Commonalities and Differences in Muscular Dystrophies: Mechanisms and Molecules Involved in Merosin-Deficient Congenital Muscular Dystrophy

Background : Congenital muscular dystrophy (CMD) refers to a group of muscular dystrophies that become apparent in early infancy or at birth. Muscular dystrophies are mostly genetic and a degenerative disease primarily affects voluntary muscles.Introduction : Alpha dystroglycanopathies both phenotypically and genetically are heterogeneous group of disorders and a subgroup of these patients has characteristic brain imaging findings.Material and methods: The case vignette shows a four year old girl presented in the OPD with history of throwing tantrums, delayed developmental milestones, irritability and anger outbursts. She had a history of admission in paediatric neurology indoor with complex partial seizures controlled by tab oxcarbazepine. She was born full term of non-consanguineous marriage by LUCS. There was progressive muscular weakness since early infancy with difficulty in sucking and breathing. No developmental regression was noticed.Results : Her development quotient was found to be 46, plasma ammonia and lactate levels were normal, creatinine kinase was high (314 IU/L). MRI of brain revealed polymicrogyria, white matter changes and subcortical cerebellar cysts. The pattern recognition of MR imaging features may serve as a clue to the diagnosis of alpha dystroglycanopathy although definite diagnosis could be obtained only by muscle biopsy and genetic testing.Conclusion : In Japan, Fukuyama disease is fairly common, second to Duchenne muscular dystrophy but milder form lie this case is rare. The mutation in FKTN gene which gives instructions for making a protein called fukutin, which chemically modify a protein alpha-dystroglycan. Highindex of suspicion and early diagnosis is required to initiate prompt therapy which is mainly supportive with rigorous physiotherapy, antiepileptic drugs, parental and genetic counseling.

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793 Obstructive Sleep Apnea and Hypoventilation in Patients with Muscular Dystrophies: Analysis of 42 Polysomnogram Studies

SLEEP ◽

10.1093/sleep/zsab072.790 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A309-A309

Author(s):

Pallav Halani ◽

Mihye Ahn ◽

Bradley Vaughn ◽

Travis Ewing ◽

Zheng Fan

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Muscular Dystrophy ◽

Pearson Correlation ◽

Tertiary Care ◽

Congenital Muscular Dystrophy ◽

Care Facility ◽

Muscular Dystrophies ◽

Obstructive Sleep ◽

Chi Squared

Abstract Introduction Patients with muscular dystrophies (dystrophinopathy, congenital muscular dystrophy and limb-girdle muscular dystrophy) are at greater risk of obstructive sleep apnea (OSA). However, few studies have examined if they are also at risk for hypoventilation and its relationship with OSA. We hypothesize that these two conditions occur independently of each other as an impaired ventilator drive and diaphragm weakness. Methods Retrospective review of diagnostic polysomnograms (PSG) in a tertiary care facility over 15 years was conducted. The polysomnography included either end tidal CO2 or transcutaneous CO2 measurements. Descriptive data analysis was performed on results described. We computed Pearson correlation coefficients to examine the relationships between PSG indices and other parameters. Pearson’s Chi-squared test with Yates’ continuity correction is used to test if hypoventilation is independent from OSA. Results 42 PSG studies in patients with muscular dystrophies were included after excluding 2 studies due to insufficient sleep duration. The average age at the time of study was 14.2 yrs with 41 being male and average BMI of 24.1. 64% of the group met the definition for OSA with average AHI 8.0. 36% of the group met the criteria for hypoventilation, and 33% patients with hypoventilation did not have OSA. Chi squared analysis (p=1.0) shows that hypoventilation is independent of OSA. Conclusion Sleep disordered breathing is common in patients with muscular dystrophy. This study supports that OSA and CO2 retention may be independent processes. Support (if any):

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Development of therapeutic genome engineering in laminin-α2-deficient congenital muscular dystrophy

Emerging Topics in Life Sciences ◽

10.1042/etls20180059 ◽

2019 ◽

Vol 3 (1) ◽

pp. 11-18

Author(s):

