Early Contractures Research Articles

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

BackgroundDysferlinopathy 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 presentationWe 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.ConclusionsThis case expands the range of clinical and phenotypic correlations of dysferlinopathy and complements the diagnostic search for spine rigidity.

A Rare Case of Amyoplasia Type of Arthrogryposis Multiplex Congenita with Midfacial Hemangioma in a Neonate

Arthrogryposis multiplex congenita is a condition where multiple contractures of the joint develop, leading to deformity and restriction of movement. It is mostly seen in the neonatal period but the deformity may persist till adulthood also. A 1-day-old male baby presented with multiple deformities and contractures of all four limbs, with breathing difficulties. On examination, there was abnormal shoulder adduction with elbow extension and ulnar deviation of the wrist with thumb and finger deformity. In the lower limb, severe knee flexion with severe bilateral talipes equinus deformity was seen. A midfacial hemangioma and ear abnormalities were also present along with a skin dimple over both knees. The child was investigated fully for other congenital and systemic malformations. Finally, a diagnosis of the amyotrophic type of arthrogryposis congenita with facial hemangioma was made, which is a very rare association. The patient was managed by a multidisciplinary team approach and was discharged successfully. When a baby is presented with such a deformity, then the child should be screened fully and a genetic study should be done to prevent a recurrence of malformation in a subsequent pregnancy. The aim is to prevent early contractures and to restore limb function in the child and proper follow-up.

Clinical and genetic characteristics of Emery-Dreifuss muscular dystrophy patients from Turkey: 30 years longitudinal follow-up study

Emery-Dreifuss muscular dystrophy (EDMD) is a rare inherited disorder usually presenting in childhood with early contractures, slowly progressive scapulohumeroperoneal weakness/atrophy and potentially fatal dilated cardiomyopathy with conduction defects. We evaluated clinical and genetic findings of 32 patients with EDMD phenotype from 14 unrelated families, diagnosed at the Department of Neurology, Istanbul Faculty of Medicine between 1989 and 2022. Twenty-three patients from 8 unrelated families were diagnosed with EDMD1 (58%), 5 patients from 3 families with EDMD2 (21%), and 2 patients from 1 family with the rare EDMD3 (7%). Genetic diagnosis was achieved in 12 unrelated kinships with classical EDMD phenotype (86%) by applying panel testing, but no mutation could be determined in 2 patients with classical EDMD phenotype from 2 unrelated families (14%). Three novel pathogenic variants (c.19delC, c.416_417delTT, c.123C > G) in EMD, and a novel (c.1441dupT) heterozygous likely pathogenic variant in LMNA gene were found. This is the largest cohort from Turkey, expanding the genetic spectrum of EDMD, and providing clues for genetic testing of EDMD in Turkey.

Preclinical Research in McArdle Disease: A Review of Research Models and Therapeutic Strategies.

McArdle disease is an autosomal recessive disorder of muscle glycogen metabolism caused by pathogenic mutations in the PYGM gene, which encodes the skeletal muscle-specific isoform of glycogen phosphorylase. Clinical symptoms are mainly characterized by transient acute “crises” of early fatigue, myalgia and contractures, which can be accompanied by rhabdomyolysis. Owing to the difficulty of performing mechanistic studies in patients that often rely on invasive techniques, preclinical models have been used for decades, thereby contributing to gain insight into the pathophysiology and pathobiology of human diseases. In the present work, we describe the existing in vitro and in vivo preclinical models for McArdle disease and review the insights these models have provided. In addition, despite presenting some differences with the typical patient’s phenotype, these models allow for a deep study of the different features of the disease while representing a necessary preclinical step to assess the efficacy and safety of possible treatments before they are tested in patients.

Microhomology-Mediated Nonhomologous End Joining Caused Rearrangement of EMD and FLNA in Emery-Dreifuss Muscular Dystrophy.

