Abstract
The Ehlers-Danlos Syndromes comprise a heterogeneous group of diseases, which are characterized by fragility of the soft connective tissues and widespread manifestations in skin, ligaments and joints, blood vessels and internal organs. The clinical spectrum varies from mild skin and joint hyperlaxity to severe physical disability and life-threatening vascular complications. The current Villefranche classification recognizes six subtypes, most of which are linked to mutations in one of the genes encoding fibrillar collagen proteins or enzymes involved in post-translational modification of these proteins. Establishing the correct EDS subtype has important implications for genetic counselling and management and is supported by specific biochemical and molecular investigations. Over the last years, the characterisation of several new EDS variants has broadened insights into the molecular pathogenesis of EDS by implicating genetic defects in the biosynthesis of other extracellular matrix molecules, such as proteoglycans and tenascin-X, or genetic defects in molecules involved in intracellular trafficking, secretion and assembly of extracellular matrix proteins.
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Abbreviations
- ATCS:
-
Adducted Thumb Clubfoot Syndrome
- ECM:
-
Extracellular Matrix
- EDS:
-
Ehlers-Danlos Syndrome
- ER:
-
Endoplasmic Reticulum
- HP:
-
Hydroxylysylpyridinoline
- JHS:
-
Joint Hypermobility Syndrome
- LP:
-
Lysylpyridinoline
References
Beighton P et al (1998) Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers- Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet 77(1):31–37
Smith SM, Birk DE (2010) Focus on molecules: collagens V and XI. Exp Eye Res 2012 May; 98(1): 105–106
Andrikopoulos K et al (1995) Targeted mutation in the col5a2 gene reveals a regulatory role for type V collagen during matrix assembly. Nat Genet 9(1):31–36
Toriello HV et al (1996) A translocation interrupts the COL5A1 gene in a patient with Ehlers- Danlos syndrome and hypomelanosis of Ito. Nat Genet 13(3):361–365
Wenstrup RJ et al (1996) A splice-junction mutation in the region of COL5A1 that codes for the carboxyl propeptide of pro alpha 1(V) chains results in the gravis form of the Ehlers-Danlos syndrome (type I). Hum Mol Genet 5(11):1733–1736
De Paepe A et al (1997) Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II. Am J Hum Genet 60(3):547–554
Schwarze U et al (2000) Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II). Am J Hum Genet 66(6):1757–1765
Wenstrup RJ et al (2000) COL5A1 haploinsufficiency is a common molecular mechanism underlying the classical form of EDS. Am J Hum Genet 66(6):1766–1776
Malfait F et al (2005) The molecular basis of classic Ehlers-Danlos syndrome: a comprehensive study of biochemical and molecular findings in 48 unrelated patients. Hum Mutat 25(1):28–37
Symoens S et al (2009) COL5A1 signal peptide mutations interfere with protein secretion and cause classic Ehlers-Danlos syndrome. Hum Mutat 30(2):E395–E403
Symoens S et al (2011) A novel splice variant in the N-propeptide of COL5A1 causes an EDS phenotype with severe kyphoscoliosis and eye involvement. PLoS One 6(5):e20121
Symoens S et al (2012) Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria. Hum Mutat 33(10):1485–1493
Beighton P, Solomon L, Soskolne CL (1973) Articular mobility in an African population. Ann Rheum Dis 32(5):413–418
Rombaut L et al (2010) Musculoskeletal complaints, physical activity and health-related quality of life among patients with the Ehlers-Danlos syndrome hypermobility type. Disabil Rehabil 32(16):1339–1345
Rombaut L et al (2011) Impairment and impact of pain in female patients with Ehlers-Danlos syndrome: a comparative study with fibromyalgia and rheumatoid arthritis. Arthritis Rheum 63(7):1979–1987
Rombaut L et al (2010) Joint position sense and vibratory perception sense in patients with Ehlers-Danlos syndrome type III (hypermobility type). Clin Rheumatol 29(3):289–295
Rombaut L et al (2012) Muscle mass, muscle strength, functional performance, and physical impairment in women with the hypermobility type of Ehlers-Danlos syndrome. Arthritis Care Res (Hoboken) 64(10):1584–1592
