Collagen VI-related muscle disorders include severe Ullrich's disease (Ullrich congenital muscular dystrophy:UCMD) and milder Bethlem myopathy Mutations in the 3 collagen VI genes, namely, COL6A1, COL6A2, and COL6A3, cause both diseases UCMD is inherited in an autosomal recessive manner, and de novo dominant mutations are also reported Bethlem myopathy is usually inherited in an autosomal dominant manner, but a rare autosomal recessive inheritance has recently been reported Patients with UCMD have generalized muscle weakness, multiple contractures of the proximal joints, and hyperextensibility of the distal joints Bethlem myopathy is characterized by a combination of proximal muscle weakness and contractures of finger, elbow, and ankle joints Because intermediate phenotypes occur, UCMD and Bethlem myopathy should be considered diseases in a continuous spectrum of collagen VI-related muscle disorders Abnormalities of cell adhesion, regeneration, mitochondrial permeability transition pore, and autophagy have been reported in UCMD Respiratory surveillance for nocturnal hypoventilation and proper respirator implementation are crinical management considerations in UCMD Orthopedic assessment in necessary if surgery for Achilles tendon contractures is being considered in patient with Bethlem myopathy We evaluated the role of nonsense-mediated mRNA decay (NMD) in UCMD associated with a premature termination codon in the COL6A2 gene, which caused the loss of collagen VI A pharmacological block of NMD caused upregulation of the mutant collagen VI and partially functional extracellular matrix formation Cyclosporin A has been reported to correct mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies, and a pilot trial of cyclosporin A was carried out

[Collagen VI-related muscle disorders].

Basement membranes (BMs) are highly specialised extracellular matrix (ECM) structures that within the heart underlie endothelial cells (ECs) and surround cardiomyocytes and vascular smooth muscle cells. They generate a dynamic and structurally supportive environment throughout cardiac development and maturation by providing physical anchorage to the underlying interstitium, structural support to the tissue, and by influencing cell behaviour and signalling. While this provides a strong link between BM dysfunction and cardiac disease, the role of the BM in cardiac biology remains under-researched and our understanding regarding the mechanistic interplay between BM defects and their morphological and functional consequences remain important knowledge-gaps. In this review, we bring together emerging understanding of BM defects within the heart including in common cardiovascular pathologies such as contractile dysfunction and highlight some key questions that are now ready to be addressed.

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The role of basement membranes in cardiac biology and disease.

Collagen VI-related dystrophy spans a clinical continuum from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy. This disease is caused by causative variants in COL6A1, COL6A2, or COL6A3. Most reported causative variants are de novo; therefore, to identify possible associated causative variants, comprehensive large cohort studies are required for different ethnicities. We retrospectively reviewed clinical information, muscle histology, and genetic analyses from 147 Japanese patients representing 130 families, whose samples were sent for diagnosis to the National Center of Neurology and Psychiatry between July 1979 and January 2020. Genetic analyses were conducted by gene-based resequencing, targeted panel resequencing, and whole exome sequencing, in combination with cDNA analysis. Of a total of 130 families with 1–5 members with collagen VI-related dystrophy, 120 had mono-allelic and 10 had bi-allelic variants in COL6A1, COL6A2, or COL6A3. Among them, 60 variants were in COL6A1, 57 in COL6A2, and 23 in COL6A3, including 37 novel variants. Mono-allelic variants were classified into four groups: missense (69, 58%), splicing (40, 33%), small in-frame deletion (7, 6%), and large genomic deletion (4, 3%). Variants in the triple helical domains accounted for 88% (105/120) of all mono-allelic variants. We report the causative variant profile of a large set of Japanese cases of collagen VI-related dystrophy. This dataset can be used as a reference to support genetic diagnosis and variant-specific treatment.