Background: Emery–Dreifuss muscular dystrophy (EDMD) is a rare disease characterized by early joint contractures, slowly progressive muscular dystrophy, and cardiac involvement, which includes arrhythmia, dilated cardiomyopathy, hypertrophic cardiomyopathy, heart failure, and sudden death. Methods: Clinical data of the proband and family members were collected. The next-generation sequencing technology was used to analyze the pathogenic variants and copy number variations. Polymerase chain reaction was used to sequence the breakpoints of gene locus rearrangements. Results: Here, we report two siblings with EDMD in a family. The proband, a 17-year-old boy, manifested a dilated right heart, bradycardia, mild muscle weakness, and joint contractures. His younger brother only showed a mild bowing limitation with elevated creatine kinase. Next-generation sequencing revealed the complete deletion of EMD and a rearrangement in FLNA (exon29_48dup) in these two patients. The EMD deletion and partial FLNA duplication were accompanied by a 5 bp overlap (GTCCC) on the background of the FLNA-EMD inversion. These findings support the pathogenic mechanism of microhomology-mediated nonhomologous end joining. Conclusion: We report two siblings with complete EMD deletion and FLNA duplication in a family. A microhomology-mediated nonhomologous end joining event involving EMD and FLNA acts as the underlying mechanism.

CONGENITAL MYOPATHIES 2: P.95 Novel mutation in KY gene causes a novel congenital myopathy with early contractures

The kyphoscoliosis peptidase (KY) gene encodes a muscle-specific a Z-disc-associated protein which is specifically expressed in skeletal-, cardiac muscle and CNS. The mutation in the Ky-gene has first been identified in a mouse mutant with progressive muscular dystrophy and thoracolumbar kyphoscoliosis. Since then, only a few cases with myofibrillar myopathy, congenital myopathy and hereditary spastic paraplegia caused by mutation in KY were described. Here, we present two brothers with congenital myopathy with early contractures carrying a novel homozygous missense (ENST00000423778.2) p.Cys243Arg (c.727T>C) mutation in the KY gene.

Cardiac Emerinopathy: A Nonsyndromic Nuclear Envelopathy With Increased Risk of Thromboembolic Stroke Due to Progressive Atrial Standstill and Left Ventricular Noncompaction.

Mutations in the nuclear envelope genes encoding LMNA and EMD are responsible for Emery-Dreifuss muscular dystrophy. However, LMNA mutations often manifest dilated cardiomyopathy with conduction disturbance without obvious skeletal myopathic complications. On the contrary, the phenotypic spectrums of EMD mutations are less clear. Our aims were to determine the prevalence of nonsyndromic forms of emerinopathy, which may underlie genetically undefined isolated cardiac conduction disturbance, and the etiology of thromboembolic complications associated with EMD mutations. Targeted exon sequencing was performed in 87 probands with familial sick sinus syndrome (n=36) and a progressive cardiac conduction defect (n=51). We identified 3 X-linked recessive EMD mutations (start-loss, splicing, missense) in families with cardiac conduction disease. All 3 probands shared a common clinical phenotype of progressive atrial arrhythmias that ultimately resulted in atrial standstill associated with left ventricular noncompaction (LVNC), but they lacked early contractures and progressive muscle wasting and weakness characteristic of Emery-Dreifuss muscular dystrophy. Because the association of LVNC with EMD has never been reported, we further genetically screened 102 LVNC patients and found a frameshift EMD mutation in a boy with progressive atrial standstill and LVNC without complications of muscular dystrophy. All 6 male EMD mutation carriers of 4 families underwent pacemaker or defibrillator implantation, whereas 2 female carriers were asymptomatic. Notably, a strong family history of stroke observed in these families was probably due to the increased risk of thromboembolism attributable to both atrial standstill and LVNC. Cardiac emerinopathy is a novel nonsyndromic X-linked progressive atrial standstill associated with LVNC and increased risk of thromboembolism.

Emery-Dreifuss muscular dystrophy.

Emery‐Dreifuss muscular dystrophy (EDMD) is a rare muscular dystrophy, but is particularly important to diagnose due to frequent life‐threatening cardiac complications. EDMD classically presents with muscle weakness, early contractures, cardiac conduction abnormalities and cardiomyopathy, although the presence and severity of these manifestations vary by subtype and individual. Associated genes include EMD, LMNA, SYNE1, SYNE2, FHL1, TMEM43, SUN1, SUN2, and TTN, encoding emerin, lamin A/C, nesprin‐1, nesprin‐2, FHL1, LUMA, SUN1, SUN2, and titin, respectively. The Online Mendelian Inheritance in Man database recognizes subtypes 1 through 7, which captures most but not all of the associated genes. Genetic diagnosis is essential whenever available, but traditional diagnostic tools can help steer the evaluation toward EDMD and assist with interpretation of equivocal genetic test results. Management is primarily supportive, but it is important to monitor patients closely, especially for potential cardiac complications. There is a high potential for progress in the treatment of EDMD in the coming years.

