Distal Myopathy Research Articles

VP.65 Screening of small molecules for activation of GNE protein carrying non-catalytic site mutation based on molecular docking simulation

GNE myopathy is an autosomal recessive distal myopathy caused by pathogenic variants in <i>GNE</i> gene, which encodes a protein having two enzymatic activities, UDP-GlcNAc 2-epimerase and ManNAc kinase on sialic acid biosynthesis. We have identified a variant, c.620A>T (p.D207V), with which majority of the homozygotes are healthy, while compound heterozygotes develop myopathy. Notwithstanding, the identified three affected homozygotes had no additional variation in the <i>GNE</i> gene nor in genes in sialic acid biosynthetic pathway, while their sialylation was mildly, but certainly decreased. We hypothesized this discrepancy can be explainable by partial failure of GNE oligomerization. The constructed full-length GNE structure by Alphafold2 indicated that Asp207 locates midway between each domain and near subunit interface, but not in catalytic site. The mutant was predicted to cause no severe changes in a whole structure, though the change of polarity of the mutated residue and failure of oligomerization are hypothesized to affect intramolecular and inter-subunit ManNAc transfer between domains. Since this pathogenic variant is in non-catalytic site and did not cause drastic structural changes, ManNAc production has possibility to be pharmacologically recovered by small molecules. Here, we performed <i>in silico</i> prediction-based screening to identify the drugs that activate GNE. First, we targeted a deep narrow cavity found in the back of the allosteric site, to find small molecules that interfere with negative feedback inhibition. We then performed docking simulation of 8042 known compounds in Drugbank database to the cavity, and selected well-fitted 8 compounds. We measured the effect of the compounds on ManNAc production. However, no compounds could activate it nor repress inhibitory effect of CMP-NeuAc. In this presentation, we will discuss brand-new approach to find activators for endogenous mutated GNE protein using structural information.

P.156 Novel repeat expansions in PLIN4 in two Spanish families suffering from autosomal dominant distal myopathy with unique pathological features

P.156 Novel repeat expansions in PLIN4 in two Spanish families suffering from autosomal dominant distal myopathy with unique pathological features

P.151 - ABSTRACT WITHDRAWN Myopathy caused by mutations in the HNRNPA1 gene

We previously described an adult-onset distal myopathy (MPD3, OMIM #610099) in a large Finnish family with a dominant mode of inheritance. Small hand muscles (intrinsic, thenar and hypothenar) were first involved with spread to the lower legs and later proximal muscles. Dystrophic changes with rimmed vacuoles and cytoplasmic inclusions were observed in muscle biopsies at advanced stage. The causative variant was identified in the <i>HNRNPA1</i> gene. This was a heterozygous deletion of the DNA segment chr12:54677979-54678138 spanning the second last exon 10 of the gene. Whole RNA sequencing showed that the main RNA product of the mutant allele results from splicing of exon 9 to 11 and encodes the predicted protein p.Gly356Asnfs*4. Additional likely disease-causing <i>HNRNPA1</i> variants were identified in other families with compatible phenotypes. Functional characterization of p.Gly356Asnfs*4 and other novel variants in cell culture models is ongoing to characterize their effects on protein properties and on stress granule dynamics.

Cardiovascular Involvement in Pediatric FLNC Variants: A Case Series of Fourteen Patients.