Hausser I, Anton-Lamprecht I (1994) Differential ultrastructural aberrations of collagen fibrils in Ehlers- Danlos syndrome types I-IV as a means of diagnostics and classification. Hum Genet 93(4):394–407
Zweers MC et al (2003) Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome. Am J Hum Genet 73(1):214–217
Schalkwijk J et al (2001) A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. N Engl J Med 345(16):1167–1175
Dalgleish R (1998) The human collagen mutation database 1998. Nucleic Acids Res 26(1):253–255
Schwarze U et al (2001) Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV. Am J Hum Genet 69(5):989–1001
Leistritz DF et al (2011) COL3A1 haploinsufficiency results in a variety of Ehlers-Danlos syndrome type IV with delayed onset of complications and longer life expectancy. Genet Med 13(8):717–722
Palmeri S et al (2003) Neurological presentation of Ehlers-Danlos syndrome type IV in a family with parental mosaicism. Clin Genet 63(6):510–515
Milewicz DM et al (1993) Parental somatic and germ-line mosaicism for a multiexon deletion with unusual endpoints in a type III collagen (COL3A1) allele produces Ehlers-Danlos syndrome type IV in the heterozygous offspring. Am J Hum Genet 53(1):62–70
Kontusaari S et al (1992) Substitution of aspartate for glycine 1018 in the type III procollagen (COL3A1) gene causes type IV Ehlers-Danlos syndrome: the mutated allele is present in most blood leukocytes of the asymptomatic and mosaic mother. Am J Hum Genet 51(3):497–507
Richards AJ et al (1992) A single base mutation in the gene for type III collagen (COL3A1) converts glycine 847 to glutamic acid in a family with Ehlers-Danlos syndrome type IV. An unaffected family member is mosaic for the mutation. Hum Genet 89(4):414–418
Pinnell SR et al (1972) A heritable disorder of connective tissue. Hydroxylysine-deficient collagen disease. New Engl J Med 286(19):1013–1020
Yeowell HN, Walker LC, Neumann LM (2005) An Ehlers-Danlos syndrome type VIA patient with cystic malformations of the meninges. Eur J Dermatol 15(5):353–358
Giunta C, Randolph A, Steinmann B (2005) Mutation analysis of the PLOD1 gene: an efficient multistep approach to the molecular diagnosis of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA). Mol Genet Metab 86(1–2):269–276
Abu A et al (2008) Deleterious mutations in the Zinc-Finger 469 gene cause brittle cornea syndrome. Am J Hum Genet 82(5):1217–1222
Burkitt Wright EM et al (2011) Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance. Am J Hum Genet 88(6):767–777
Meani N et al (2009) The tumor suppressor PRDM5 regulates Wnt signaling at early stages of zebrafish development. PLoS One 4(1):e4273
Steinmann B, Royce P, Superti-Furga A (2002) The Ehlers-Danlos syndrome. In: Royce P, Steinmann B (eds) Connective tissue and its heritable disorders. Wiley-Liss, New York, pp 431–523
Malfait F et al (2010) Musculocontractural Ehlers-Danlos Syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene. Hum Mutat 31(11):1233–1239
Kosho T et al (2010) A new Ehlers-Danlos syndrome with craniofacial characteristics, multiple congenital contractures, progressive joint and skin laxity, and multisystem fragility-related manifestations. Am J Med Genet A 152A(6):1333–1346
Miyake N et al (2010) Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome. Hum Mutat 31(8):966–974
Shimizu K et al (2011) Delineation of dermatan 4-O-sulfotransferase 1 deficient Ehlers-Danlos syndrome: observation of two additional patients and comprehensive review of 20 reported patients. Am J Med Genet A 155A(8):1949–1958
Quentin E et al (1990) A genetic defect in the biosynthesis of dermatan sulfate proteoglycan: galactosyltransferase I deficiency in fibroblasts from a patient with a progeroid syndrome. Proc Natl Acad Sci U S A 87(4):1342–1346
Malfait F, Kariminejad A, Van Damme T, Gauche C, Syx D, Merhi-Soussi F, Gulberti S, Symoens S, Vanhauwaert S, Willaert A, Bozorgmehr B, Kariminejad MH, Ebrahimiadib N, Hausser I, Huysseune A, Fournel-Gigleux S, De Paepe A (2013) Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos syndrome-like connective tissue disorder. Am J Hum Genet 2013 May 7 (E-pub ahead of print)
