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PLoS One 2021 9;16(6):e0252953. Epub 2021 Jun 9.

Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.

Background: Our aim was to present the experience of systematic, routine use of next generation sequencing (NGS) in clinical diagnostics of myopathies.

Methods: Exome sequencing was performed on patients with high risk for inherited myopathy, which were selected based on the history of the disease, family history, clinical presentation, and diagnostic workup. Exome target capture was performed, followed by sequencing on HiSeq 2500 or MiSeq platforms. Read More

Int J Mol Sci 2021 May 10;22(9). Epub 2021 May 10.

PhyMedExp, University of Montpellier, INSERM, CNRS, 34295 Montpellier, France.

Duchenne muscular dystrophy (DMD) is a devastating condition shortening the lifespan of young men. DMD patients suffer from age-related dilated cardiomyopathy (DCM) that leads to heart failure. Several molecular mechanisms leading to cardiomyocyte death in DMD have been described. Read More

Medicina (Kaunas) 2021 May 12;57(5). Epub 2021 May 12.

"Carol Davila" University of Medicine and Pharmacy, 050474 Bucharest, Romania.

Muscular disorders are mainly characterized by progressive skeletal muscle weakness. There are several aspects that can be monitored, which are used to differentiate between the types of muscular disorders, ranging from the targeted muscle up to the mutated gene. An aspect that holds critical importance when managing muscular dystrophies is that most of them exhibit cardiac abnormalities. Read More

Nephron 2021 May 31:1-6. Epub 2021 May 31.

Department of Pediatric Nephrology, Medical University of Lublin, Lublin, Poland.

Pierson syndrome (PIERSS) is a rare autosomal recessive disorder characterized by the combination of congenital nephrotic syndrome (CNS) and extrarenal symptoms including ocular malformations and neurodevelopmental deficits. PIERSS is caused by biallelic pathogenic variants in the LAMB2 gene leading to the defects of β2-laminin, the protein mainly expressed in the glomerular basement membrane, ocular structures, and neuromuscular junctions. Severe complications of PIERSS lead to the fatal outcome in early childhood in majority of the cases. Read More

Neuromuscul Disord 2021 Apr 26. Epub 2021 Apr 26.

Department of Medical Chemistry and Biochemistry, Medical University Sofia, Sofia, Bulgaria; Genetic Medico-Diagnostic Laboratory "Genica", Sofia, Bulgaria.

Pathogenic variants in MYH7 cause a wide range of cardiac and skeletal muscle diseases with childhood or adult onset. These include dilated and/or hypertrophic cardiomyopathy, left ventricular non-compaction cardiomyopathy, congenital myopathies with multi-minicores and myofiber type disproportion, myosin storage myopathy, Laing distal myopathy and others (scapulo-peroneal or limb-girdle muscle forms). Here we report the results from molecular genetic analyses (NGS and Sanger sequencing) of 4 patients in two families with variable neuromuscular phenotypes with or without cardiac involvement. Read More

Semin Cell Dev Biol 2021 May 11. Epub 2021 May 11.

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address:

Heart malformation is the leading cause of human birth defects, and many of the congenital heart diseases (CHDs) originate from genetic defects that impact cardiac development and maturation. During development, the vertebrate heart undergoes a series of complex morphogenetic processes that increase its ability to pump blood. One of these processes leads to the formation of the sheet-like muscular projections called trabeculae. Read More

Neurol Genet 2021 Jun 26;7(3):e589. Epub 2021 Apr 26.

Division of Neurology and Developmental Neuroscience (D.G.C., I.H., D.P., T.L.), Department of Pediatrics, Baylor College of Medicine, Houston, TX; Texas Children's Hospital (D.G.C., I.H., D.P., J.R.L.), Houston, TX; Department of Molecular and Human Genetics (D.G.C., J.F., I.H., Z.C.A., H.D., R.A.G., D.M., D.P., J.E.P., J.R.L.), Baylor College of Medicine, Houston, TX; Human Genome Sequencing Center (S.N.J., R.A.G., J.R.L.), Baylor College of Medicine, Houston, TX; Department of Pediatrics (D.M.), Faculty of Medicine, Kuwait University, Safat, Kuwait; Division of Child and Adolescent Neurology (P.M.), Department of Pediatrics, University of Texas Health Science Center, Houston, TX; Pathology and Laboratory Medicine (M.B.B.), University of Texas Health Science Center at Houston-McGovern Medical School, Houston, TX; and Department of Pediatrics (J.R.L.), Baylor College of Medicine, Houston, TX.