Dwi U. Kemaladewi ◽

Ronald D. Cohn

Keyword(s):

Muscular Dystrophy ◽

Gene Editing ◽

Genome Engineering ◽

Congenital Muscular Dystrophy ◽

Splice Site Mutation ◽

Muscular Dystrophies ◽

Connective Tissues ◽

Site Mutation ◽

Targeted Gene Editing ◽

Therapeutic Tools

Abstract Muscular dystrophies are a heterogeneous group of genetic muscle diseases that are often characterized by pathological findings of muscle fiber degeneration and the replacement of muscle fibers with fibrotic/connective tissues. In spite of the genetic causes of many of these conditions having been identified, curative treatments are still lacking. Recently, genome engineering technologies, including targeted gene editing and gene regulation, have emerged as attractive therapeutic tools for a variety of muscular dystrophies. This review summarizes the genome engineering strategies that are currently under preclinical evaluation for the treatment of LAMA2-deficient congenital muscular dystrophy. In particular, we focus on the applications of CRISPR/Cas9 to correct a splice site mutation in LAMA2 and to up-regulate a disease-modifying gene LAMA1. Finally, the challenges faced in the clinical translation of these strategies are discussed.

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Congenital Muscular Dystrophy With Abnormal Radiographic Myelin Pattern

Journal of Child Neurology ◽

10.1177/08830738920070010811 ◽

1992 ◽

Vol 7 (1_suppl) ◽

pp. S51-S63 ◽

Cited By ~ 19

Author(s):

J.D. Cook ◽

G.G. Gascon ◽

A. Haider ◽

R. Coates ◽

B. Stigsby ◽

...

Keyword(s):

Muscular Dystrophy ◽

Nerve Conduction Velocity ◽

Phenotypic Diversity ◽

Congenital Muscular Dystrophy ◽

Internal Capsule ◽

Clinical Syndrome ◽

Muscular Dystrophies ◽

Structural Protein ◽

Muscle Groups ◽

Normal Nerve Conduction

We report 11 children with a homogeneous clinical syndrome affecting both sexes, characterized by weakness at birth, slowly improving course, weakness of all muscle groups, arreflexia, elevated blood creatine kinase, normal nerve conduction velocity, dystrophic changes on muscle biopsy, and diffuse periventricular cortical white-matter abnormalities with sparing of corpus callosum, internal capsule, and brain stem. We compare them to 48 other previously reported similar cases and designate them as altered myelin radiographic pattern congenital muscular dystrophy (CMD), which is the same as occidental CMD. We compare them to the other presently accepted phenotypes: progressive Fukuyama CMD, Walker-Warburg or cerebral-ocular CMD, and Santavuori or muscle-eye-brain CMD. We suggest that the different phenotypes are alleles of the same gene, which regulates or expresses a structural protein required for muscle integrity, myelination, and formation of the cortex. Such phenotypic diversity has been established for mutations of Xp21 in X-linked muscular dystrophies. (J Child Neurol 1992;7(Suppl):S51-S63.)

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CONGENITAL MUSCULAR DYSTROPHY. CARE OF CHILDREN AND FAMILIES

Scandinavian Journal of Rehabilitation Medicine ◽

10.1080/003655098443904 ◽

1998 ◽

Vol 30 (0) ◽

pp. 53-57

Author(s):

Karin Edebol Eeg-Olofsson

Keyword(s):

Muscular Dystrophy ◽

Congenital Muscular Dystrophy ◽

Children And Families

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Congenital muscular dystrophy: Phospho-glycan connection

Functional Glycomics ◽

10.1038/fg.2010.3 ◽

2010 ◽

Author(s):

Emma Leah

Keyword(s):

Muscular Dystrophy ◽

Congenital Muscular Dystrophy

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P.347Urinary titin fragment in Fukuyama congenital muscular dystrophy

Neuromuscular Disorders ◽

10.1016/j.nmd.2019.06.461 ◽

2019 ◽

Vol 29 ◽

pp. S168-S169

Author(s):

T. Sato ◽

N. Taniguchi ◽

K. Ishiguro ◽

M. Shichiji ◽

T. Murakami ◽

...

