Pearls & Oy-sters: Use of Muscle Ultrasound as a Clinical Tool in INPP5K-Related Muscular Dystrophy: A Case Report.

Biallelic pathogenic variants in INPP5K have been associated with a rare congenital muscular dystrophy that presents with muscle weakness, short stature, intellectual disability, and early-onset cataracts. A characteristic pattern of muscle involvement has been identified on muscle MRI in a small case series, including involvement of the vasti, anterior tibialis, and peronei with relative sparing of the rectus femoris, sartorius, and gracilis muscles. This case describes a patient who initially presented in infancy with hypotonia, motor delays, and short stature. She was eventually diagnosed at almost 3 years with INPP5K-related muscular dystrophy after extensive workup that included multiple subspecialist evaluations, genetic testing for non-neuromuscular disorders, and a muscle biopsy. Muscle ultrasound (MUS) was performed at the end of this diagnostic journey, which demonstrated characteristic features that supported the diagnosis, including notable involvement of the vasti muscles with sparing of the rectus femoris. This case highlights how MUS can be a useful tool in the evaluation of children for neuromuscular disorders. MUS can help refine the differential and guide further steps in evaluation when performed early in the diagnostic process and may help clarify interpretation of genetic testing results when performed later.

A CCG expansion in ABCD3 causes oculopharyngodistal myopathy in individuals of European ancestry.

Oculopharyngodistal myopathy (OPDM) is an inherited myopathy manifesting with ptosis, dysphagia and distal weakness. Pathologically it is characterised by rimmed vacuoles and intranuclear inclusions on muscle biopsy. In recent years CGG • CCG repeat expansion in four different genes were identified in OPDM individuals in Asian populations. None of these have been found in affected individuals of non-Asian ancestry. In this study we describe the identification of CCG expansions in ABCD3, ranging from 118 to 694 repeats, in 35 affected individuals across eight unrelated OPDM families of European ancestry. ABCD3 transcript appears upregulated in fibroblasts and skeletal muscle from OPDM individuals, suggesting a potential role of over-expression of CCG repeat containing ABCD3 transcript in progressive skeletal muscle degeneration. The study provides further evidence of the role of non-coding repeat expansions in unsolved neuromuscular diseases and strengthens the association between the CGG • CCG repeat motif and a specific pattern of muscle weakness.

Pharmacological Treatments and Therapeutic Targets in Muscle Dystrophies Generated by Alterations in Dystrophin-Associated Proteins.

Muscular dystrophies (MDs) are a heterogeneous group of diseases of genetic origin characterized by progressive skeletal muscle degeneration and weakness. There are several types of MDs, varying in terms of age of onset, severity, and pattern of the affected muscles. However, all of them worsen over time, and many patients will eventually lose their ability to walk. In addition to skeletal muscle effects, patients with MDs may present cardiac and respiratory disorders, generating complications that could lead to death. Interdisciplinary management is required to improve the surveillance and quality of life of patients with an MD. At present, pharmacological therapy is only available for Duchene muscular dystrophy (DMD)-the most common type of MD-and is mainly based on the use of corticosteroids. Other MDs caused by alterations in dystrophin-associated proteins (DAPs) are less frequent but represent an important group within these diseases. Pharmacological alternatives with clinical potential in patients with MDs and other proteins associated with dystrophin have been scarcely explored. This review focuses on drugs and molecules that have shown beneficial effects, mainly in experimental models involving alterations in DAPs. The mechanisms associated with the effects leading to promising results regarding the recovery or maintenance of muscle strength and reduction in fibrosis in the less-common MDs (i.e., with respect to DMD) are explored, and other therapeutic targets that could contribute to maintaining the homeostasis of muscle fibers, involving different pathways, such as calcium regulation, hypertrophy, and maintenance of satellite cell function, are also examined. It is possible that some of the drugs explored here could be used to affordably improve the muscular function of patients until a definitive treatment for MDs is developed.

The Multifaceted Cause of Lipid Storage Myopathies, Genetics, and Treatment.

Several inherited metabolic fatty acid disorders present with myopathies. Skeletal muscle accounts for 40% of the body and is important for metabolism, exercise, and movement. Muscle energy failure is manifested by metabolic crises with muscle weakness, sometimes associated with muscle fatigue and failure resulting in acute necrosis or rhabdomyolysis/myoglobinuria episodes. Lack of energy leads to muscle necrosis. Other presentations are weakness and myalgias with lipid storage myopathies in the biopsy. The biomarkers of such disorders are acyl-carnitine with various profiles and need to be carefully evaluated to plan supplementary therapy and specific diets. If red flags are not distinctly followed and diagnosed in time they might lead to a metabolic or cardiac failure.