Objective: Pathogenic variants in , the gene encoding fast skeletal muscle troponin T, were first described in autosomal dominant distal arthrogryposis type 2B2. Recently, a homozygous splice site variant, c.681+1G>A, was identified in a patient with nemaline myopathy and distal arthrogryposis. Read More

World J Clin Pediatr 2021 May 9;10(3):15-28. Epub 2021 May 9.

Department of Pediatrics, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama P.O. Box 26671, Bahrain, Bahrain.

Medical comorbidities are more common in children with autism spectrum disorders (ASD) than in the general population. Some genetic disorders are more common in children with ASD such as Fragile X syndrome, Down syndrome, Duchenne muscular dystrophy, neurofibromatosis type I, and tuberous sclerosis complex. Children with autism are also more prone to a variety of neurological disorders, including epilepsy, macrocephaly, hydrocephalus, cerebral palsy, migraine/headaches, and congenital abnormalities of the nervous system. Read More

J Cutan Pathol 2021 May 8. Epub 2021 May 8.

Razi laboratory, Rasht, Iran.

Rhabdomyomatous mesenchymal hamartoma (RMH) is a rare congenital malformation of the dermis and subcutaneous tissue. Usually, RMH occurs in the midline of the face and neck region. We described a case of RMH presenting as telangiectasia in a 57-year-old man with a history of pityriasis lichenoides chronicus. Read More

Ann Hum Genet 2021 May 8. Epub 2021 May 8.

Department of Medical Genetics, University of Health Sciences, Dışkapı Yıldırım Beyazıt Research and Training Hospital, Ankara, Turkey.

Hereditary myopathies are a heterogeneous disorder known to be associated with more than 100 genes. Although hereditary myopathy subgroups can be partially described with traditional methods such as muscle biopsy, next-generation sequencing (NGS) is essential to reveal the disease's underlying genetic etiology and molecular mechanisms. In this study, we performed clinical exome sequencing or whole-exome sequencing (CES/WES) in 20 unrelated Turkish patients. Read More

Eur J Paediatr Neurol 2021 May 20;32:115-121. Epub 2021 Apr 20.

Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, Poland.

LMNA-related congenital muscular dystrophy (L-CMD) is the most severe phenotypic form of skeletal muscle laminopathies. This paper reports clinical presentation of the disease in 15 Polish patients from 13 families with genetically confirmed skeletal muscle laminopathy. In all these patients floppy infant syndrome was the first manifestation of the disease. Read More

Mol Ther 2021 May 1. Epub 2021 May 1.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR7104, INSERM U1258, Université de Strasbourg, 67404 Illkirch, France. Electronic address:

Omics analyses are powerful methods to obtain an integrated view of complex biological processes, disease progression, or therapy efficiency. However, few studies have compared different disease forms and different therapy strategies to define the common molecular signatures representing the most significant implicated pathways. In this study, we used RNA sequencing and mass spectrometry to profile the transcriptomes and proteomes of mouse models for three forms of centronuclear myopathies (CNMs), untreated or treated with either a drug (tamoxifen), antisense oligonucleotides reducing the level of dynamin 2 (DNM2), or following modulation of DNM2 or amphiphysin 2 (BIN1) through genetic crosses. Read More

Acta Neuropathol Commun 2021 04 29;9(1):79. Epub 2021 Apr 29.

Department of Neurology, Mayo Clinic, 200 1st St SW, Rochester, MN, 55905, USA.

The MYH2 gene encodes the skeletal muscle myosin heavy chain IIA (MyHC-IIA) isoform, which is expressed in the fast twitch type 2A fibers. Autosomal dominant or recessive pathogenic variants in MYH2 lead to congenital myopathy clinically featured by ophthalmoparesis and predominantly proximal weakness. MYH2-myopathy is pathologically characterized by loss and atrophy of type 2A fibers. Read More

BMC Pediatr 2021 04 29;21(1):209. Epub 2021 Apr 29.

Department of Pediatrics, Peking University First Hospital, No.1 Xi'an Men Street, West District, Beijing, 100034, China.

Background: Centronuclear myopathy (CNM), a subtype of congenital myopathy (CM), is a group of clinical and genetically heterogeneous muscle disorders. Since the discovery of the SPEG gene and disease-causing variants, only a few additional patients have been reported.

Case Presentation: The child, a 13-year-old female, had delayed motor development since childhood, weakness of both lower extremities for 10 years, gait swinging, and a positive Gower sign. Read More

Int J Mol Sci 2021 Apr 20;22(8). Epub 2021 Apr 20.

