Anesthetic Approach for a Pediatric Patient With Facioscapulohumeral Muscular Dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) belongs to the group of rare diseases known as muscular dystrophies. Patients with muscular dystrophies face a heightened risk of intraoperative complications, including severe hyperkalemia and acute rhabdomyolysis. This case report outlines the anesthetic approach employed for a pediatric patient diagnosed with FSHD undergoing a planned exploratory tympanotomy. To the best of our knowledge, it is the first documented case in the literature detailing pediatric general anesthesia in a patient with FSHD, with the additional use of neuromuscular blockade reversal with sugammadex.

A meta-analysis of the prevalence of neuropsychiatric disorders and their association with disease onset in myotonic dystrophy.

There is a high prevalence of neuropsychiatric disorders in myotonic dystrophy types 1 and 2 (DM1 and DM2), including autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in DM1, and depression and anxiety in both DMs. The aim of this systematic review and meta-analysis was to estimate the prevalence of ASD, ADHD, depression and anxiety in the population with DM, and their association with disease onset. A systematic search of Medline, Scopus, Web of Science, and the Cochrane Library was conducted from inception to November 2023. Observational studies estimating the prevalence of these disorders in DM1 or DM2 were included. A meta-analysis of the prevalence of these disorders and an association study with disease onset by prevalence ratio meta-analysis were performed. Thirty-eight studies were included. In DM1, the prevalence of ASD was 14%, with congenital onset being 79% more common than juvenile onset, while the prevalence of ADHD was 21%, with no difference between congenital and juvenile onset, and the prevalence of depression and anxiety were 14% and 16%. Depression was more common in the adult onset. Finally, the prevalence of depression in DM2 was 16%. A higher prevalence of neuropsychiatric disorders is observed in individuals with DM1 and DM2 than in the general population. Therefore, actively screening for congenital and juvenile neurodevelopmental disorders in DM1 and emotional disorders in DM1 and DM2 may improve the quality of life of those affected.

Tubular Aggregates as a Marker of Aging in Skeletal Muscle.

Tubular aggregates (TA) are skeletal muscle structures that arise from the progressive accumulation of sarcoplasmic reticulum proteins, mainly with aging. Muscle regeneration plays a role in TA formation. TA quantification may aid in the evaluation of muscle aging and genetic muscle degeneration. TA form over time, appears in aging in normal murine muscles. TA reduction in injured conditions may be due to the degeneration-regeneration process in muscles, with loss of damaged muscle fibers and formation of new fibers that do not present protein aggregation. These new regenerated fibers do not improve the function capacity of the aged muscle. Here, we present a methodology for labeling and identifying tubular aggregates in muscle fibers and also the standardization of its quantification.

Cobblestone lissencephaly (Type II), clinical, and neuroimaging: A case report and literature review.

Cobblestone lissencephaly (C-LIS) (TYPE II) is a rare and severe neuronal migration disorder characterized by a smooth brain surface with overmigrated neurons and abnormal formation of cerebral convolutions or gyri during fetal development, resulting in a cobblestone appearance. C-LIS is associated with eye anomalies and muscular dystrophy. This case report presents a detailed clinical and neuroimaging analysis of a patient diagnosed with cobblestone lissencephaly (Type II). It reviews pertinent literature to enhance our understanding of this complex condition. We report a case of a 6-year-old female child with cobblestone lissencephaly (C-LIS) (Type II) severe developmental delays, hypotonia, and recurrent intractable seizures. Magnetic resonance imaging (MRI) revealed a characteristic cobblestone appearance on the brain surface, indicative of abnormal neuronal migration. In addition to the classic findings of Type II Cobblestone lissencephaly, the patient displayed ventriculomegaly and cerebellar hypoplasia, contributing to the overall neurological impairment observed. The literature review highlights the genetic basis of cobblestone lissencephaly, emphasizing the involvement of genes associated with glycosylation processes and basement membrane integrity. Neuroimaging findings, including MRI and computed tomography scans, are crucial for accurate diagnosis and prognostication. Early identification of cobblestone lissencephaly allows for appropriate counseling and management strategies. However, the prognosis remains guarded, and interventions primarily focus on supportive care and seizure management. This case report contributes to the knowledge of cobblestone lissencephaly, shedding light on the clinical spectrum and neuroimaging features associated with this rare disorder. To clarify the underlying genetic mechanisms and possible therapeutic pathways for better patient outcomes, more investigation is necessary.