Thrombospondin-4 deletion does not exacerbate muscular dystrophy in ß-sarcoglycan-deficient and laminin α2 chain-deficient mice.

Muscular dystrophy is a group of genetic disorders that lead to muscle wasting and loss of muscle function. Identifying genetic modifiers that alleviate symptoms or enhance the severity of a primary disease helps to understand mechanisms behind disease pathology and facilitates discovery of molecular targets for therapy. Several muscular dystrophies are caused by genetic defects in the components of the dystrophin-glycoprotein adhesion complex (DGC). Thrombospondin-4 overexpression has been shown to mitigate dystrophic disease in mouse models for Duchenne muscular dystrophy (dystrophin deficiency) and limb-girdle muscular dystrophy type 2F (LGMD2F, δ-sarcoglycan deficiency), while deletion of the thrombospondin-4 gene exacerbated the diseases. Hence, thrombospondin-4 has been considered a candidate molecule for therapy of muscular dystrophies involving the DGC. We have investigated whether thrombospondin-4 could act as a genetic modifier for other DGC-associated diseases: limb-girdle muscular dystrophy type 2E (LGMD2E, ß-sarcoglycan deficiency) and laminin α2 chain-deficient muscular dystrophy (LAMA2-RD). Deletion of the thrombospondin-4 gene in mouse models for LGMD2E and LAMA2-RD, respectively, did not result in worsening of the dystrophic phenotype. Loss of thrombospondin-4 did not enhance sarcolemma damage and did not impair trafficking of transmembrane receptors integrin α7ß1 and dystroglycan in double knockout muscles. Our results suggest that thrombospondin-4 might not be a relevant therapeutic target for all muscular dystrophies involving the DGC. This data also demonstrates that molecular pathology between very similar diseases like LGMD2E and 2F can differ significantly.

Congenital LMNA-Related Muscular Dystrophy in Paediatrics: Cardiac Management in Monozygotic Twins.

Pathogenic variants in LMNA have been associated with a wide spectrum of muscular conditions: the laminopathies. LMNA-related congenital muscular dystrophy is a laminopathy characterised by the early onset of symptoms and often leads to a fatal outcome at young ages. Children face a heightened risk of malignant arrhythmias. No established paediatric protocols for managing this condition are available. We review published cases and provide insights into disease progression in two twin sisters with LMNA-related muscular dystrophy. Our objective is to propose a cardiac surveillance and management plan tailored specifically for paediatric patients. We present a family of five members, including two twin sisters with LMNA-related muscular dystrophy. A comprehensive neuromuscular and cardiac work-up was performed in all family members. Genetic analysis using massive sequencing technology was performed in both twins. Clinical assessment showed that only the twins showed diagnoses of LMNA-related muscular dystrophy. Follow-up showed an early onset of symptoms and life-threatening arrhythmias, with differing disease progressions despite both twins passing away. Genetic analysis identified a de novo rare missense deleterious variant in the LMNA gene. Other additional rare variants were identified in genes associated with myasthenic syndrome. Early-onset neuromuscular symptoms could be related to a prognosis of worse life-threatening arrhythmias in LMNA related muscular dystrophy. Being a carrier of other rare variants may be a modifying factor in the progression of the phenotype, although further studies are needed. There is a pressing need for specific cardiac recommendations tailored to the paediatric population to mitigate the risk of malignant arrhythmias.

Polymerizing laminins in development, health, and disease.

Polymerizing laminins are multi-domain basement membrane (BM) glycoproteins that self-assemble into cell-anchored planar lattices to establish the initial BM scaffold. Nidogens, collagen-IV and proteoglycans then bind to the scaffold at different domain loci to create a mature BM. The LN domains of adjacent laminins bind to each other to form a polymer node, while the LG domains attach to cytoskeletal-anchoring integrins and dystroglycan, as well as to sulfatides and heparan sulfates. The polymer node, the repeating unit of the polymer scaffold, is organized into a near-symmetrical triskelion. The structure, recently solved by cryo-electron microscopy in combination with AlphaFold2 modeling and biochemical studies, reveals how the LN surface residues interact with each other and how mutations cause failures of self-assembly in an emerging group of diseases, the LN-lamininopathies, that include LAMA2-related dystrophy and Pierson syndrome.

Diagnoses of muscular dystrophy in a veterans health system.