CNR Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza", Unit of Bologna, 40136 Bologna, Italy.

Intermediate filaments are major components of the cytoskeleton. Desmin and synemin, cytoplasmic intermediate filament proteins and A-type lamins, nuclear intermediate filament proteins, play key roles in skeletal and cardiac muscle. Desmin, encoded by the gene (OMIM *125660) and A-type lamins by the gene (OMIM *150330), have been involved in striated muscle disorders. Read More

Int J Mol Sci 2021 Apr 25;22(9). Epub 2021 Apr 25.

Department of Human Pathology in Adult and Developmental Age "Gaetano Barresi, Unit of Pediatric Nephrology and Dialysis, University of Messina, Via Consolare Valeria 1, 98124 Messina, Italy.

Microphthalmia, anophthalmia, and coloboma (MAC) are a group of congenital eye anomalies that can affect one or both eyes. Patients can present one or a combination of these ocular abnormalities in the so called "MAC spectrum". The gene encodes the kinesin-like protein Kif17, a microtubule-based, ATP-dependent, motor protein that is pivotal for outer segment development and disc morphogenesis in different animal models, including mice and zebrafish. Read More

Int J Mol Sci 2021 Apr 6;22(7). Epub 2021 Apr 6.

Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center-University of Freiburg, 79106 Freiburg, Germany.

In general, metabolic flexibility refers to an organism's capacity to adapt to metabolic changes due to differing energy demands. The aim of this work is to summarize and discuss recent findings regarding variables that modulate energy regulation in two different pathways of mitochondrial fatty metabolism: β-oxidation and fatty acid biosynthesis. We focus specifically on two diseases: very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and malonyl-CoA synthetase deficiency (acyl-CoA synthetase family member 3 (ACSF3)) deficiency, which are both characterized by alterations in metabolic flexibility. Read More

Int J Mol Sci 2021 Apr 1;22(7). Epub 2021 Apr 1.

Molecular and Clinical Sciences, St. George's, University of London, London SW17 0RE, UK.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare disease for which there are currently no validated outcome measures for assessing therapeutic intervention efficacy. The aim of this study was to identify a plasma and/or serum microRNA (miRNA) biomarker panel for MNGIE. Sixty-five patients and 65 age and sex matched healthy controls were recruited and assigned to one of four study phases: (i) discovery for sample size determination; (ii) candidate screening; (iii) candidate validation; and (iv) verifying the performance of the validated miRNA panel in four patients treated with erythrocyte-encapsulated thymidine phosphorylase (EE-TP), an enzyme replacement under development for MNGIE. Read More

Hum Mol Genet 2021 Apr 28. Epub 2021 Apr 28.

Dept. of Physiology, Amsterdam UMC (location VUmc), The Netherlands.

Nemaline myopathy, a disease of the actin-based thin filament, is one of the most frequent congenital myopathies. To date, no specific therapy is available to treat muscle weakness in nemaline myopathy. We tested the ability of tirasemtiv, a fast skeletal troponin activator that targets the thin filament, to augment muscle force-both in vivo and in vitro-in a nemaline myopathy mouse model with a mutation (H40Y) in Acta1. Read More

Rev Neurol 2021 Apr;72(8):283-287

Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisboa, Portugal.

Introduction:

Background And Aim: Muscle biopsy is still an important exam on the investigation of neuromuscular diseases although data regarding its diagnostic yield can be disappointing. We aimed to analyze the diagnostic yield of muscle biopsies in the pediatric population.

Patients And Methods: We retrospectively analyzed a tertiary Neuropathology laboratory database to identify patients (<18 years old), submitted to muscle biopsy between January 2015 and August 2019. Read More

Orphanet J Rare Dis 2021 Apr 13;16(1):176. Epub 2021 Apr 13.

Child Psychiatry, Hopital Pitié Salpêtrière APHP and Sorbonne Université, Paris, France.

Background: Rare diseases may result in motor impairment, which in turn may affect parenthood. Our purpose was to evaluate perinatal outcomes, parenting needs, mother-infant interactions and infant development in a set of volunteer women with motor impairment due to a rare disease. In a parenting support institution, we recruited a consecutive series of 22 volunteer pregnant women or young mothers, recorded perinatal outcomes, and followed mother-infant interaction and relationship and infant development up to 14 months postpartum. Read More

J Med Genet 2021 Apr 2. Epub 2021 Apr 2.

Neurology Department, University Hospital Antwerp, Antwerp, Belgium

Background: Pathogenic variants are a frequent cause of developmental and epileptic encephalopathy.