/pdf/causative-variant-profile-of-collagen-vi-related-dystrophy-1rbk0wltb8.pdf

Causative variant profile of collagen VI-related dystrophy in Japan

Background Congenital muscular dystrophy (CMD) refers to hypotonia and delayed motor development that is manifested at or near the birth. Additional presentations have been observed in CMD syndromes. Methods Thorough clinical examinations were performed on two unrelated Iranian families with typical symptoms of CMD and uncommon features such as intellectual disability and nephrolithiasis. The genomic DNA of probands were subjected to whole exome sequencing. Following the detection of candidate variants with a bioinformatic pipeline, the familial co-segregation analysis was carried out using polymerase chain reaction-based Sanger sequencing. Results We identified a missense homozygous variant in the fukutin-related protein (FKRP) gene (c.968G>A, p.Arg323His) related to CMD-dystroglycanopathy type B5 (MDDGB5) and a frameshift homozygous variant in the selenoprotein N (SELENON) gene (c.1446delC, p.Asn483Thrfs*11) associated with congenital rigid-spine muscular dystrophy 1 (RSMD1), which were completely segregated with the phenotypes in the families. These variants were not found in either the 1000 Genomes Project or the Exome Aggregation Consortium. The present study provides the first report of these homozygous sequence variants in Iran. Moreover, our study was the first observation of nephrolithiasis in FKRP-related dystroglycanopathy and intellectual disability in SELENON-related myopathies. Based on in silico studies and molecular docking, these variations induced pathogenic effects on the proteins. Conclusions Our findings extend the genetic database of Iranian patients with CMD and, in general, the phenotypical spectrum of syndromic CMD. It is recommended to consider these variants for a more accurate clinical interpretation, prenatal diagnosis and genetic counseling in families with a history of CMD, especially in those combined with cognitive impairments or renal dysfunctions.

The first report of two homozygous sequence variants in FKRP and SELENON genes associated with syndromic congenital muscular dystrophy in Iran: Further expansion of the clinical phenotypes.

Here, we described three affected boys from two unrelated families of Ossetian-Digor origin from the Republic of North Ossetia-Alania who were admitted to the Research Centre for Medical Genetics with unspecified muscular dystrophy. High-throughput sequencing was performed and revealed two novel frameshift variants in the COL6A2 gene (NM_001849.3) in a heterozygous state each in both cases: c.508_535delinsCTGTGG and c.1659_1660del (case 1) and c.1689del and c.1659_1660del (case 2). In two cases, the same nucleotide variant in the COL6A2 gene (c.1659_1660del) was observed. We have suggested that the variant c.1659_1660del may be common in the Ossetian-Digor population because two analyzed families have the same ancestry from the same subethnic group of Ossetians). The screening for an asymptomatic carriage of the nucleotide variant c.1659_1660del in 54 healthy donors from Ossetian-Digor population revealed that the estimated carrier frequency is 0.0093 (CI: 0.0002–0.0505), which is high for healthy carriers of the pathogenic variant. Molecular genetic, anamnestic data and clinical examination results allowed us to diagnose Ullrich muscular dystrophy in those affected boys. Genetic heterogeneity and phenotypic diversity of muscular dystrophies complicate diagnosis. It is important to make a differential diagnosis of such conditions and use HTS methods to determine the most accurate diagnosis.

/pdf/the-presentation-of-two-unrelated-clinical-cases-from-the-3agc6mhz.pdf

The Presentation of Two Unrelated Clinical Cases from the Republic of North Ossetia-Alania with the Same Previously Undescribed Variant in the COL6A2 Gene