INTRODUCTION/AIMS: Early diagnosis of a chronic neuromuscular disease such as muscular dystrophy (MD) generally excludes an individual from active-duty military service. However, it is not known whether veterans are sometimes diagnosed with milder forms of MD at a later timepoint. We aimed to determine the prevalence of MD in a veterans health system. METHODS: We abstracted clinical and genetic test data on patients who received care for a diagnosis of MD at the North Florida/South Georgia Veterans Health System between 2008 and 2021. We then determined which of these individuals would meet criteria for a definite diagnosis of MD, based on electrodiagnostic testing, muscle biopsy, and genetic testing of the individual or an affected first degree relative. RESULTS: We identified 12 patients with definite MD and 36 with possible or probable MD. The definite cases included myotonic dystrophy type 1 (4), myotonic dystrophy type 2 (3), oculopharyngeal MD (2), Becker MD (1), distal MD (1), and facioscapulohumeral MD (1). At least five of the cases classified as definite developed symptoms after discharge from active duty. DISCUSSION: Clinicians who care for veterans should be knowledgeable about, and have access to, diagnostic testing and treatment options for MD. When conducting MD surveillance, it is important to include veterans health systems as a data source. Mild cases of MD and those of later onset appear to be compatible in some cases with successful completion of military service.

A novel deep intronic variant in LAMA2 identified by RNA sequencing.

LAMA2-related muscular dystrophy is caused by pathogenic variants of the alpha2 subunit of Laminin. This common form of muscular dystrophy is characterized by elevated CK >1000IU/L, dystrophic changes on muscle biopsy, complete or partial absence of merosin staining, and both central and peripheral nervous system involvement. Advancements in genomic testing using NGS and wider application of RNA sequencing has expanded our knowledge of novel non-coding pathogenic variants in LAMA2. RNA sequencing is an increasingly utilized technique to directly analyze the transcriptome, through creation of a complementary DNA (cDNA) from the transcript within a tissue sample. Here we describe a homozygous deep intronic variant that produces a novel splice junction in LAMA2 identified by RNA sequencing analysis in a patient with a clinical phenotype in keeping with LAMA2-related muscular dystrophy. Furthermore, in this case merosin staining was retained suggestive of a functional deficit.

Defects in integrin complex formation promote CHKB-mediated muscular dystrophy.

Phosphatidylcholine (PC) is the major membrane phospholipid in most eukaryotic cells. Bi-allelic loss of function variants in CHKB, encoding the first step in the synthesis of PC, is the cause of a rostrocaudal muscular dystrophy in both humans and mice. Loss of sarcolemma integrity is a hallmark of muscular dystrophies; however, how this occurs in the absence of choline kinase function is not known. We determine that in Chkb -/- mice there is a failure of the α7ß1 integrin complex that is specific to affected muscle. We observed that in Chkb -/- hindlimb muscles there is a decrease in sarcolemma association/abundance of the PI(4,5)P2 binding integrin complex proteins vinculin, and α-actinin, and a decrease in actin association with the sarcolemma. In cells, pharmacological inhibition of choline kinase activity results in internalization of a fluorescent PI(4,5)P2 reporter from discrete plasma membrane clusters at the cell surface membrane to cytosol, this corresponds with a decreased vinculin localization at plasma membrane focal adhesions that was rescued by overexpression of CHKB.

Anaesthesia management of a patient with Bethlem Myopathy for elective tonsillectomy: a case report.

BACKGROUND: Bethlem Myopathy is a collagen VI-related myopathy presenting as a rare hereditary muscular disorder with progressive muscular weakness and joint contractures. Despite its milder clinical course relative to other myopathies, anaesthetic management can be challenging. High arched palates and fixed flexion deformities may contribute to a difficult airway. A progressive decline in pulmonary function can present later into adulthood. This respiratory decline can carry secondary cardiovascular consequences due to the progressive nature of restrictive lung disease, including right sided heart disease and pulmonary hypertension. We describe a case of a male patient with Bethlem Myopathy undergoing anaesthesia, to contribute to the limited body of literature on this condition and enhance awareness and guidance amongst anaesthesiologists on approaching patients with this condition. This is the first case report within the literature of its kind. CASE PRESENTATION: This case details a 33-year-old male with Bethlem Myopathy undergoing tonsillectomy. Diagnosed in childhood following developmental delays, the patient had no prior anaesthetic exposure and no family history of anaesthetic complications. Anaesthetic induction was achieved without complications, avoiding depolarizing muscle relaxants and careful airway management. Extreme care was taken in patient positioning to prevent complications. The surgery proceeded without incident and muscle paralysis was reversed with Suggammadex, resulting in no adverse post-operative respiratory complications. The patient was discharged on the first post-operative day without any respiratory or cardiovascular compromise. CONCLUSIONS: Bethlem Myopathy, while often exhibiting a mild clinical course, can present anaesthetic challenges. Awareness of potential complications including a difficult airway, cardiovascular and respiratory implications as well as the need for specialised monitoring and positioning is crucial to ensure a safe peri-operative course.

Ambient floor vibration sensing advances the accessibility of functional gait assessments for children with muscular dystrophies.

