Myopathic EDS (mEDS) is characterized by muscle weakness that manifests in childhood with proximal contractures of the large joints and distal joint hypermobility. Typically, muscle weakness improves in young adulthood, although it may deteriorate again in the fourth decade of life. The spectrum of disorders characterized by muscle weakness, hypotonia, myopathy, and connective tissue symptomatology was originally associated with collagen type VI disorders.
Pathogenic variants in COL12A1, which encodes the α1-chain of type XII collagen, are the molecular cause of mEDS. Collagen XII is present as a homotrimer on the surface of type I collagen fibers. It forms a link between type I collagen fibers and extracellular matrix components such as decorin, fibromodulin, and tenascin. To date, mEDS has been described in both an autosomal dominantly inherited form with heterozygous missense variants and an autosomal recessively inherited form with homozygous frameshift variants.
1 gene: COL12A1
Delbaere et al. 2019, Genet Med 22:112 / Jezela-Stanek et al. 2019, Clin Genet 95(6):736 / Punetha et al. 2017, Muscle Nerve 55:277 / Brady et al. 2017, Am J Med Genet C 175:70 / Zou et al. 2014, Hum Mol Genet 23:2339 / Hicks et al. 2014, Hum Mol Genet 23:2353
The autosomal dominantly inherited periodontal EDS (pEDS) is characterized by severe, early onset periodontitis. Clinical symptoms start in childhood with extensive gingivitis leading to destruction of the periodontium and premature tooth loss in adolescence. Other clinical features include pretibial hyperpigmentation, acrogeria, vulnerable skin and gums, abnormal scarring, generalized joint hypermobility, and easy bruising. Rupture of arteries and internal organs and CNS involvement in the form of microangiopathy and leukoencephalopathy have also been described in individual cases.
In 2003, a candidate region was located on chromosome 12p13.1, but no gene was identified. In 2016, complementary exome analysis of 19 families identified pathogenic variants in C1R in 15 families and in C1S in two families. The C1R and C1S genes, which are directly adjacent in region 12p13.1, encode the C1r and C1s subunits of the complement pathway. The proteins form a heterotetramer that combines with six C1q subunits. The pathogenic variants identified so far lead to intracellular retention of the complement complex and endoplasmic reticulum enlargement.
2 genes: C1R, C1S
Kapferer-Seebacher et al. 2019, Neurogenetics 20:1 / Wu et al. 2018, J Clin Periodontol 45:1311 / Brady et al. 2017, Am J Med Genet C 175:70 / Kapferer-Seebacher et al. 2017, J Clin Periodontol 44:1088 / Kapferer-Seebacher et al. 2016, Am J Hum Genet 99:1005 / Reinstein et al. 2013, Eur J Hum Genet 21:233 / Rahman et al. 2003, Am J Hum Genet 73:198 / Hartsfield et al. 1990, Am J Med Genet 37:465 / Stewart et al. 1977, Birth Defects Orig Art Ser XIII:85