Miyoshi myopathy associated with spine rigidity and multiple contractures: a case report.

BACKGROUND: Dysferlinopathy is a phenotypically heterogeneous group of hereditary diseases caused by mutations in the DYSF gene. Early contractures are considered rare, and rigid spine syndrome in dysferlinopathy has been previously reported only once. CASE PRESENTATION: We describe a 23-year-old patient with Miyoshi myopathy with a rigid spine and multiple contractures, a rare phenotypic variant. The disease first manifested when the patient was 13 years old, with fatigue of the gastrocnemius muscles and the development of pronounced contractures of the Achilles tendons, flexors of the fingers, and extensors of the toes, followed by the involvement of large joints and the spine. Magnetic resonance imaging revealed signs of connective tissue and fatty replacement of the posterior muscles of the thighs and lower legs. Edema was noted in the anterior and medial muscle groups of the thighs, lower legs, and the multifidus muscle of the back. Whole genome sequencing revealed previously described mutations in the DYSF gene in exon 39 (c.4282 C > T) and intron 51 (c.5785-824 C > T). An immunohistochemical analysis and Western blot showed the complete absence of dysferlin protein expression in the muscle fibers. CONCLUSIONS: This case expands the range of clinical and phenotypic correlations of dysferlinopathy and complements the diagnostic search for spine rigidity.

Extreme Tolerance of Extraocular Muscles to Diseases and Aging: Why and How?

The extraocular muscles (EOMs) possess unique characteristics that set them apart from other skeletal muscles. These muscles, responsible for eye movements, exhibit remarkable resistance to various muscular dystrophies and aging, presenting a significant contrast to the vulnerability of skeletal muscles to these conditions. In this review, we delve into the cellular and molecular underpinnings of the distinct properties of EOMs. We explore their structural complexity, highlighting differences in fiber types, innervation patterns, and developmental origins. Notably, EOM fibers express a diverse array of myosin heavy-chain isoforms, retaining embryonic forms into adulthood. Moreover, their motor innervation is characterized by a high ratio of nerve fibers to muscle fibers and the presence of unique neuromuscular junctions. These features contribute to the specialized functions of EOMs, including rapid and precise eye movements. Understanding the mechanisms behind the resilience of EOMs to disease and aging may offer insights into potential therapeutic strategies for treating muscular dystrophies and myopathies affecting other skeletal muscles.

Artificial microvesicles: new perspective on healing tendon wounds.

Tendons have a limited capacity to repair both naturally and following clinical interventions. Damaged tissue often presents with structural and functional differences, adversely affecting animal performance, mobility, health and welfare. Advances in cell therapies have started to overcome some of these issues, however complications such as the formation of ectopic bone remain a complication of this technique. Regenerative medicine is therefore looking towards future therapies such as the introduction of microvesicles (MVs) derived from stem cells (SCs). The aim of the present study was to assess the characteristics of artificially derived MVs, from equine mesenchymal stem cells (MSCs), when delivered to rat tendon cells in vitro and damaged tendons in vivo. The initial stages of extracting MVs from equine MSCs and identifying and characterising the cultured tendon stem/progenitor cells (TSCs) from rat Achilles tendons were undertaken successfully. The horse MSCs, and the rat tendon cells, were both capable of differentiating in three directions: adipogenic, osteogenic and chondrogenic pathways. The artificially derived equine MVs successfully fused with the TSC membranes, and no cytotoxic or cytostimulating effects were observed. In addition, co-cultivation of TSCs with MVs lead to stimulation of cell proliferation and migration, and cytokine VEGF and Fractalkine expression levels were significantly increased. These experiments are the first to show that artificially derived MVs exhibited regeneration-stimulating effects in vitro, and that fusion of cytoplasmic membranes from diploid cell lines originating from different species was possible. Explorations in vivo showed accelerated regeneration of injury tendons after introduction of the MVs into damaged areas. The results from the studies performed indicated obvious positive modifying effects following the administration of MVs. This represents the initial successful steps required prior to translating this regenerative medicine technique into clinical trials, such as for tendon repair in injured horses.