Long-term prognosis of penetrating keratoplasty in a patient with limited form of Scleroderma- a case report.

PURPOSE: To explore the challenges of managing recurrent graft rejections in patients with Macular Corneal Dystrophy (MCD) undergoing Penetrating Keratoplasty (PKP) who also have an underlying diagnosis of Systemic Sclerosis, specifically the limited form known as CREST syndrome. METHODS: The case of a 47-year-old female diagnosed with MCD who underwent multiple PKPs over a 13 year period was reviewed. The patients treatment included extensive surgical interventions (PKPs, amniotic membrane transplatation, tarsorrhaphy) and medical management involving systemic and topical steroids and immunosuppressive therapy (Tacrolimus ointment). RESULTS: Initial PKP surgeries improved the patients vision, but subsequently graft rejections,both acute and chronic, required further surgical and medical interventions. Despite aggressive management, the patient experienced multiple graft failures, with the final visual outcome being significantly compromised (vision 6/60). the presence of CREST syndrome complicated the management and prognosis of graft survival. CONCLUSION: This case illustrates the significant impact of systemic autoimmune disorders like CREST syndrome on the prognosis of PKP in patients with MCD. It highlights the necessity for diligent systemic evaluation and possibly more aggressive immunosuppresive strategies to manage graft rejections and prolong graft survival in such complex clinical scenarios.

Expanding the mutational and phenotypical spectrum of FHONDA syndrome.

Foveal hypoplasia, optic nerve decussation, and anterior segment dysgenesis (FHONDA) is a rare recessively inherited syndrome first described in 2013. FHONDA is associated with biallelic disease-causing variants in the SLC38A8 gene, which has a strong expression in the photoreceptor layer. To date, 60 different disease-causing variants in the SLC38A8 gene have been described. In this cross-sectional case series, we included three unrelated female patients with FHONDA syndrome who presented with congenital nystagmus and decreased visual acuity from infancy. Best-corrected visual acuity was 20/100 OD and 20/60 OS for Patient 1 (P1) (72 years old); light perception OD and hand motion OS for Patient 2 (P2) (66 years old); and 20/100 OD and 20/100 OS for Patient 3 (P3) (25 years old). While normal retinal pigmentation was seen on P1 and P3, P2 presented retinal features of retinitis pigmentosa, including a pale optic nerve head, vessel thinning, and 360° dense bone spicule hyperpigmentation OU. Spectral-domain optical coherence tomography revealed grade 4 foveal hypoplasia in all patients. In P1 and P2, the novel class IV c.388 + 1G > T p.? variant in SLC38A8 was present in homozygosity; while P3 harboured the novel c.214G > C p.(Gly72Arg) variant in homozygosity, classified as class III. Thus, we expand the mutational spectrum of FHONDA by reporting two novel variants. In addition, we describe features of retinitis pigmentosa for the first time in a patient with biallelic homozygous SLC38A8 variants, thus broadening our understanding of the clinical phenotype associated with this rare syndrome.

The association between oxidative balance score and muscular dystrophies.