Methods: We recruited 13 adults (between 18 years and 45 years of age) with encephalopathy and reviewed their clinical, EEG, neuroimaging and treatment history.

Results: While most patients had daily seizures at seizure onset, seizure frequency declined or remitted during childhood and adulthood. Read More

Int J Neonatal Screen 2021 Mar 5;7(1). Epub 2021 Mar 5.

Norwegian National Unit for Newborn Screening, 0424 Oslo, Norway.

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders ("conditions") then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40-50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. Read More

Int J Mol Sci 2021 Mar 7;22(5). Epub 2021 Mar 7.

Division of Newborn Medicine, Boston Children's Hospital, Boston, MA 02115, USA.

microRNAs (miRNAs) regulate messenger RNA (mRNA) abundance and translation during key developmental processes including muscle differentiation. Assessment of miRNA targets can provide insight into muscle biology and gene expression profiles altered by disease. mRNA and miRNA libraries were generated from C2C12 myoblasts during differentiation, and predicted miRNA targets were identified based on presence of miRNA binding sites and reciprocal expression. Read More

Eur J Hum Genet 2021 Mar 26. Epub 2021 Mar 26.

Department of Neuropediatrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin und Humboldt Universität zu Berlin, Berlin, Germany.

Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND, OMIM #617519) is an autosomal recessive disease caused by homozygous or compound heterozygous variants in SPTBN4 coding for type 4 βIV-spectrin, a non-erythrocytic member of the β-spectrin family. Variants in SPTBN4 disrupt the cytoskeletal machinery that controls proper localization of ion channels and the function of axonal domains, thereby generating severe neurological dysfunction. We set out to analyze the genetic causes and describe the clinical spectrum of suspected cases of NEDHND. Read More

Clin Case Rep 2021 Mar 3;9(3):1672-1676. Epub 2021 Feb 3.

Department of Paediatrics Children's Hospital London Health Sciences Centre London ON Canada.

We report a case of neonatal nemaline myopathy with a de novo mutation, which has been classified as a likely pathogenic mutation. With the expanding use of genetic testing in congenital myopathies, genotype-phenotype descriptions of novel variants are important to inform clinical care, diagnosis, genetic counseling, and management of disease. Read More

BMC Neurol 2021 Mar 9;21(1):105. Epub 2021 Mar 9.

Human Genetics Unit, Department of Anatomy, Faculty of Medicine, University of Colombo, Colombo 8, Sri Lanka.

Background: Collagen VI-related dystrophies are a subtype of congenital muscular dystrophy caused by pathogenic variants in COL6A1, COL6A2 or COL6A3 genes affecting skeletal muscles and connective tissue. The clinical phenotype ranges from the milder Bethlem myopathy to the severe Ullrich congenital muscular dystrophy (UCMD). Herein, we report the first consanguineous Sri Lankan family with two children affected with UCMD due to a novel variant in the COL6A1 gene. Read More

Eur Heart J 2021 05;42(20):1976-1984

Service d'Explorations Fonctionnelles, Hôpital Raymond Poincaré, Garches, FranceINSERM Université de Versailles Saint Quentin en Yvelines, France.

Aims: To estimate the effect of prophylactic angiotensin-converting enzyme inhibitors (ACEi) on survival in Duchenne muscular dystrophy (DMD).

Methods And Results: We analysed the data from the French multicentre DMD Heart Registry (ClinicalTrials.gov: NCT03443115). Read More

Am J Med Genet A 2021 Jun 10;185(6):1678-1690. Epub 2021 Mar 10.

Department of Pediatrics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Congenital myopathies (CMs) are a heterogeneous group of inherited muscle disorders characterized by muscle weakness at birth, while limb-girdle muscular dystrophies (LGMD) have a later onset and slower disease progression. Thus, detailed clinical phenotyping of genetically defined disease entities are required for the full understanding of genotype-phenotype correlations. A recently defined myopathic genetic disease entity is caused by bi-allelic variants in a gene coding for pyridine nucleotide-disulfide oxidoreductase domain 1 (PYROXD1) with unknown substrates. Read More

Int J Mol Sci 2021 Feb 20;22(4). Epub 2021 Feb 20.

Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy.

Distal Arthrogryposis type 5D (DA5D) is characterized by congenital contractures involving the distal joints, short stature, scoliosis, ptosis, astigmatism, and dysmorphic features. It is inherited in an autosomal recessive manner, and it is a result of homozygous or compound heterozygous variants in the ECEL1 gene. Here, we report two patients of Sardinian origin harboring a new intronic homozygous variant in ECEL1 (c. Read More