Filamin C is a protein specifically expressed in myocytes and cardiomyocytes and is involved in several biological functions, including sarcomere contractile activity, signaling, cellular adhesion, and repair. FLNC variants are associated with different disorders ranging from striated muscle (myofibrillar distal or proximal) myopathy to cardiomyopathies (CMPs) (restrictive, hypertrophic, and dilated), or both. The outcome depends on functional consequences of the detected variants, which result either in FLNC haploinsufficiency or in an aberrant protein, the latter affecting sarcomere structure leading to protein aggregates. Cardiac manifestations of filaminopathies are most often described as adult onset CMPs and limited reports are available in children or on other cardiac spectrums (congenital heart defects—CHDs, or arrhythmias). Here we report on 13 variants in 14 children (2.8%) out of 500 pediatric patients with early-onset different cardiac features ranging from CMP to arrhythmias and CHDs. In one patient, we identified a deletion encompassing FLNC detected by microarray, which was overlooked by next generation sequencing. We established a potential genotype–phenotype correlation of the p.Ala1186Val variant in severe and early-onset restrictive cardiomyopathy (RCM) associated with a limb-girdle defect (two new patients in addition to the five reported in the literature). Moreover, in three patients (21%), we identified a relatively frequent finding of long QT syndrome (LQTS) associated with RCM (n = 2) and a hypertrabeculated left ventricle (n = 1). RCM and LQTS in children might represent a specific red flag for FLNC variants. Further studies are warranted in pediatric cohorts to delineate potential expanding phenotypes related to FLNC.

Anoctamin 5 (ANO5) Muscle Disorders: A Narrative Review.

Anoctaminopathy-5 refers to a group of hereditary skeletal muscle or bone disorders due to mutations in the anoctamin 5 (ANO5)-encoding gene, ANO5. ANO5 is a 913-amino acid protein of the anoctamin family that functions predominantly in phospholipid scrambling and plays a key role in the sarcolemmal repairing process. Monoallelic mutations in ANO5 give rise to an autosomal dominant skeletal dysplastic syndrome (gnathodiaphyseal dysplasia or GDD), while its biallelic mutations underlie a continuum of four autosomal recessive muscle phenotypes: (1). limb–girdle muscular dystrophy type R12 (LGMDR12); (2). Miyoshi distal myopathy type 3 (MMD3); (3). metabolic myopathy-like (pseudometabolic) phenotype; (4). asymptomatic hyperCKemia. ANO5 muscle disorders are rare, but their prevalence is relatively high in northern European populations because of the founder mutation c.191dupA. Weakness is generally asymmetric and begins in proximal muscles in LGMDR12 and in distal muscles in MMD3. Patients with the pseudometabolic or asymptomatic hyperCKemia phenotype have no weakness, but conversion to the LGMDR12 or MMD3 phenotype may occur as the disease progresses. There is no clear genotype–phenotype correlation. Muscle biopsy displays a broad spectrum of pathology, ranging from normal to severe dystrophic changes. Intramuscular interstitial amyloid deposits are observed in approximately half of the patients. Symptomatic and supportive strategies remain the mainstay of treatment. The recent development of animal models of ANO5 muscle diseases could help achieve a better understanding of their underlying pathomechanisms and provide an invaluable resource for therapeutic discovery.

Expanded clinical spectrum of oculopharyngodistal myopathy type 1.

Heterozygous CGG repeat expansions in low-density lipoprotein receptor-related protein 12 (LRP12) have recently been identified as a cause of oculopharyngodistal myopathy (OPDM), and the disease is designated as OPDM type 1 (OPDM1). In contrast to broadening of our knowledge on the genetic background of OPDM, what we know of the clinical phenotype of genetically confirmed OPDM1 remains limited. This investigation was a single-center case series study of OPDM consisting of ten patients from seven families. Repeat-primed polymerase chain reaction and Southern blot analyses were performed to confirm the CGG repeat expansions in LRP12. Clinical findings were retrospectively reviewed. Seven patients from five families were identified as having CGG repeat expansions in LRP12. We found a high prevalence of axial muscle involvement, such as neck muscle weakness (6/7) and fatty infiltration in the rectus abdominis muscle, as revealed by computed tomography (5/5). We identified patients with very subtle oculopharyngeal symptoms, mimicking isolated distal myopathy. Muscle specimens were collected from the biceps brachii and tibialis anterior muscles of three patients. Myopathic changes were more severe with more atrophic fibers forming clusters in the tibialis anterior than the biceps brachii muscles of these three patients. No rimmed vacuoles were observed in the biceps brachii muscles in two of the three patients. This study shows the expanded clinical spectrum of OPDM1, highlighting the importance of axial muscle evaluation in OPDM1. Considering patients with very subtle oculopharyngeal symptoms, genetic analysis of LRP12 should be considered in patients with isolated distal myopathy.

