scholarly journals Phenotypic Spectrum of α-Dystroglycanopathies Associated With the c.919T>a Variant in the FKRP Gene in Humans and Mice

2020 ◽  
Vol 79 (12) ◽  
pp. 1257-1264
Author(s):  
Susan C Brown ◽  
Marta Fernandez-Fuente ◽  
Francesco Muntoni ◽  
John Vissing
Keyword(s):  
Muscular Dystrophy ◽  
Congenital Muscular Dystrophy ◽  
Early Death ◽  
Muscle Disease ◽  
Compound Heterozygous ◽  
Homozygous State ◽  
Multisystem Disease ◽  
Phenotypic Spectrum ◽  
Severe Mutation ◽  
Human And Mouse

Abstract Mutations in the fukutin-related protein gene, FKRP, are the most frequent single cause of α-dystroglycanopathy. Rare FKRP mutations are clinically not well characterized. Here, we review the phenotype associated with the rare c.919T>A mutation in FKRP in humans and mice. We describe clinical and paraclinical findings in 6 patients, 2 homozygous, and 4-compound heterozygous for c.919T>A, and compare findings with a mouse model we generated, which is homozygous for the same mutation. In patients, the mutation at the homozygous state is associated with a severe congenital muscular dystrophy phenotype invariably characterized by severe multisystem disease and early death. Compound heterozygous patients have a severe limb-girdle muscular dystrophy phenotype, loss of ambulation before age 20 and respiratory insufficiency. In contrast, mice homozygous for the same mutation show no symptoms or signs of muscle disease. Evidence therefore defines the FKRP c.919T>A as a very severe mutation in humans. The huge discrepancy between phenotypes in humans and mice suggests that differences in protein folding/processing exist between human and mouse Fkrp. This emphasizes the need for more detailed structural analyses of FKRP and shows the challenges of developing appropriate animal models of dystroglycanopathies that mimic the disease course in humans.

Exome Sequencing Reveals Diagnosis of LAMA2-Muscular Dystrophy and Possibility of Coexisting Bethlem Myopathy in a Neonate

2021 ◽  
Author(s):  
Shruti Bajaj ◽  
Piyush Shah ◽  
Venu Seenappa ◽  
Jayashree Kalyankar ◽  
Divyata Hingwala
Keyword(s):  
Muscular Dystrophy ◽  
Exome Sequencing ◽  
Autosomal Recessive ◽  
Age Of Onset ◽  
Fatty Infiltration ◽  
Congenital Muscular Dystrophy ◽  
Carrier State ◽  
Muscle Disease ◽  
Bethlem Myopathy ◽  
Musculoskeletal Mri

AbstractWe reported a neonate presenting with muscle weakness, hypotonia, and joint contractures since birth. Investigations revealed significantly elevated creatinine-phosphokinase, abnormal electromyography suggestive of muscle disease and normal magnetic resonance imaging (MRI) of the brain. Exome sequencing revealed homozygous pathogenic mutations in LAMA2 (NM_000426.3: c.7881T > G, p.(His2627Gln)) and a heterozygous likely-pathogenic mutation in COL6A2 (NM_001849.3: c.1970–2A > G). Parental segregation by Sanger sequencing confirmed a heterozygous carrier state for the LAMA2 variant in both parents, thus confirming the diagnosis of autosomal recessive LAMA2-muscular dystrophy (LAMA2-MD) in the proband. The COL6A2 variant segregated with the as-yet asymptomatic mother. Musculoskeletal MRI of the proband at 12 months of age revealed peripheral involvement of the vastii, rectus femoris, gastrocnemius and the soleus, with relative central sparing, without areas of fatty infiltration; not serving to distinguish clearly between LAMA-MD and COL6A2- related disease. Reverse phenotyping of a 27-year-old mother revealed a normal musculoskeletal MRI and clinically absent red flags. Potential explanations for the heterozygous likely-pathogenic COL6A2 variant in the proband and the mother include (a) a coexisting diagnosis of autosomal dominant COL6A2-related myopathy, likely Bethlem myopathy, which has a variable clinical phenotype and age of onset; (b) a carrier state for autosomal recessive Ullrich congenital muscular dystrophy; or (c) a heterozygous COL6A2 variant contributing as a synergistic factor along with homozygous LAMA2 mutation. The couple was offered genetic counseling regarding the proband and the future pregnancies.