How to Cite This Article: Bozorgmehr B, Kariminejad A, Nafissi Sh, Jebelli B, Andoni U, Gartioux C, Ledeuil C, Allamand Y, Richard P, Kariminejad MH. Ullrich Congenital Muscular Dystrophy (UCMD):Clinical and Genetic Correlations. Iran J Child Neurol. 2013 Summer; 7(3): 15-22. Obj ective: Ullrich congenital muscular dystrophy (UCMD) corresponds to the severe end of the clinical spectrum of neuromuscular disorders caused by mutations in the genes encoding collagen VI (COL VI). We studied four unrelated families with six affected children that had typical UCMD with dominant and recessive inheritance. Materials & Methods Four unrelated Iranian families with six affected children with typical UCMD were analyzed for COLVI secretion in skin fibroblast culture and the secretion of COLVI in skin fibroblast culture using quantitative RT–PCR (Q-RT-PCR), and mutation identification was performed by sequencing of complementary DNA. Results COL VI secretion was altered in all studied fibroblast cultures. Two affected sibs carried a homozygous nonsense mutation in exon 12 of COL6A2, while another patient had a large heterozygous deletion in exon 5-8 of COL6A2. The two other affected sibs had homozygote mutation in exon 24 of COL6A2, and the last one was homozygote in COL6A1. Conclusion In this study, we found out variability in clinical findings and genetic inheritance among UCMD patients, so that the patient with complete absence of COLVI was severely affected and had a large heterozygous deletion in COL6A2. In contrast, the patients with homozygous deletion had mild to moderate decrease in the secretion of COL VI and were mildly to moderately affected. References 1. Voit T. Congenital Muscular Dystrophies Brain Dev 1998;20(2): 65-74. 2. Ullrich OZ Ges. Scleroatonic Muscular Dystrophy. Neurol Psychiatr 1930;126:171-201. 3. Ullrich O. Monatsschr. Kinderheilkd 1930;47:502-10. 4. Mercuri E, Yuva Y, Brown SC, Brockington M, Kinali M, Jungbluth H, et al. Collagen VI involvement in Ullrich Syndrome: A Clinical, genetic and Immunohistochemical study. Neurology 2002;58(9):1354-9. 5. Lampe AK, Bushby KM. Collagen VI related muscle disorders. J Med Genet 2005;42(9):673-85. 6. Mercuri E, Muntoni F. Congenital Muscular Dystrophies. In: Emery AEH, editors. The muscular dystrophies. Oxford: Oxford University Press: 2001. p. 10-38. 7. Furukawa T, Toyokura Y. Congenital Hypotonic-Sclerotic muscular dystrophy. J Med Genet 1977;14(6):426-9. 8. Nonaka I, Une Y, Ishihara T, Miyoshino S, Nakashima T, Sugita H. A clinical and histological study of Ullrich’s disease (congenital atonic-sclerotic muscular dystrophy). Neuropediatrics 1981; 12(3):197-208. 9. Pan TC, Zhang RZ, Sudano DG, Marie SK, Bonnemann CG, Chu ML. New molecular mechanism for Ullrich Congenital Muscular Dystrophy: A heterozygous inframe deletion in the COL6A1 gene causes a severe phenotype. Am J Hum Genet 2003;73(2):355-69. 10. Baker NL, Morgelin M, Peat R, Goemans N, North KN, Baterman JF, et al. Dominant Collagen VI Mutations are a common cause of ullrich congenital muscular dystrophy. Hum Mol Genet 2005;14(2]):279-93. 11. Pace RA, Peat RA, Baker NL, Zamurs L, Morgelin M, Irving M et al. Collagen VI glycine mutations: Perturbed assembly and a spectrum of clinical severity. Ann Neurol 2008;64(3):294-303. 12. Bethlem J, Wijngaarden GK. Benign myopathy, with autosomal dominant inheritance. A report on three pedigress. Brain 1976;99(1):91-100. 13. Gualandi F, Urciuolo A, Martoni E, Sabatelli P, Squarzoni S, Bovolenta M, et al Auotosomal recessive Bethlem myopath. Neurology 2009;73(22):1883-91. 14. Foley AR, Hu Y, Zou Y, Columbus A, Shoffiner J, Dunn DM, et al. Autosomal recessive Bethlam Myopathy. Neuromuscular Disord 2009;19(10):813-7.

/pdf/ullrich-congenital-muscular-dystrophy-ucmd-clinical-and-1f5bns17yo.pdf

Ullrich Congenital Muscular Dystrophy (UCMD): Clinical and Genetic Correlations.

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Ullrich Congenital Muscular Dystrophy (UCMD): Clinical and Genetic Correlations.