ALS mutations in the TIA-1 prion-like domain trigger highly condensed pathogenic structures

T cell intracellular antigen-1 (TIA-1) plays a central role in stress granule (SG) formation by self-assembly via the prion-like domain (PLD). In the TIA-1 PLD, amino acid mutations associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) or Welander distal myopathy (WDM), have been identified. However, how these mutations affect PLD self-assembly properties has remained elusive. In this study, we uncovered the implicit pathogenic structures caused by the mutations. NMR analysis indicated that the dynamic structures of the PLD are synergistically determined by the physicochemical properties of amino acids in units of five residues. Molecular dynamics simulations and three-dimensional electron crystallography, together with biochemical assays, revealed that the WDM mutation E384K attenuated the sticky properties, whereas the ALS mutations P362L and A381T enhanced the self-assembly by inducing β-sheet interactions and highly condensed assembly, respectively. These results suggest that the P362L and A381T mutations increase the likelihood of irreversible amyloid fibrillization after phase-separated droplet formation, and this process may lead to pathogenicity.

Myogenesis defects in a patient-derived iPSC model of hereditary GNE myopathy

Hereditary muscle diseases are disabling disorders lacking effective treatments. UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) myopathy (GNEM) is an autosomal recessive distal myopathy with rimmed vacuoles typically manifesting in late adolescence/early adulthood. GNE encodes the rate-limiting enzyme in sialic acid biosynthesis, which is necessary for the proper function of numerous biological processes. Outside of the causative gene, very little is known about the mechanisms contributing to the development of GNE myopathy. In the present study, we aimed to address this knowledge gap by querying the underlying mechanisms of GNE myopathy using a patient-derived induced pluripotent stem-cell (iPSC) model. Control and patient-specific iPSCs were differentiated down a skeletal muscle lineage, whereby patient-derived GNEM iPSC clones were able to recapitulate key characteristics of the human pathology and further demonstrated defects in myogenic progression. Single-cell RNA sequencing time course studies revealed clear differences between control and GNEM iPSC-derived muscle precursor cells (iMPCs), while pathway studies implicated altered stress and autophagy signaling in GNEM iMPCs. Treatment of GNEM patient-derived iMPCs with an autophagy activator improved myogenic differentiation. In summary, we report an in vitro, iPSC-based model of GNE myopathy and implicate defective myogenesis as a contributing mechanism to the etiology of GNE myopathy.

Dysferlinopathies: Clinical and genetic variability.

Dysferlinopathies are a clinically heterogeneous group of diseases caused by mutations in the DYSF gene encoding the dysferlin protein. Dysferlin is mostly expressed in muscle tissues and is localized in the sarcolemma, where it performs its main function of resealing and maintaining of the integrity of the cell membrane. At least four forms of dysferlinopathies have been described: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset, and isolated hyperCKemia. Here we review the clinical features of different forms of dysferlinopathies and attempt to identify genotype-phenotype correlations. Because of the great clinical variability and rarety of the disease and mutations little is known, how different phenotypes develop as a result of different mutations. However, missense mutations seem to induce more severe disease than LoF, which is typical for many muscle dystrophies. The role of several specific mutations and possible gene modifiers is also discussed in the paper.