Role of Mesenchymal Stem Cells and Extracellular Vesicles in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial fibrotic disease that leads to disability and death within 5 years of diagnosis. Pulmonary fibrosis is a disease with a multifactorial etiology. The concept of aberrant regeneration of the pulmonary epithelium reveals the pathogenesis of IPF, according to which repeated damage and death of alveolar epithelial cells is the main mechanism leading to the development of progressive IPF. Cell death provokes the migration, proliferation and activation of fibroblasts, which overproduce extracellular matrix, resulting in fibrotic deformity of the lung tissue. Mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) are promising therapies for pulmonary fibrosis. MSCs, and EVs derived from MSCs, modulate the activity of immune cells, inhibit the expression of profibrotic genes, reduce collagen deposition and promote the repair of damaged lung tissue. This review considers the molecular mechanisms of the development of IPF and the multifaceted role of MSCs in the therapy of IPF. Currently, EVs-MSCs are regarded as a promising cell-free therapy tool, so in this review we discuss the results available to date of the use of EVs-MSCs for lung tissue repair.

Increasing ß-hexosaminidase A activity using genetically modified mesenchymal stem cells.

GM2 gangliosidoses are a group of autosomal-recessive lysosomal storage disorders. These diseases result from a deficiency of lysosomal enzyme ß-hexosaminidase A (HexA), which is responsible for GM2 ganglioside degradation. HexA deficiency causes the accumulation of GM2-gangliosides mainly in the nervous system cells, leading to severe progressive neurodegeneration and neuroinflammation. To date, there is no treatment for these diseases. Cell-mediated gene therapy is considered a promising treatment for GM2 gangliosidoses. This study aimed to evaluate the ability of genetically modified mesenchymal stem cells (MSCs-HEXA-HEXB) to restore HexA deficiency in Tay-Sachs disease patient cells, as well as to analyze the functionality and biodistribution of MSCs in vivo. The effectiveness of HexA deficiency cross-correction was shown in mutant MSCs upon interaction with MSCs-HEXA-HEXB. The results also showed that the MSCs-HEXA-HEXB express the functionally active HexA enzyme, detectable in vivo, and intravenous injection of the cells does not cause an immune response in animals. These data suggest that genetically modified mesenchymal stem cells have the potentials to treat GM2 gangliosidoses.

Immunogenic Properties of MVs Containing Structural Hantaviral Proteins: An Original Study.

Hemorrhagic fever with renal syndrome (HFRS) is an emerging infectious disease that remains a global public health threat. The highest incidence rate is among zoonotic disease cases in Russia. Most cases of HFRS are reported in the Volga region of Russia, which commonly identifies the Puumala virus (PUUV) as a pathogen. HFRS management is especially challenging due to the lack of specific treatments and vaccines. This study aims to develop new approaches for HFRS prevention. Our goal is to test the efficacy of microvesicles (MVs) as PUUV nucleocapsid (N) and glycoproteins (Gn/Gc) delivery vehicles. Our findings show that MVs could deliver the PUUV N and Gn/Gc proteins in vitro. We have also demonstrated that MVs loaded with PUUV proteins could elicit a specific humoral and cellular immune response in vivo. These data suggest that an MV-based vaccine could control HFRS.

Postnatal development of the microstructure of cortical GABAergic synapses and perineuronal nets requires sensory input.

The brain synaptic circuitry is formed as a result of pre-defined genetic programs and sensory experience during postnatal development. Perineuronal nets ensheath synaptic boutons and control several crucial features of the synapse physiology. Formation of the perineuronal net microstructure during the brain development remains largely unstudied. Here we provide a detailed quantitative description of the 3-dimensional geometry of the synapse and the surrounding perineuronal net in the mouse somatosensory cortex layer IV. We compare the morphology of the synapse+perineuronal net complex in the adult brain formed under normal conditions or in the whisker shaving model of somatosensory deprivation. We demonstrate that the sensory deprivation causes flattening of the 3D PNN mesh geometry and reduction of the VGAT-positive cluster volume in presynaptic boutons. These results reveal a mechanism of the sensory input-dependent synapse morphogenesis during the brain development.

Magnetic resonance imaging pattern variability in dysferlinopathy.

