain energy and angular distributions of muons

Clonal hematopoiesis as a pitfall in germline variant interpretation in the context of Mendelian disorders

Clonal hematopoiesis because of somatic mutations in hematopoietic stem/progenitor cells is an age-related phenomenon and commonly observed when sequencing blood DNA in elderly individuals. Several genes that are implicated in clonal hematopoiesis are also associated with Mendelian disorders when mutated in the germline, potentially leading to variant misinterpretation. We performed a literature search to identify genes associated with age-related clonal hematopoiesis followed by an OMIM query to identify the subset of genes in which germline variants are associated with Mendelian disorders. We retrospectively screened for diagnostic cases in which the presence of age-related clonal hematopoiesis confounded exome sequencing data interpretation. We found 58 genes in which somatic mutations are implicated in clonal hematopoiesis, while germline variants in the same genes are associated with Mendelian (mostly neurodevelopmental) disorders. Using five selected cases of individuals with suspected monogenic disorders, we illustrate how clonal hematopoiesis in either variant databases or exome sequencing datasets poses a pitfall, potentially leading to variant misclassification and erroneous conclusions regarding gene-disease associations

A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders

\ua9 2024 The AuthorsMitochondrial DNA (mtDNA) deletions which clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impair mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions arise and accumulate in perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in the accumulation and spread of mtDNA deletions, and that knowledge of how muscle fibres respond to mitochondrial dysfunction is key to our understanding of disease mechanisms. To understand the contribution of mito-nuclear signalling to the spread of mitochondrial dysfunction, we use imaging mass cytometry. We characterise the levels of mitochondrial Oxidative Phosphorylation proteins alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance disorders. Our expanded panel included protein markers of key signalling pathways, allowing us to investigate cellular responses to different combinations of oxidative phosphorylation dysfunction and ragged red fibres. We find combined Complex I and IV deficiency to be most common. Interestingly, in fibres deficient for one or more complexes, the remaining complexes are often upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in the abundance of proteins involved in proteostasis, e.g. HSP60 and LONP1, and regulation of mitochondrial metabolism (including oxidative phosphorylation and proteolysis, e.g. PHB1). Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each fibre