Recurrent, non-traumatic, non-exertional rhabdomyolysis after immunologic stimuli in a healthy adolescent female: a case report

BackgroundDysferlinopathy refers to a heterogenous group of autosomal recessive disorders that affect a skeletal muscle protein called dysferlin. These mutations are associated with limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, asymptomatic hyperCKemia, and distal myopathy with anterior tibial onset.Case presentationA 16 year old female presented with myalgia, weakness and dark urine one week after her second BNT162b2 mRNA (Pfizer) vaccine. Initial serum creatine kinase (CK) was measured at 153,000 IU/L, eventually up-trending to over 200,000 IU/L. However, stable renal function precluded hemodialysis allowing discharge after 10 days of intravenous (IV) hydration and alkaline diuresis.Just two years prior to the current presentation, the patient was hospitalized following Group A Streptococcal pharyngitis infection complicated by rhabdomyolysis. She presented with fatigue, lower extremity weakness, and dark oliguria with CK measuring 984,800 IU/L. IV hydration was attempted however hemodialysis was ultimately required throughout her 24-day hospital stay. Her episode was presumed to be idiopathic and no further work-up was performed at that time.During the patient’s current hospitalization, she reported similar symptomology (myalgias and weakness) following her first quadrivalent Gardasil vaccine at age 11. No hospitalization was required at that time. A comprehensive workup was now initiated while the patient was being treated for her suspected second or third non-exertional, non-traumatic rhabdomyolysis. Rheumatologic, metabolic, infectious, and endocrinologic workup were all unremarkable. Patient eventually had whole exome sequencing performed which revealed a heterozygous pathogenic variant in the DYSF gene (DYSF c.2643 + 1G > A) encoding dysferlin. No clinically significant sequelae occurred thus far.ConclusionsWhile there have been reports of symptomatic heterozygote carriers of dysferlinopathies, to our knowledge none have been associated with recurrent rhabdomyolysis after immunogenic stimuli. This unique case presentation highlights the importance of a multi-disciplinary care team, the utility of modern whole-exome gene sequencing, and the future challenges of balancing vaccine risk vs benefit.

Autophagic vacuolar myopathy involving the phenotype of spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is a form of autosomal dominant cerebellar ataxia with a wide range of clinical manifestations, including ataxia and pyramidal and extrapyramidal signs. A few SCA3 patients have been noticed to be predisposed to the development of inclusion body myositis. It is still unknown whether muscle can be primarily involved in the pathogenesis of SCA3. This study reported an SCA3 family in which the index patient initially presented with parkinsonism, sensory ataxia, and distal myopathy but the absence of cerebellar and pyramidal symptoms. The clinical and electrophysiological studies implied a possible combination of distal myopathy and sensory-motor neuropathy or neuronopathy. MRI muscle showed selective fat infiltration and absence of denervated edema-like changes, indicating the distal muscle weakness had a myopathic origin. Muscle pathology showed the myopathic involvement, besides neurogenic involvement, characterized by chronic myopathic changes with multiple autophagic vacuoles. Genetic screening revealed expanded CAG of 61 repeats in the ATXN3 gene, which showed co-segregation in the family. Besides the neurogenic origin, the myopathic origin may be partly attributed to the limb weakness of SCA3 patients, which expands the spectrum of the clinical manifestation of SCA3.

Hospital based study on laboratory investigations on heriditary muscle disorders

Background: Myopathies are a group of neuro muscular diseases that cause muscle weakness, cramps, and spasms due to a primary defect of the muscle fiber. We undertook this study of hereditary muscle disorders to identify the clinical patterns and laboratory findings in these conditions and study the correlation between them, which will help in recognizing them early for adequate management with rehabilitation measures and for prognostication. Aim: To assess the correlation between the clinical and investigational profile in Hereditary muscle disorders. Methods: A cross sectional study was conducted among 44 patients with clinical features suggestive of hereditary muscle disorders who sort health care at Institute of neurology, Madras Medical college, Chennai using various investigation techniques like Serum CK measurement, Nerve conduction Study, Electromyography, Muscle biopsy. Results: CK elevation was found in all patients in our study, but the degree of elevation differs among various hereditary muscle disorders. It was maximal (&gt;25 times normal) in patients with DMD (50%), BMD (40%) and in LGMD (4%). High degree of correlation between clinical diagnosis of hereditary muscle disorders and myopathic EMG was found. Myopathic pattern was observed in all patients of Muscular dystrophy, congenital myopathy and distal myopathy.