Keyword(s):

Muscular Dystrophy ◽

Congenital Muscular Dystrophy

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Annexins and Membrane Repair Dysfunctions in Muscular Dystrophies

International Journal of Molecular Sciences ◽

10.3390/ijms22105276 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5276

Author(s):

Coralie Croissant ◽

Romain Carmeille ◽

Charlotte Brévart ◽

Anthony Bouter

Keyword(s):

Skeletal Muscle ◽

Muscular Dystrophy ◽

Genetic Disorders ◽

Muscle Cells ◽

Cell Types ◽

Clinical Severity ◽

Skeletal Muscle Cells ◽

Muscular Dystrophies ◽

Membrane Repair ◽

Human Skeletal Muscle Cells

Muscular dystrophies constitute a group of genetic disorders that cause weakness and progressive loss of skeletal muscle mass. Among them, Miyoshi muscular dystrophy 1 (MMD1), limb girdle muscular dystrophy type R2 (LGMDR2/2B), and LGMDR12 (2L) are characterized by mutation in gene encoding key membrane-repair protein, which leads to severe dysfunctions in sarcolemma repair. Cell membrane disruption is a physiological event induced by mechanical stress, such as muscle contraction and stretching. Like many eukaryotic cells, muscle fibers possess a protein machinery ensuring fast resealing of damaged plasma membrane. Members of the annexins A (ANXA) family belong to this protein machinery. ANXA are small soluble proteins, twelve in number in humans, which share the property of binding to membranes exposing negatively-charged phospholipids in the presence of calcium (Ca2+). Many ANXA have been reported to participate in membrane repair of varied cell types and species, including human skeletal muscle cells in which they may play a collective role in protection and repair of the sarcolemma. Here, we discuss the participation of ANXA in membrane repair of healthy skeletal muscle cells and how dysregulation of ANXA expression may impact the clinical severity of muscular dystrophies.

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Skeletal and Cardiac Muscle Disorders Caused by Mutations in Genes Encoding Intermediate Filament Proteins

International Journal of Molecular Sciences ◽

10.3390/ijms22084256 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4256

Author(s):

Lorenzo Maggi ◽

Manolis Mavroidis ◽

Stelios Psarras ◽

Yassemi Capetanaki ◽

Giovanna Lattanzi

Keyword(s):

Muscular Dystrophy ◽

Cardiac Muscle ◽

Intermediate Filament ◽

Striated Muscle ◽

Congenital Muscular Dystrophy ◽

Left Ventricular ◽

Intermediate Filament Proteins ◽

Muscle Disorders ◽

Genes Encoding ◽

Molecular Aspects

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 DES gene (OMIM *125660) and A-type lamins by the LMNA gene (OMIM *150330), have been involved in striated muscle disorders. Diseases include desmin-related myopathy and cardiomyopathy (desminopathy), which can be manifested with dilated, restrictive, hypertrophic, arrhythmogenic, or even left ventricular non-compaction cardiomyopathy, Emery–Dreifuss Muscular Dystrophy (EDMD2 and EDMD3, due to LMNA mutations), LMNA-related congenital Muscular Dystrophy (L-CMD) and LMNA-linked dilated cardiomyopathy with conduction system defects (CMD1A). Recently, mutations in synemin (SYNM gene, OMIM *606087) have been linked to cardiomyopathy. This review will summarize clinical and molecular aspects of desmin-, lamin- and synemin-related striated muscle disorders with focus on LMNA and DES-associated clinical entities and will suggest pathogenetic hypotheses based on the interplay of desmin and lamin A/C. In healthy muscle, such interplay is responsible for the involvement of this network in mechanosignaling, nuclear positioning and mitochondrial homeostasis, while in disease it is disturbed, leading to myocyte death and activation of inflammation and the associated secretome alterations.

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