Introduction: This research utilized data from the NHANES 2011-2018 study to investigate the connection between the Oxidative Balance Score (OBS) and muscular dystrophies. Methods: This study is a cross-sectional, observational, secondary analysis utilizing data from the NHANES 2011-2018. Spearman's correlation, chi-square tests, logistic regression, and restricted cubic spline plots were employed for statistical analyses. Results: This association remained significant after adjustment for various demographic and medical history factors (For continuous OBS: crude model, odds ratio [OR], 0.95, 95% confidence interval [CI:] 0.94, 0.97, p < 0.001; Model 1, OR, 0.94, 95% CI: 0.92, 0.96, p < 0.001; Model 2, OR, 0.95, 95% CI: 0.93, 0.97, p < 0.001; Model 3, OR, 0.95, 95% CI: 0.93, 0.97, p < 0.001; In quartile Q4 vs. Q1: Crude model, OR, 0. 42, 95% CI: 0.26, 0.66, p < 0.001; Model 1, OR, 0.33, 95% CI: 0.21, 0.52, p < 0.001; Model 2, OR, 0.37, 95% CI: 0.23, 0.58, p < 0.001; Model 3, OR, 0.38, 95% CI: 0.23, 0.60, p < 0.001). Restricted cubic spline (RCS) analysis further supported this inverse relationship, suggesting that OBS values above 10 may confer protection against muscular dystrophies (p for overall <0.001, p for non-linear = 0.536). However, the relationship between OBS and muscular dystrophies was not statistically significant in the subgroups with education level below high school, presence of cancer, or diabetes (p = 0.735, p = 0.574, p = 0.409, respectively). Conclusion: The study found a significant inverse correlation between the OBS and muscular dystrophies, suggesting that individuals with higher oxidative balance had a lower risk of developing muscular dystrophies. The study highlights the potential role of oxidative balance in muscular dystrophies prevention and management.

Saturation mutagenesis-reinforced functional assays for disease-related genes.

Interpretation of disease-causing genetic variants remains a challenge in human genetics. Current costs and complexity of deep mutational scanning methods are obstacles for achieving genome-wide resolution of variants in disease-related genes. Our framework, saturation mutagenesis-reinforced functional assays (SMuRF), offers simple and cost-effective saturation mutagenesis paired with streamlined functional assays to enhance the interpretation of unresolved variants. Applying SMuRF to neuromuscular disease genes FKRP and LARGE1, we generated functional scores for all possible coding single-nucleotide variants, which aid in resolving clinically reported variants of uncertain significance. SMuRF also demonstrates utility in predicting disease severity, resolving critical structural regions, and providing training datasets for the development of computational predictors. Overall, our approach enables variant-to-function insights for disease genes in a cost-effective manner that can be broadly implemented by standard research laboratories.

Improved diagnostic performance of high-sensitivity cardiac troponins in muscle dystrophies using comprehensive definition criteria for cardiac involvement: A longitudinal study on 35 patients.

BACKGROUND AND PURPOSE: Sparse information is available on the correct interpretation of elevated high-sensitivity cardiac troponin (hs-cTn) in confirmed muscular dystrophies. METHODS: Serum concentrations of hs-cTn T (hs-cTnT) and hs-cTn I (hs-cTnI) were determined in 35 stable outpatients with confirmed skeletal muscle dystrophies. We calculated sensitivities, specificities, and positive and negative predictive values of hs-cTnT and hs-cTnI for identification of cardiac involvement using a comprehensive definition that included diastolic left ventricular and right ventricular function, strain analysis using two-dimensional transthoracic echocardiogram and magnetic resonance imaging, myocardial biopsies, and consideration of a variety of triggers for cardiac injury, including arrhythmias, conduction disorders, and hypoxemia due to respiratory failure. RESULTS: Cardiac involvement was diagnosed in 34 of 35 cases. Specificities of hs-cTnT increased from 12.5% to 100% (p = 0.0006) applying the comprehensive definition compared to a definition based on electrocardiography and echocardiography alone. At the recommended 99th percentile upper limit of normal, sensitivities were significantly lower for hs-cTnI than for hs-cTnT (29.4% vs. 100%, p = 0.0164). Conversely, the specificities of hs-cTnT and hs-cTnI increased to 100% when using the comprehensive definition criteria for diagnosing cardiac involvement. CONCLUSIONS: Elevated hs-cTnT but not hs-cTnI discriminates cardiac involvement in cases with confirmed skeletal muscle dystrophies with very high sensitivity and 100% specificity. Prior reports on worse performance may be explained by the use of less sensitive imaging methods or incomplete assessment of cardiac involvement.