Expanding the Phenotypic Spectrum of Vocal Cord and Pharyngeal Weakness With Distal Myopathy due to the p.S85C MATR3 Mutation.

ObjectivesThe c.254C>G (p.S85C) MATR3 variant causes vocal cord and pharyngeal weakness with distal myopathy (VCPDM), which is characterized by progressive, asymmetric, predominantly distal muscle weakness, dysphonia, dysphagia, and respiratory impairment. Herein, we describe an Italian patient who harbored the p.S85C MATR3 variant and showed a composite phenotype of VCPDM and sensorimotor polyneuropathy.MethodsThe proband underwent neurologic evaluation, muscular MRI of the lower limbs, neurophysiologic assessment, muscle biopsy, and spirometry. After excluding common acquired and genetic causes of sensorimotor polyneuropathy, a larger group of genes involved in inherited forms of neuropathy, distal myopathy, and motor neuron disorders were analyzed by next-generation sequencing targeted panels.ResultsThe patient, affected by progressive distal muscle weakness and hypotrophy, myalgias, dysphonia, dysphagia, respiratory impairment, and sensory abnormalities, harbored the heterozygous c.254C>G (p.S85C) MATR3 substitution. Neurophysiologic assessment revealed a severe sensorimotor polyneuropathy. Variation of fiber size, central nuclei, and nonrimmed vacuoles were evident at muscle biopsy.DiscussionThis finding extends the MATR3-associated VCPDM phenotypic spectrum and suggests considering MATR3 analysis in suspected congenital polyneuropathies with odd features, including dysphonia, dysphagia, and respiratory insufficiency.

Muscle dystrophies in children

Muscular dystrophies are a heterogeneous inherited group of disorders characterized by a variable distribution of weakness, various ages of onset, the pattern of inheritance, rate of progression, and clinical severity. Muscle degeneration and regeneration characterize muscle biopsy and these disorders are typically associated with elevated serum creatine kinase. Objective: We wanted to study the clinical characteristics of patients with muscle dystrophies and study clinical and genetic correlation in patients with Duchenne muscular dystrophy. Methods: This cross-sectional descriptive study included a cohort of 60 patients diagnosed with muscular dystrophy and fulfilling the inclusion criteria. All patients were subjected to full history taking and full neurological examination. Results: Patients are divided into five groups to study clinical characteristics in each group. 1. Duchenne muscular dystrophy group: included 30 patients who have genetically confirmed DMD cases (50 %), 2. Limb-girdle muscular dystrophy group: included 23 patients (38.3 %), 3. Myotonic dystrophy group: included 3 patients (5 %), 4. Congenital muscular dystrophy group: included 3 patients who were diagnosed clinically as merosin deficient congenital muscle dystrophy (5 %), 5. Distal dystrophy group: included 1 patient with distal muscle dystrophy (1.7 %). Mean age, gender, age of symptoms onset, main motor symptoms, CPK level, echocardiography.

Muscle dystrophies in children

Muscular dystrophies are a heterogeneous inherited group of disorders characterized by a variable distribution of weakness, various ages of onset, the pattern of inheritance, rate of progression, and clinical severity. Muscle degeneration and regeneration characterize muscle biopsy and these disorders are typically associated with elevated serum creatine kinase. Objective: We wanted to study the clinical characteristics of patients with muscle dystrophies and study clinical and genetic correlation in patients with Duchenne muscular dystrophy. Methods: This cross-sectional descriptive study included a cohort of 60 patients diagnosed with muscular dystrophy and fulfilling the inclusion criteria. All patients were subjected to full history taking and full neurological examination. Results: Patients are divided into five groups to study clinical characteristics in each group. 1. Duchenne muscular dystrophy group: included 30 patients who have genetically confirmed DMD cases (50 %), 2. Limb-girdle muscular dystrophy group: included 23 patients (38.3 %), 3. Myotonic dystrophy group: included 3 patients (5 %), 4. Congenital muscular dystrophy group: included 3 patients who were diagnosed clinically as merosin deficient congenital muscle dystrophy (5 %), 5. Distal dystrophy group: included 1 patient with distal muscle dystrophy (1.7 %). Mean age, gender, age of symptoms onset, main motor symptoms, CPK level, echocardiography.