A multistage sequencing strategy pinpoints novel candidate alleles for Emery-Dreifuss muscular dystrophy and supports gene misregulation as its pathomechanism.

BackgroundAs genome-wide approaches prove difficult with genetically heterogeneous orphan diseases, we developed a new approach to identify candidate genes. We applied this to Emery-Dreifuss muscular dystrophy (EDMD), characterised by early onset contractures, slowly progressive muscular wasting, and life-threatening heart conduction disturbances with wide intra- and inter-familial clinical variability. Roughly half of EDMD patients are linked to six genes encoding nuclear envelope proteins, but the disease mechanism remains unclear because the affected proteins function in both cell mechanics and genome regulation.MethodsA primer library was generated to test for mutations in 301 genes from four categories: (I) all known EDMD-linked genes; (II) genes mutated in related muscular dystrophies; (III) candidates generated by exome sequencing in five families; (IV) functional candidates — other muscle nuclear envelope proteins functioning in mechanical/genome processes affected in EDMD. This was used to sequence 56 unlinked patients with EDMD-like phenotype.FindingsTwenty-one patients could be clearly assigned: 18 with mutations in genes of similar muscular dystrophies; 3 with previously missed mutations in EDMD-linked genes. The other categories yielded novel candidate genes, most encoding nuclear envelope proteins with functions in gene regulation.InterpretationOur multi-pronged approach identified new disease alleles and many new candidate EDMD genes. Their known functions strongly argue the EDMD pathomechanism is from altered gene regulation and mechanotransduction due to connectivity of candidates from the nuclear envelope to the plasma membrane. This approach highlights the value of testing for related diseases using primer libraries and may be applied for other genetically heterogeneous orphan diseases.FundingThe Wellcome Trust, Muscular Dystrophy UK, Medical Research Council, European Community's Seventh Framework Programme “Integrated European –omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)”.

Targeted next-generation sequencing identified a known EMD mutation in a Chinese patient with Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is a rare X-linked recessive disease characterized by the clinical triad of early childhood joint contractures, progressive weakness in muscles and cardiac involvement and can result in sudden death. Targeted next-generation sequencing was performed for a Chinese patient with EDMD and the previously reported mutation [NM_000117.2: c.251_255del (p.Leu84Profs*7)] in exon 3 of the emerin gene (EMD) was identified.

Alteration of performance in a mouse model of Emery–Dreifuss muscular dystrophy caused by A-type lamins gene mutation

Autosomal Emery-Dreifuss muscular dystrophy (EDMD) is caused by mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. Classically, the disease manifests as scapulo-humero-peroneal muscle wasting and weakness, early joint contractures and dilated cardiomyopathy with conduction blocks; however, variable skeletal muscle involvement can be present. Previously, we and other demonstrated altered activity of signaling pathways in hearts and striated muscles of LmnaH222P/H222P mice, a model of autosomal EDMD. We showed that blocking their activation improved cardiac function. However, the evaluation of the benefit of these treatments on the whole organism is suffering from a better knowledge of the performance in mouse models. We show in the present study that LmnaH222P/H222P mice display a significant loss of lean mass, consistent with the dystrophic process. This is associated with altered VO2 peak and respiratory exchange ratio. These results showed for the first time that LmnaH222P/H222P mice have decreased performance and provided a new useful means for future therapeutic interventions on this model of EDMD.

GUIDELINES FOR ICD IN EMERY-DREIFUSS MUSCULAR DYSTROPHY

EDMD is a rare form of muscular dystrophy characterized by slowly progressive muscle weakness, early contractures and progressive cardiac involvement. In contrast to Duchenne and Becker forms of muscular dystrophy, locomotor abnormalities are typically more mild and progress slower. Cardiac

The Pathogenesis and Therapies of Striated Muscle Laminopathies.

Emery-Dreifuss muscular dystrophy (EDMD) is a genetic condition characterized by early contractures, skeletal muscle weakness, and cardiomyopathy. During the last 20 years, various genetic approaches led to the identification of causal genes of EDMD and related disorders, all encoding nuclear envelope proteins. By their respective localization either at the inner nuclear membrane or the outer nuclear membrane, these proteins interact with each other and establish a connection between the nucleus and the cytoskeleton. Beside this physical link, these proteins are also involved in mechanotransduction, responding to environmental cues, such as increased tension of the cytoskeleton, by the activation or repression of specific sets of genes. This ability of cells to adapt to environmental conditions is altered in EDMD. Increased knowledge on the pathophysiology of EDMD has led to the development of drug or gene therapies that have been tested on mouse models. This review proposed an overview of the functions played by the different proteins involved in EDMD and related disorders and the current therapeutic approaches tested so far.