Nanopore Deep Sequencing as a Tool to Characterize and Quantify Aberrant Splicing Caused by Variants in Inherited Retinal Dystrophy Genes.

The contribution of splicing variants to molecular diagnostics of inherited diseases is reported to be less than 10%. This figure is likely an underestimation due to several factors including difficulty in predicting the effect of such variants, the need for functional assays, and the inability to detect them (depending on their locations and the sequencing technology used). The aim of this study was to assess the utility of Nanopore sequencing in characterizing and quantifying aberrant splicing events. For this purpose, we selected 19 candidate splicing variants that were identified in patients affected by inherited retinal dystrophies. Several in silico tools were deployed to predict the nature and estimate the magnitude of variant-induced aberrant splicing events. Minigene assay or whole blood-derived cDNA was used to functionally characterize the variants. PCR amplification of minigene-specific cDNA or the target gene in blood cDNA, combined with Nanopore sequencing, was used to identify the resulting transcripts. Thirteen out of nineteen variants caused aberrant splicing events, including cryptic splice site activation, exon skipping, pseudoexon inclusion, or a combination of these. Nanopore sequencing allowed for the identification of full-length transcripts and their precise quantification, which were often in accord with in silico predictions. The method detected reliably low-abundant transcripts, which would not be detected by conventional strategies, such as RT-PCR followed by Sanger sequencing.

Secondary mitochondrial dysfunction across the spectrum of hereditary and acquired muscle disorders.

Mitochondria form a dynamic network within skeletal muscle. This network is not only responsible for producing adenosine triphosphate (ATP) through oxidative phosphorylation, but also responds through fission, fusion and mitophagy to various factors, such as increased energy demands, oxidative stress, inflammation, and calcium dysregulation. Mitochondrial dysfunction in skeletal muscle not only occurs in primary mitochondrial myopathies, but also other hereditary and acquired myopathies. As such, this review attempts to highlight the clinical and histopathologic aspects of mitochondrial dysfunction seen in hereditary and acquired myopathies, as well as discuss potential mechanisms leading to mitochondrial dysfunction and therapies to restore mitochondrial function.

Genetic therapies and potential therapeutic applications of CRISPR activators in the eye.

Conventional gene therapy involving supplementation only treats loss-of-function diseases and is limited by viral packaging sizes, precluding therapy of large genes. The discovery of CRISPR/Cas has led to a paradigm shift in the field of genetic therapy, with the promise of precise gene editing, thus broadening the range of diseases that can be treated. The initial uses of CRISPR/Cas have focused mainly on gene editing or silencing of abnormal variants via utilising Cas endonuclease to trigger the target cell endogenous non-homologous end joining. Subsequently, the technology has evolved to modify the Cas enzyme and even its guide RNA, leading to more efficient editing tools in the form of base and prime editing. Further advancements of this CRISPR/Cas technology itself have expanded its functional repertoire from targeted editing to programmable transactivation, shifting the therapeutic focus to precise endogenous gene activation or upregulation with the potential for epigenetic modifications. In vivo experiments using this platform have demonstrated the potential of CRISPR-activators (CRISPRa) to treat various loss-of-function diseases, as well as in regenerative medicine, highlighting their versatility to overcome limitations associated with conventional strategies. This review summarises the molecular mechanisms of CRISPRa platforms, the current applications of this technology in vivo, and discusses potential solutions to translational hurdles for this therapy, with a focus on ophthalmic diseases.

On RNA-programmable gene modulation as a versatile set of principles targeting muscular dystrophies.

The repurposing of RNA-programmable CRISPR systems from genome editing into epigenome editing tools is gaining pace, including in research and development efforts directed at tackling human disorders. This momentum stems from the increasing knowledge regarding the epigenetic factors and networks underlying cell physiology and disease etiology and from the growing realization that genome editing principles involving chromosomal breaks generated by programmable nucleases are prone to unpredictable genetic changes and outcomes. Hence, engineered CRISPR systems are serving as versatile DNA-targeting scaffolds for heterologous and synthetic effector domains that, via locally recruiting transcription factors and chromatin remodeling complexes, seek interfering with loss-of-function and gain-of-function processes underlying recessive and dominant disorders, respectively. Here, after providing an overview about epigenetic drugs and CRISPR-Cas-based activation and interference platforms, we cover the testing of these platforms in the context of molecular therapies for muscular dystrophies. Finally, we examine attributes, obstacles, and deployment opportunities for CRISPR-based epigenetic modulating technologies.

