Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s)

Abstract

Collagen VI is widely distributed throughout extracellular matrices (ECMs) in various tissues. In skeletal muscle, collagen VI is particularly concentrated in and adjacent to basement membranes of myofibers. Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in either COL6A1, COL6A2 or COL6A3 gene, thereby leading to collagen VI deficiency in the ECM. It is known to occur through either recessive or dominant genetic mechanism, the latter most typically by de novo mutations. UCMD is well defined by the clinicopathological hallmarks including distal hyperlaxity, proximal joint contractures, protruding calcanei, scoliosis and respiratory insufficiency. Recent reports have depicted the robust natural history of UCMD; that is, loss of ambulation by early teenage years, rapid decline in respiratory function by 10 years of age and early-onset, rapidly progressive scoliosis. Muscle pathology is characterised by prominent interstitial fibrosis disproportionate to the relative paucity of necrotic and regenerating fibres. To date, treatment for patients is supportive for symptoms such as joint contractures, respiratory failure and scoliosis. There have been clinical trials based on the theory of mitochondrion-mediated myofiber apoptosis or impaired autophagy. Furthermore, the fact that collagen VI producing cells in skeletal muscle are interstitial mesenchymal cells can support proof of concept for stem cell-based therapy.

Genetic and clinical findings in a Chinese cohort of patients with collagen VI‐related myopathies

“…Both types of mutation were probably to disrupt the central helical structure of collagen VI monomers but not hamper the formation of dimers or tetramers. However, mutant‐containing tetramers are secreted but they have a reduced ability to associate end‐to‐end into microfibrils and this leads to loss of normal localization of collagen VI in the basement membrane . Our immunohistochemical and double immunostaining analysis (U23, U27 and U25) showed aberrant accumulation of mutant collagen VI in the interstitial and perivascular space rather than at the basement membrane (SSCD) and support this dominant‐negative effect.…”

“…Scoliosis can also aggravate respiratory function by reducing the rib cage compliance in combination with the proximal joint contractures. Thus non‐invasive ventilation is usually sufficient to effectively treat this situation for many years …”

“…Collagen VI in muscle is involved in maintaining tissue integrity by providing a structural link between the extracellular matrix and the basement membrane and by anchoring the muscle basement membrane to the pericellular space. It is also involved in signal transduction, supporting adhesion, spreading and migration of cells, and regulation of cell survival . Collagen VI is made up of 3 distinct chains, α1, α2 and α3.…”

Targeted massively parallel sequencing and histological assessment of skeletal muscles for the molecular diagnosis of inherited muscle disorders

“…Immunohistochemical analysis was performed using mouse monoclonal antibodies against dystrophin C-terminus (NCL-DYS2), dystrophin rod (NCL-DYS1), dystrophin N-terminus (NCL-DYS3), α-sarcoglycan (NCL-a-SALC), β-sarcoglycan (NCL-b-SALC), γ-sarcoglycan (NCL-g-SALC), δ-sarcoglycan (NCL-d-SALC), β-dystroglycan (NCL-b-DG), utrophin (NCL-DRP2), dysferlin (NCL-Hamlet), emerin (NCL-EMERIN) (all from Novocastra Lab); merosin M-chain (MAB1922; CHEMICON International); glycosylated α-dystroglycan (VIA4-1; Upstate); caveolin 3 (C38320; Transduction Lab) and collagen type VI (63175; ICN Biomedicals). Immunofluorescence staining of collagen types IV and VI was performed as described previously25 by using rabbit anti-collagen IV (ab6586; Abcam) and mouse anti-collagen VI (VI-26; Abnova) antibodies.…”

Novel Nonsense Mutation in SLC39A13 Initially Presenting as Myopathy: Case Report and Review of the Literature

“…Glycosaminoglycan and collagen VI both function as connective tissue elements, specifically as ECM components. Bethlem myopathy may present with skin features similar to the ones described in this case report, including cigarette paper-like appearance or scaling skin [Camacho et al, 2001;Kirschner et al, 2005;Yonekawa and Nishino, 2015], and UCMD patients often present with considerable small joint hypermobility within their myopathy disorder [Yonekawa and Nishino, 2015]. UCDM was even considered as a potential diagnosis for our patient, but not confirmed through genetic testing.…”