Muscular dystrophies (MD) are a group of genetic neuromuscular disorders that cause progressive weakness and loss of muscles over time, influencing 1 in 3500-5000 children worldwide. New and exciting treatment options have led to a critical need for a clinical post-marketing surveillance tool to confirm the efficacy and safety of these treatments after individuals receive them in a commercial setting. For MDs, functional gait assessment is a common approach to evaluate the efficacy of the treatments because muscle weakness is reflected in individuals' walking patterns. However, there is little incentive for the family to continue to travel for such assessments due to the lack of access to specialty centers. While various existing sensing devices, such as cameras, force plates, and wearables can assess gait at home, they are limited by privacy concerns, area of coverage, and discomfort in carrying devices, which is not practical for long-term, continuous monitoring in daily settings. In this study, we introduce a novel functional gait assessment system using ambient floor vibrations, which is non-invasive and scalable, requiring only low-cost and sparsely deployed geophone sensors attached to the floor surface, suitable for in-home usage. Our system captures floor vibrations generated by footsteps from patients while they walk around and analyzes such vibrations to extract essential gait health information. To enhance interpretability and reliability under various sensing scenarios, we translate the signal patterns of floor vibration to pathological gait patterns related to MD, and develop a hierarchical learning algorithm that aggregates insights from individual footsteps to estimate a person's overall gait performance. When evaluated through real-world experiments with 36 subjects (including 15 patients with MD), our floor vibration sensing system achieves a 94.8% accuracy in predicting functional gait stages for patients with MD. Our approach enables accurate, accessible, and scalable functional gait assessment, bringing MD progressive tracking into real life.

Is Cardiac Transplantation Still a Contraindication in Patients with Muscular Dystrophy-Related End-Stage Dilated Cardiomyopathy? A Systematic Review.

Inherited muscular diseases (MDs) are genetic degenerative disorders typically caused by mutations in a single gene that affect striated muscle and result in progressive weakness and wasting in affected individuals. Cardiac muscle can also be involved with some variability that depends on the genetic basis of the MD (Muscular Dystrophy) phenotype. Heart involvement can manifest with two main clinical pictures: left ventricular systolic dysfunction with evolution towards dilated cardiomyopathy and refractory heart failure, or the presence of conduction system defects and serious life-threatening ventricular arrhythmias. The two pictures can coexist. In these cases, heart transplantation (HTx) is considered the most appropriate option in patients who are not responders to the optimized standard therapeutic protocols. However, cardiac transplant is still considered a relative contraindication in patients with inherited muscle disorders and end-stage cardiomyopathies. High operative risk related to muscle impairment and potential graft involvement secondary to the underlying myopathy have been the two main reasons implicated in the generalized reluctance to consider cardiac transplant as a viable option. We report an overview of cardiac involvement in MDs and its possible association with the underlying molecular defect, as well as a systematic review of HTx outcomes in patients with MD-related end-stage dilated cardiomyopathy, published so far in the literature.

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.

System-level analysis of genes mutated in muscular dystrophies reveals a functional pattern associated with muscle weakness distribution.

Muscular dystrophies (MDs) are inherited genetic diseases causing weakness and degeneration of muscles. The distribution of muscle weakness differs between MDs, involving distal muscles or proximal muscles. While the mutations in most of the MD-associated genes lead to either distal or proximal onset, there are also genes whose mutations can cause both types of onsets. We hypothesized that the genes associated with different MD onsets code proteins with distinct cellular functions. To investigate this, we collected the MD-associated genes and assigned them to three onset groups: genes mutated only in distal onset dystrophies, genes mutated only in proximal onset dystrophies, and genes mutated in both types of onsets. We then systematically evaluated the cellular functions of these gene sets with computational strategies based on functional enrichment analysis and biological network analysis. Our analyses demonstrate that genes mutated in either distal or proximal onset MDs code proteins linked with two distinct sets of cellular processes. Interestingly, these two sets of cellular processes are relevant for the genes that are associated with both onsets. Moreover, the genes associated with both onsets display high centrality and connectivity in the network of muscular dystrophy genes. Our findings support the hypothesis that the proteins associated with distal or proximal onsets have distinct functional characteristics, whereas the proteins associated with both onsets are multifunctional.

Genetic profile of Brazilian patients with LAMA2-related dystrophies.

LAMA2-related dystrophies (LAMA2-RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype-phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2-RD patients enrolled at seven research centers in Brazil. We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049_2050del, c.3976 C>T, c.5234+1G>A, and c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A>C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (p < 0.0001). Although no specific hotspot regions existed in the LAMA2, 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960-17C>A) and revealed an out-of-frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype-genotype correlations and provided valuable insights, particularly regarding the Latin American population.