Nakajima M, Mizumoto S, Miyake N, Kogawa R, Iida A, Ito H, Kitoh H, Hirayama A, Mitsubuchi H, Miyazaki O, Kosaki R, Horikawa R, Lai A, Mendoza-Londono R, Dupuis L, Chitayat D, Howard A, Leal GF, Cavalcanti D, Tsurusaki Y, Saitsu H, Watanabe S, Lausch E, Unger S, Bonafé L, Ohashi H, Superti-Furga A, Matsumoto N, Sugahara K, Nishimura G, Ikegawa S (2013) Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders. Am J Hum Genet 2013 May 7 (E-pub ahead of print)
Giunta C et al (2008) Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome–an autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. Am J Hum Genet 82(6):1290–1305
Baumann M et al (2012) Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. Am J Hum Genet 90(2):201–216
Cabral WA et al (2005) Mutations near amino end of alpha 1(I) collagen cause combined OI/EDS by interference with N-propeptide processing. J Biol Chem 280(19):19259–19269
Malfait F, Symoens S, Goemans N, Gyftodimou Y, Holmberg E, López-González V, Mortier G, Nampoothiri S, Petersen MB, De Paepe A (2013) Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome. Orphanet J Rare Dis 8:78
Makareeva E et al (2006) Molecular mechanism of alpha 1(I)-osteogenesis imperfecta/Ehlers-Danlos syndrome: unfolding of an N-anchor domain at the N-terminal end of the type I collagen triple helix. J Biol Chem 281(10):6463–6470
Malfait F et al (2004) The natural history, including orofacial features of three patients with Ehlers-Danlos syndrome, dermatosparaxis type (EDS type VIIC). Am J Med Genet A 131(1):18–28
Pierard GE, Lapiere M (1976) Skin in dermatosparaxis. Dermal microarchitecture and biomechanical properties. J Invest Dermatol 66(1):2–7
Nusgens BV et al (1992) Evidence for a relationship between Ehlers-Danlos type VII C in humans and bovine dermatosparaxis. Nat Genet 1(3):214–217
Schwarze U et al (2004) Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am J Hum Genet 74(5):917–930
Malfait F et al (2006) Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems. J Med Genet 43(7):e36
Nuytinck L et al (2000) Classical Ehlers-Danlos syndrome caused by a mutation in type I collagen. Am J Hum Genet 66(4):1398–1402
Malfait F et al (2007) Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat 28(4):387–395
Cabral WA et al (2007) Y-position cysteine substitution in type I collagen (alpha1(I) R888C/p.R1066C) is associated with osteogenesis imperfecta/Ehlers-Danlos syndrome phenotype. Hum Mutat 28(4):396–405
Lund A et al (2008) A novel arginine-to-cysteine substitution in the triple helical region of the alpha1(I) collagen chain in a family with an osteogenesis imperfecta/Ehlers-Danlos phenotype. Clin Genet 73(1):97–101
Gensure RC et al (2005) A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders. J Clin Invest 115(5):1250–1257
Rohrbach M et al (2011) Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation. Orphanet J Rare Dis 6:46
Faber P et al (2007) The successful use of recombinant factor VIIa in a patient with vascular-type Ehlers-Danlos syndrome. Acta Anaesthesiol Scand 51(9):1277–1279
Freeman RK, Swegle J, Sise MJ (1996) The surgical complications of Ehlers-Danlos syndrome. Am Surg 62(10):869–873
Cikrit DF, Miles JH, Silver D (1987) Spontaneous arterial perforation: the Ehlers-Danlos specter. J Vasc Surg 5(2):248–255
Oderich GS et al (2005) The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV: a 30-year experience. J Vasc Surg 42(1):98–106
Pepin M et al (2000) Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 342(10):673–680
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Malfait, F., De Paepe, A. (2014). The Ehlers-Danlos Syndrome. In: Halper, J. (eds) Progress in Heritable Soft Connective Tissue Diseases. Advances in Experimental Medicine and Biology, vol 802. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7893-1_9
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DOI: https://doi.org/10.1007/978-94-007-7893-1_9
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