Quantifying Muscle Regeneration: Activated Muscle Satellite Cells and New Regenerated Myofibers in Chronic and Acute Degeneration Models.

Regeneration is a remarkable characteristic of the skeletal muscle. Triggered by common lesions, regeneration is stimulated resulting in muscle fiber repair and restoration of muscle homeostasis in normal muscle. In genetic dystrophic muscle, the cycle of degeneration/regeneration is an endless loop that leads to impaired regeneration and substitution of muscle fibers by connective and adipose tissue, causing muscle weakness. Identification and characterization of muscle regeneration steps can help discover potential therapy targets for muscle diseases and aging. Muscle regeneration markers such as the number of satellite cells in the muscle, the proportion of activated satellite cells, and the quantity of regenerating muscle fiber can be quantified using immunolabeling.Here we are presenting a quantitative method to measure muscle regeneration that can be applied to different proposals. To demonstrate the protocol applicability, we used models for acute and chronic muscle injuries. As model of acute degeneration, a wild-type C57BL6 mice with muscle injury induced by electroporation was used, and the muscle was analyzed after 5 and 10 days post-injury. DMDmdx mouse muscle was used as a model of chronic degeneration. The methodologies presented here are among the gold standard methodologies for muscle regeneration analysis and can be easily applied to any type of muscle regeneration study.

Comprehensive analysis of 2097 patients with dystrophinopathy based on a database from 2011 to 2021.

BACKGROUND: An increasing number of clinical trials for new therapeutic strategies are underway or being considered for dystrophinopathy. Having detailed data on the natural progression of this condition is crucial for assessing the effectiveness of new drugs. However, there's a lack of data regarding the long-term data on the natural course and how it's managed in China. In this study, we offer a comprehensive overview of clinical and molecular findings, as well as treatment outcomes in the Chinese population. METHODS: Institutional data on all patients with dystrophinopathy from August 2011 to August 2021 were retrospectively reviewed. The data included geographic distribution, age at diagnosis, molecular findings, and treatment options, such as corticosteroids, cardiac interventions, and clinical outcomes. RESULTS: In total, 2097 patients with dystrophinopathy, including 1703 cases of Duchenne muscular dystrophy (DMD), 311 cases of Becker muscular dystrophy (BMD), 46 cases of intermediate muscular dystrophy (IMD), and 37 cases categorized as "pending" (individuals with an undetermined phenotype), were registered in the Children's Hospital of Fudan University database for dystrophinopathy from August 2011 to August 2021. The spectrum of identified variants included exonic deletions (66.6%), exonic duplications (10.7%), nonsense variants (10.3%), splice-site variants (4.5%), small deletions (3.5%), small insertions/duplications (1.8%), and missense variants (0.9%). Four deep intronic variants and two inversion variants were identified. Regarding treatment, glucocorticoids were administered to 54.4% of DMD patients and 39.1% of IMD patients. The median age at loss of ambulation was 2.5 years later in DMD patients who received glucocorticoid treatment. Overall, one cardiac medicine at least was prescribed to 7.4% of DMD patients, 8.3% of IMD patients, and 2.6% of BMD patients. Additionally, ventilator support was required by four DMD patients. Eligibility for exon skipping therapy was found in 55.3% of DMD patients, with 12.9%, 10%, and 9.6% of these patients being eligible for skipping exons 51, 53, and 45, respectively. CONCLUSIONS: This is one of the largest studies to have evaluated the natural history of dystrophinopathy in China, which is particularly conducive to the recruitment of eligible patients for clinical trials and the provision of real-world data to support drug development.