DUCHENNE MUSCULAR DYSTROPHY - PHYSIOTHERAPY: P.302Genetic association study of articular range of motion in the CINRG Duchenne natural history study

Joint contracture severity in DMD is variable between patients with comparable muscle weakness. We planned a genetic association study of contracture severity in participants in the CINRG Duchenne natural history study. We selected 109 participants of European American ancestry for genotyping with the illumina exome chip, in order to minimize population stratification bias. SNPs with minor allele frequency >0.05 were included in the analyses. Range of motion (ROM) was assessed using a standard goniometer. Prevalent DMD contractures were measured on the dominant side: elbow extension (n=104), wrist extension (n=104), knee extension (n=62), and ankle dorsiflexion (n=61). A linear model of association between articular ROM and genotype was used, with brooke upper extremity score and vignos lower extremity score as covariates, to adjust for muscle weakness in upper or lower limbs as relevant. QQ plots were visualized in order to control for type I or II error inflation. A bonferroni correction for 27,025 SNPs with MAF>0.05 was applied, leading to ``exome-wide'' significance of P=1.85*10-6. A more permissive ``suggestive'' threshold of P=10-4 was also considered. The only exome-wide significant association signal (P=1.36*10-7) was observed using an autosomal dominant inheritance model for rs12506517 (70kb upstream BANK1, encoding a B-cell-specific scaffold protein that mobilizes Ca++ from intracellular stores). This protein promotes Lyn-mediated tyrosine phosphorylation of inositol 1,4,5-trisphosphate (IP3) receptors. Several ``suggestive'' signals were observed, including SNPs in FAM26F (Ca++ homeostasis regulator), DST, DYSF, and LTBP4. This study suggests a role of SNPs in Ca++ homeostasis genes and other genes in predisposing DMD patients to early contractures. Further studies are needed to validate these associations and elucidate their mechanistic underpinnings, before these genes and the corresponding proteins can be considered as biomarkers or therapeutic targets.

Congenital Titinopathy: Comprehensive characterization and pathogenic insights

ObjectiveComprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder.MethodsUsing massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients.ResultsAll patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap‐like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near‐normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One‐third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder.InterpretationThis detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105–1124

Muscular MRI-based algorithm to differentiate inherited myopathies presenting with spinal rigidity.

Inherited myopathies are major causes of muscle atrophy and are often characterized by rigid spine syndrome, a clinical feature designating patients with early spinal contractures. We aim to present a decision algorithm based on muscular whole body magnetic resonance imaging (mWB-MRI) as a unique tool to orientate the diagnosis of each inherited myopathy long before the genetically confirmed diagnosis. This multicentre retrospective study enrolled 79 patients from referral centres in France, Brazil and Chile. The patients underwent 1.5-T or 3-T mWB-MRI. The protocol comprised STIR and T1 sequences in axial and coronal planes, from head to toe. All images were analyzed manually by multiple raters. Fatty muscle replacement was evaluated on mWB-MRI using both the Mercuri scale and statistical comparison based on the percentage of affected muscle. Between February 2005 and December 2015, 76 patients with genetically confirmed inherited myopathy were included. They were affected by Pompe disease or harbored mutations in RYR1, Collagen VI, LMNA, SEPN1, LAMA2 and MYH7 genes. Each myopathy had a specific pattern of affected muscles recognizable on mWB-MRI. This allowed us to create a novel decision algorithm for patients with rigid spine syndrome by segregating these signs. This algorithm was validated by five external evaluators on a cohort of seven patients with a diagnostic accuracy of 94.3% compared with the genetic diagnosis. We provide a novel decision algorithm based on muscle fat replacement graded on mWB-MRI that allows diagnosis and differentiation of inherited myopathies presenting with spinal rigidity. • Inherited myopathies are rare, diagnosis is challenging and genetic tests require specialized centres and often take years. • Inherited myopathies are often characterized by spinal rigidity. • Whole body magnetic resonance imaging is a unique tool to orientate the diagnosis of each inherited myopathy presenting with spinal rigidity. • Each inherited myopathy in this study has a specific pattern of affected muscles that orientate diagnosis. • A novel MRI-based algorithm, usable by every radiologist, can help the early diagnosis of these myopathies.