Different electrophysiology patterns in GNE myopathy

BackgroundGNE myopathy is a rare distal myopathy caused by mutations of the GNE gene. A few cases of GNE myopathy accompanied by neurogenic features of electrophysiology mimicking hereditary motor neuropathy were reported recently. We confirmed this feature and described the clinical phenotype and mutations of GNE myopathy in these rare cases.ResultsThe absence of lower limb tendon reflexes, decreased compound muscle action potentials in lower leg motor nerves, and neurogenic pattern of electromyography suggested neuropathy in four patients. However, muscle pathology revealed a predominantly myogenic pattern. The follow-up electroneurography results implied that the compound motor action potential amplitudes deteriorated over time. Next-generation sequencing identified three novel variants of the GNE gene, c.2054T > C (p.Val685Ala), c.424G > A (p.Gly142Arg) and c.944T > C (p.Phe315Ser), as well as two hotspot mutations, c.115C > T(p.Arg39*) and c.620A > T(p.Asp207Val), in these patients. These novel mutations cosegregated with disease in the family.ConclusionsThese rare cases supported the existence of neurogenic features of electrophysiology different from the typical myopathic pattern of GNE myopathy.

Congenital myopathies: The current status.

Within the history of neuromuscular diseases (NMD), congenital myopathies (CM) represent a relatively new category introduced in the mid-nineteen hundreds upon advent and subsequent application of enzyme histochemistry and electron microscopy by establishing the three major CM, central core disease, nemaline myopathy, and centronuclear myopathy which later pluralized each when the molecular era began at the end of last century. Quickly, during the following 5 decades, many new CM entities were described, based on muscle biopsies and their CM-characteristic myopathology, the former a prerequisite to recognizing an individual CM, the latter of the nosological hallmark of the individual CM. When the molecular era ushered in immunohistochemistry the spectrum and nosography of CM altered in that some CM became allelic to other cohorts of NMD, e.g., congenital muscular dystrophies, other muscular dystrophies, distal myopathies based on different or identical mutations in the same gene. The nosological spectrum of a defective gene also enlarged by recognizing several entities with mutations in the same gene, and same or similar nosological conditions originated from mutations in different genes. Lately, however, CM were reported which lacked any individual myopathological hallmarks, but were clearly based on molecular defects, a fair number of them being newly identified ones. Few CM still remain without any molecular clarification. This nosographic development rendered the original definition of such new CM questionable and brought uncertainty to their classification and nomenclature.

Gene analysis and clinical features of 22 GNE myopathy patients.

GNE myopathy is an autosomal recessive distal myopathy caused by a biallelic mutation in UDP-N-acetylglucosamine 2-epomerase/N-acetylmannosamine kinase. In this study, we discuss the clinical features, pathological characteristics, genetic profiles, and atypical clinical manifestations of 22 Chinese GNE patients. Retrospective analysis was performed for GNE myopathy patients at our institute between 2005 and 2021. Histopathological analysis and gene testing were done according to standard protocols. Molecular analysis revealed 14-reported and 7 novel mutations, including c.125G > A (p.P42Q), c.226G > A (p.V76I), c.970C > G (p.H324D), c.155A > G (p.D52G), c.1055G > A (p.R352H), c.1064G > A (p.G355E), and c.491T > C (p.I164T) in GNE. D207V was the most frequent mutation showing an allele frequency of 25%. A total of 21 patients presented classic clinical manifestation, and only 1 patient had signs of proximal muscle weakness. A patient containing p.V603L and p.R160X mutations showed idiopathic thrombocytopenia and distal weakness. There were 4 female patients who experienced rapid deterioration after pregnancy. Our study revealed 7 novel mutations in GNE, where p.D207V was shown as a potential hotspot mutation in Chinese patients. Idiopathic thrombocytopenia should be a concern in GNE myopathy patients. Twenty-seven percent of female patients experienced rapid deterioration during pregnancy or after delivery.