Novel compound heterozygous laminina2-chain gene (LAMA2) mutations in congenital muscular dystrophy

1998 ◽  
Vol 12 (2) ◽  
pp. 135-135 ◽  
Author(s):  
Joshua T. Mendell ◽  
Shirly G. Panicker ◽  
Chang-Yong Tsao ◽  
Bo Feng ◽  
Zarife Sahenk ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Congenital Muscular Dystrophy ◽  
Chain Gene ◽  
Compound Heterozygous

scholarly journals Novel LAMA2 variants identified in a patient with white matter abnormalities

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Keiko Yamamoto-Shimojima ◽  
Hiroaki Ono ◽  
Taichi Imaizumi ◽  
Toshiyuki Yamamoto
Keyword(s):  
Creatine Kinase ◽  
White Matter ◽  
Muscular Dystrophy ◽  
Developmental Delay ◽  
Congenital Muscular Dystrophy ◽  
Genomic Analysis ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
White Matter Abnormalities ◽  
Pathogenic Variants

AbstractComprehensive genomic analysis was performed in a patient with mild psychomotor developmental delay, elevated creatine kinase, and white matter abnormalities. The results revealed biallelic pathogenic variants in the gene related to merosin-deficient congenital muscular dystrophy, NM_000426.3(LAMA2):c.1338_1339del [p.Gly447Phefs*7] and c.2749 + 2dup, which consist of compound heterozygous involvement with predicted loss-of-function and splicing abnormalities.

scholarly journals Enhanced Expression of the α7β1 Integrin Reduces Muscular Dystrophy and Restores Viability in Dystrophic Mice

2001 ◽  
Vol 152 (6) ◽  
pp. 1207-1218 ◽  
Author(s):  
Dean J. Burkin ◽  
Gregory Q. Wallace ◽  
Kimberly J. Nicol ◽  
David J. Kaufman ◽  
Stephen J. Kaufman
Keyword(s):  
Extracellular Matrix ◽  
Muscular Dystrophy ◽  
Congenital Muscular Dystrophy ◽  
Transgenic Animals ◽  
Muscle Disease ◽  
Muscle Creatine Kinase ◽  
Glycoprotein Complex ◽  
Enhanced Expression ◽  
Dystrophin Glycoprotein Complex ◽  
Dystrophin Glycoprotein

Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the α7β1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), α2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and α7 integrin congenital muscular dystrophy. Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle. To test whether the α7β1 integrin can compensate for the absence of dystrophin, we expressed the rat α7 chain in mdx/utr−/− mice that lack both dystrophin and utrophin. These mice develop a severe muscular dystrophy highly akin to that in DMD, and they also die prematurely. Using the muscle creatine kinase promoter, expression of the α7BX2 integrin chain was increased 2.0–2.3-fold in mdx/utr−/− mice. Concomitant with the increase in the α7 chain, its heterodimeric partner, β1D, was also increased in the transgenic animals. Transgenic expression of the α7BX2 chain in the mdx/utr−/− mice extended their longevity by threefold, reduced kyphosis and the development of muscle disease, and maintained mobility and the structure of the neuromuscular junction. Thus, bolstering α7β1 integrin–mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/utr−/− mice and compensates for the absence of the dystrophin- and utrophin-mediated linkage systems. This suggests that enhanced expression of the α7β1 integrin may provide a novel approach to treat DMD and other muscle diseases that arise due to defects in the dystrophin glycoprotein complex. A video that contrasts kyphosis, gait, joint contractures, and mobility in mdx/utr−/− and α7BX2-mdx/utr−/−mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.