Sensory motor axonal neuropathy and early onset osteotendinous contractures caused by mutation in MYH14

Sensory motor axonal neuropathy and early onset osteotendinous contractures caused by mutation in MYH14

Phenotypic Variability of Dystrophinopathy Symptomatic Female Carriers

Dystrophinopathies are X-linked muscular dystrophies characterized by pathogenic mutations in the dystrophin gene. Symptomatic dystrophinopathy female carriers may present with limb-girdle weakness. The diagnosis may be challenging in the absence of affected male relatives. We aimed to describe the phenotypic variability in a series of molecular-confirmed female dystrophinopathy patients. This is a retrospective analysis of medical records from 1997 to 2015. Ten female dystrophinopathy patients were selected, two with unusual phenotypes: one with early joint contractures muscular dystrophy and the other with very late onset myopathy. Muscle imaging studies demonstrated predominant asymmetric fat replacement. Muscle biopsy immunohistochemistry demonstrated clear mosaic pattern in two cases and only subtle reduction of dystrophin intensity in three. Adequate diagnosis is fundamental for genetic counseling and cardiologic follow-up. Female patients with dystrophinopathy may present unusual phenotypes such as early contractures and very late onset myopathy.

Clinical and Pathological Heterogeneity of Korean Patients with CAPN3 Mutations.

PurposeThis study was designed to investigate the characteristics of Korean patients with calpainopathy.Materials and MethodsThirteen patients from ten unrelated families were diagnosed with calpainopathy via direct or targeted sequencing of the CAPN3 gene. Clinical, mutational, and pathological spectra were then analyzed.ResultsNine different mutations, including four novel mutations (NM_000070: c.1524+1G>T, c.1789_1790inA, c.2184+1G>T, and c.2384C>T) were identified. The median age at symptom onset was 22 (interquartile range: 15-28). Common clinical findings were joint contracture in nine patients, winged scapula in four, and lordosis in one. However, we also found highly variable clinical features including early onset joint contractures, asymptomatic hyperCKemia, and heterogeneous clinical severity in three members of the same family. Four of nine muscle specimens revealed lobulated fibers, but three showed normal skeletal muscle histology.ConclusionWe identified four novel CAPN3 mutations and demonstrated clinical and pathological heterogeneity in Korean patients with calpainopathy.

FHL1 protein isoforms in Emery-Dreifuss muscular dystrophy

Emery-Dreifuss muscular dystrophy (EDMD) is a hereditary muscular disorder characterized by early joint contractures, progressive muscular wasting and weakness of scapuloperoneal distribution, and at adult age, patients develop cardiac abnormalities with a high risk of sudden death[1]. EDMD encompasses both X-linked and autosomal inheritance due to mutations in the genes encoding the nuclear envelope proteins emerin, lamin A/C[2-4]. First mutations in the Four-and-a-half LIM domain 1 gene (FHL1) being responsible for X-linked EDMD were described by Gueneau et al.[5]. The human FHL1 gene encodes three alternatively spliced isoforms, named FHL1A, FHL1B and FHL1C, with FHL1A being the most abundantly expressed protein isoform in striated muscle. There is still little known about the precise localization and functions of the three different FHL1 isoforms in human skeletal muscle. Here, we describe for the first time the subcellular localization of FHL1A, FHL1B, and FHL1C in vitro in differentiating human primary myoblasts. Localization of FHL1 protein isoforms was studied at the myoblast and myotube stages by confocal microscope analysis. Endogenous FHL1B protein localization was detected by an anti-FHL1B specific antibody, while for FHL1A and FHL1C, as no efficient isoform-specific antibodies were available, an anti-Flag antibody was used to follow Flag-tagged FHL1A and Flag-tagged FHL1C protein expression, after lentiviral transduction of human primary myoblasts. Successful transduction was confirmed by western blotting of whole extracts from myoblasts and myotubes using an anti-Flag antibody. In human myoblasts, Flag-FHL1A and Flag-FHL1C showed both a cytoplasmic and a nuclear distribution, while the nuclear staining was more pronounced in Flag-FHL1C transduced myoblasts. Endogenous FHL1B protein gave a moderate cytoplasmic and a strong nuclear staining. During 6- and 12-days of human myoblast differentiation, localization of all three FHL1 protein isoforms shifted from the nucleus to the cytoplasm. In addition, all FHL1 protein isoforms were observed to co-localize with phalloidin-stained actin fibers. Collectively, these results indicate differentiation-related changes in expression and subcellular localization of the human FHL1 protein isoforms.