A Case of Muscular Dystrophy with Dilated Cardiomyopathy: Do Not Forget Your Basics

<h3>Introduction</h3> Becker muscular dystrophy (BMD) is an X-linked recessive disorder with dystrophin mutation. Dilated Cardiomyopathy (DCM) is a leading cause of death in BMD patients. Herein, we are presenting a patient with BMD that initially sought medical attention for acute onset of systolic heart failure that highlights the importance of careful clinical assessment and appropriate work up. <h3>Case Report</h3> A 29-year-old male with medical history of asthma presented to the hospital with progressive dyspnea and leg swelling. He was diagnosed with DCM with an LVIDD of 6.5 cm and LV ejection fraction of 20-25% by echocardiogram. Coronary angiogram revealed no coronary artery disease. Initial blood work and electrocardiogram are below (Figure). Cardiac MRI showed severely reduced biventricular systolic function with near circumferential, sub-epicardial to mid-myocardial delayed gadolinium enhancement (Figure). Initial differential diagnosis included prior myocarditis vs. burnt out sarcoidosis. It was subsequently noted that patient began recurrently falling with muscle weakness from age 20 years with chronically elevated AST and CK. His exam was notable for atrophy of the bilateral quadriceps muscles, decreased muscular strength and bilateral calves hypertrophy. Electromyography showed evidence of chronic proximal and distal myopathy, predominantly affecting the lower extremity. Skeletal muscle biopsy showed fascicular atrophy and hypertrophy, focal endomyosial fibrosis and an increase of central nuclei without evidence of inflammation or granuloma which was most suggestive of a muscular dystrophy. Genetic testing was then completed and showed hemizygous dystrophin mutation confirming diagnosis of BMD. <h3>Summary</h3> BMD has a diffuse phenotype and should be considered in young patients with cardiomyopathy and chronically elevated CK and AST. A thorough clinical history, exam, and CMR can assist in directing need for skeletal muscle biopsy and subsequent genetic testing.

The Role of Impaired Mitochondrial Dynamics in MFN2-Mediated Pathology.

The Mitofusin 2 protein (MFN2), encoded by the MFN2 gene, was first described for its role in mediating mitochondrial fusion. However, MFN2 is now recognized to play additional roles in mitochondrial autophagy (mitophagy), mitochondrial motility, lipid transfer, and as a tether to other organelles including the endoplasmic reticulum (ER) and lipid droplets. The tethering role of MFN2 is an important mediator of mitochondrial-ER contact sites (MERCs), which themselves have many important functions that regulate mitochondria, including calcium homeostasis and lipid metabolism. Exemplifying the importance of MFN2, pathogenic variants in MFN2 are established to cause the peripheral neuropathy Charcot-Marie-Tooth Disease Subtype 2A (CMT2A). However, the mechanistic basis for disease is not clear. Moreover, additional pathogenic phenotypes such as lipomatosis, distal myopathy, optic atrophy, and hearing loss, can also sometimes be present in patients with CMT2A. Given these variable patient phenotypes, and the many cellular roles played by MFN2, the mechanistic underpinnings of the cellular impairments by which MFN2 dysfunction leads to disease are likely to be complex. Here, we will review what is known about the various functions of MFN2 that are impaired by pathogenic variants causing CMT2A, with a specific emphasis on the ties between MFN2 variants and MERCs.