The widespread use of magnetic resonance imaging (MRI) in the diagnosis of myopathies has made it possible to clarify the typical MRI pattern of dysferlinopathy. However, sufficient attention has not been given to the variability of MRI patterns in dysferlinopathy. MATERIALS AND METHODS: Twenty-five patients with the clinical manifestations of dysferlinopathy were examined. For all patients, creatine phosphokinase levels were measured and molecular genetics were examined. In two patients, immunohistochemical examinations of muscle biopsies were performed. MRI scanning was included T2 multi-slice multi-echo, T1 weighted, T2 weighted and Short Tau Inversion Recovery T2 weighted sequences. Quantitative and semi-quantitative evaluations of fatty replacement and swelling of the muscles were undertaken. RESULTS: Variability in the MRI patterns was lowest in the pelvis and leg muscles and highest in the thigh muscles. Three main types of MRI patterns were distinguished: posterior-dominant (80%), anterior-dominant (16%), and diffuse (4%). Among patients with the anterior-dominant pattern, the collagen-like variant (4%), proximal variant (4%) and pseudo-myositis (8%) were separately distinguished. CONCLUSIONS: Awareness of atypical MRI patterns in dysferlinopathy is important for increasing the efficiency of routine diagnostics and optimizing the search for causative gene mutations.

Intrafamilial Phenotypic Variability of Collagen VI-Related Myopathy Due to a New Mutation in the COL6A1 Gene.

A family of five male siblings (three survivors at 48, 53 and 58 years old; two deceased at 8 months old and 2.5 years old) demonstrating significant phenotypic variability ranging from intermediate to the myosclerotic like Bethlem myopathy is presented. Whole-exome sequencing (WES) identified a new homozygous missense mutation chr21:47402679 T > C in the canonical splice donor site of the second intron (c.227 + 2T>C) in the COL6A1 gene. mRNA analysis confirmed skipping of exon 2 encoding 925 amino-acids in 94-95% of resulting transcripts. Three sibs presented with intermediate phenotype of collagen VI-related dystrophies (48, 53 and 2.5 years old) while the fourth sibling (58 years old) was classified as Bethlem myopathy with spine rigidity. The two older siblings with the moderate progressive phenotype (48 and 53 years old) lost their ability to maintain a vertical posture caused by pronounced contractures of large joints, but continued to ambulate throughout life on fully bent legs without auxiliary means of support. Immunofluorescence analysis of dermal fibroblasts demonstrated that no type VI collagen was secreted in any of the siblings' cells, regardless of clinical manifestations severity while fibroblast proliferation and colony formation ability was decreased. The detailed genetic and long term clinical data contribute to broadening the genotypic and phenotypic spectrum of COL6A1 related disease.

Caroli syndrome: a clinical case with detailed histopathological analysis.

Herein we present a clinical case of the Caroli syndrome caused by the compound heterozygous mutation in the PKHD1 gene. Histopathological assessment of liver detected biliary cirrhosis, numerous dilated bile ducts of various sizes, hyperplastic cholangiocytes containing a large amount of acid mucopolysaccharides, decreased ß-tubulin expression and increased proliferation of cholangiocytes. A significant proportion of hepatic tissue was composed of giant cysts lined with a single layer of cholangiocytes, containing pus and bile in its lumen and surrounded by granulation tissue. An accumulation of neutrophils in the lumen of the bile ducts was observed, as well as an infiltration of the ducts and cysts surrounding connective tissue by CD4+ and to a lesser extent CD8+ lymphocytes. This may be caused by the expression of HLA-DR by cholangiocytes. Atrophy and desquamation of the epithelium of collecting tubules with the formation of microcysts were detected in the kidneys without a clinically significant loss of renal function. Morphopathogenetic mechanisms of the Caroli syndrome can be targets for a potential pathogenetic therapy and prevention of its manifestations and complications.

Cytokine Storm Combined with Humoral Immune Response Defect in Fatal Hemorrhagic Fever with Renal Syndrome Case, Tatarstan, Russia.

Hemorrhagic fever with renal syndrome (HFRS) is endemic in Tatarstan, where thousands of cases are registered annually. Puumalaorthohantavirus is commonly detected in human case samples as well as in captured bank voles, the rodent hosts. The pathogenesis of HFRS is still not well described, although the cytokine storm hypothesis is largely accepted. In this study, we present a comprehensive analysis of a fatal HFRS case compared with twenty four non-fatal cases where activation of the humoral and cellular immune responses, pro-inflammatory cytokines and disturbed blood coagulation were detected using immunological, histological, genetic and clinical approaches. Multiple organ failure combined with disseminated intravascular coagulation syndrome and acute renal failure was the cause of death. Decreased Interleukin (IL)-7 and increased IL-18, chemokine (C-C motif) ligand (CCL)-5, stem cell growth factor (SCGF)-b and tumor necrosis factor-beta (TNF-ß) serum levels were found, supporting the cytokine storm hypothesis of hantavirus pathogenesis.