Molecular diagnosis of Alpha-sarcoglycanopathies by NGS in seven Moroccan families and report of two novel variants.

BACKGROUND: Limb-girdle muscular dystrophies constitute a heterogeneous group of neuromuscular diseases, both clinically and genetically. Limb-girdle muscular dystrophy by alpha-sarcoglycan deficiency or LGMD R3 α-sarcoglycan-related is a subtype of the autosomal recessive sarcoglycanopathies caused by variants in the alpha-sarcoglycan gene (SGCA) at 17q21.33. It appears in childhood by progressive weakness of pelvic and/or scapular girdle muscles and calf hypertrophy, with a wide range of clinical inter- and intra-familial clinical variability. AIMS: Our report extends the molecular spectrum of SGCA gene with the identification of variant disease causing and will help for better management of patients and genetic counseling of families. METHODS: In our study, seven unrelated families presented a clinical and paraclinical picture consistent with alpha-sarcoglycanopathy. A molecular study using Next-Generation Sequencing (NGS) was carried out on them. RESULTS: Six different homozygous variants of the SGCA gene were identified in the patients analyzed, including four previously reported variants and two novel variants predicted to be deleterious by the prediction tools. CONCLUSIONS: Our results expand the spectrum of variants in Moroccan patients with sarcoglycanopathy, specifically LGMDR3, most importantly as this form is not common in the Moroccan population.

Co-occurrence of CAPN3 homozygous mutation and CCTG expansion in the CNBP gene in a patient with muscular dystrophy.

Purpose: Muscular dystrophy is a group of heterogeneous diseases causing progressive muscle weakness and atrophy. Many types have been defined, including Duchenne/Becker, myotonic, limb-girdle, congenital, and facioscapulohumeral muscular dystrophies. This study aims to present the first patient with both a homozygous CAPN3 mutation and a CCTG expansion in the CNBP gene, which suggests the co-occurrence of two diseases in a single patient. Case description: Homozygous pathogenic variant c.550delA (p.Thr184ArgfsTer36) in the CAPN3 gene, as well as a heterozygous expansion of a CCTG repeat of the CNBP gene, were identified in a single patient. Segregation analysis showed both maternal and paternal heterozygous carriers for CAPN3 mutation, and a maternally inherited CNBP expansion. Comment: In general, the co-occurrence of two diseases in a single patient is considered as uncommon, although possible, and therefore it should be taken into consideration in the populations with a relatively high prevalence of myotonic dystrophy type 2.

Bubble-graft coverage after Descemet Membrane Endothelial Keratoplasty depending on gaze angle.

PURPOSE: In Descemet Membrane Endothelial Keratoplasty (DMEK) a gas bubble is usually used to attach the graft to the host cornea. In this study, we observed the bubble size and bubble-graft coverage at different gaze angles following DMEK. METHODS: This observational prospective study analyzed 465 images of patients who underwent an uneventful DMEK. Intraoperatively, the anterior chamber was filled up to 90% of its volume with a 20% Sulfur Hexafluoride (SF6) gas-air mixture. Postoperatively, the bubble was photographed daily in different gaze angles ranging from a supine position (0°) to an upright position (90°) and a slightly inclined position (105°). The primary outcomes were bubble-graft coverage and bubble diameters depending on the gaze angle and time after DMEK. RESULTS: The highest bubble-graft coverage was achieved at a 0° gaze angle at all times of measurement. In the first 48 h after DMEK, the mean bubble-graft coverage was over 85% at a gaze angle between 0° and 45°. Starting 72 h after DMEK, the graft coverage declined at all gaze angles. The graft coverage at a 0° gaze angle was 88.61 ± 10.90% after 96 postoperative hours, while the graft coverage was below 85% at all other gaze angles. CONCLUSION: Our clinical results provide novel insight into variation in bubble-graft coverage as a function of gaze angle and may be used to aid in patient counselling for appropriate body positioning following DMEK to prevent early graft detachment. Maintaining supine positioning seems to be most advantageous starting 48 h after DMEK.