scholarly journals Laminin-111 protein therapy after disease onset slows muscle disease in a mouse model of laminin-α2 related congenital muscular dystrophy

2020 ◽  
Vol 29 (13) ◽  
pp. 2162-2170
Author(s):  
Pamela Barraza-Flores ◽  
Katherine E Bukovec ◽  
Marisela Dagda ◽  
Brandon W Conner ◽  
Ariany Oliveira-Santos ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Life Expectancy ◽  
Mouse Model ◽  
Replacement Therapy ◽  
Disease Onset ◽  
Congenital Muscular Dystrophy ◽  
Muscle Disease ◽  
Muscle Pathology ◽  
Protein Therapy ◽  
Laminin Α2

Abstract Laminin-α2 related congenital muscular dystrophy (LAMA2-CMD) is a fatal muscle disease caused by mutations in the LAMA2 gene. Laminin-α2 is critical for the formation of laminin-211 and -221 heterotrimers in the muscle basal lamina. LAMA2-CMD patients exhibit hypotonia from birth and progressive muscle loss that results in developmental delay, confinement to a wheelchair, respiratory insufficiency and premature death. There is currently no cure or effective treatment for LAMA2-CMD. Several studies have shown laminin-111 can serve as an effective protein-replacement therapy for LAMA2-CMD. Studies have demonstrated early treatment with laminin-111 protein results in an increase in life expectancy and improvements in muscle pathology and function. Since LAMA2-CMD patients are often diagnosed after advanced disease, it is unclear if laminin-111 protein therapy at an advanced stage of the disease can have beneficial outcomes. In this study, we tested the efficacy of laminin-111 protein therapy after disease onset in a mouse model of LAMA2-CMD. Our results showed laminin-111 treatment after muscle disease onset increased life expectancy, promoted muscle growth and increased muscle stiffness. Together these studies indicate laminin-111 protein therapy either early or late in the disease process could serve as an effective protein replacement therapy for LAMA2-CMD.

scholarly journals A Successful Treatment of Endoscopic Third Ventriculostomy with Choroid Plexus Cauterization for Hydrocephalus in Walker-Warburg Syndrome

2016 ◽  
Vol 2016 ◽  
pp. 1-5
Author(s):  
Tomoko Tanaka ◽  
Catharine J. Harris ◽  
Sarah S. Barnett ◽  
N. Scott Litofsky
Keyword(s):  
Muscular Dystrophy ◽  
Choroid Plexus ◽  
Successful Treatment ◽  
Endoscopic Third Ventriculostomy ◽  
Third Ventricle ◽  
Congenital Muscular Dystrophy ◽  
Third Ventriculostomy ◽  
Csf Flow ◽  
Phenotypic Spectrum ◽  
Choroid Plexus Cauterization

Walker-Warburg syndrome (WWS) is a rare autosomal recessive congenital muscular dystrophy with brain malformations and ocular abnormalities that falls under the wider phenotypic spectrum of the dystroglycanopathies. Mutations in a number of genes including POMT1, POMT2, POMGNT1, POMGNT2, FKTN, FKRP, LARGE, and ISPD are known to cause alpha dystroglycan-related muscular dystrophy. Mutations in these genes result in a broad phenotypic spectrum ranging from the severe WWS to a mild congenital muscular dystrophy with no brain involvement. WWS is fatal to most patients early in life with mean survival of 9 months. The most common brain finding is cobblestone lissencephaly with the vast majority of patients (97%) also having ventricular dilation with or without hydrocephalus. Surgical treatment has not been frequently detailed. This report describes our successful treatment of a patient with WWS and hydrocephalus with Endoscopic Third Ventriculostomy (ETV) with choroid plexus cauterization (CPC). Fourteen months following treatment, a follow-up MRI CSF flow study demonstrated robust CSF flow through floor of third ventricle from interpeduncular cistern to lateral ventricle.

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