Congenital myasthenic syndrome caused by novel COL13A1 mutations
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Collagen XIII is a non-fibrillar transmembrane collagen which has been long recognized for its critical role in synaptic maturation of the neuromuscular junction. More recently, biallelic COL13A1 loss-of-function mutations were identified in three patients with congenital myasthenic syndrome (CMS), a rare inherited condition with defective neuromuscular transmission, causing abnormal fatigability and fluctuating muscle weakness and often successfully treated with acetylcholinesterase inhibitors. Here we report six additional CMS patients from three unrelated families with previously unreported homozygous COL13A1 loss-of-function mutations (p.Tyr216*, p.Glu543fs and p.Thr629fs). The phenotype of our cases was similar to the previously reported patients including respiratory distress and severe dysphagia at birth that often resolved or improved in the first days or weeks of life. All individuals had prominent eyelid ptosis with only minor ophthalmoparesis as well as generalized muscle weakness, predominantly affecting facial, bulbar, respiratory and axial muscles. Response to acetylcholinesterase inhibitor treatment was generally negative while salbutamol proved beneficial. Our data further support the causality of COL13A1 variants for CMS and suggest that this type of CMS might be clinically homogenous and requires alternative pharmacological therapy.
KeywordsCOL13A1 Collagen type XIII alpha 1 chain Autosomal recessive Congenital myasthenic syndrome Neuromuscular junction
We thank the families for participating in this study. M. Dusl is a postdoctoral fellow of the Bayerische Gleichstellungsförderung (BGF). This work was supported by the Fritz-Thyssen-Stiftung (Az.10.15.1.021MN; to J. Senderek).
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Conflicts of interest
The authors declare no conflict of interest.
- 1.Abicht A, Muller JS, Lochmuller H (1993) Congenital myasthenic syndromes. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews®. University of Washington, Seattle, WAGoogle Scholar
- 2.Chen YC, Auer-Grumbach M, Matsukawa S, Zitzelsberger M, Themistocleous AC, Strom TM, Samara C, Moore AW, Cho LT, Young GT, Weiss C, Schabhuttl M, Stucka R, Schmid AB, Parman Y, Graul-Neumann L, Heinritz W, Passarge E, Watson RM, Hertz JM, Moog U, Baumgartner M, Valente EM, Pereira D, Restrepo CM, Katona I, Dusl M, Stendel C, Wieland T, Stafford F, Reimann F, von Au K, Finke C, Willems PJ, Nahorski MS, Shaikh SS, Carvalho OP, Nicholas AK, Karbani G, McAleer MA, Cilio MR, McHugh JC, Murphy SM, Irvine AD, Jensen UB, Windhager R, Weis J, Bergmann C, Rautenstrauss B, Baets J, De Jonghe P, Reilly MM, Kropatsch R, Kurth I, Chrast R, Michiue T, Bennett DL, Woods CG, Senderek J (2015) Transcriptional regulator PRDM12 is essential for human pain perception. Nat Genet 47:803–808CrossRefGoogle Scholar
- 3.Haronen H, Zainul Z, Tu H, Naumenko N, Sormunen R, Miinalainen I, Shakirzyanova A, Oikarainen T, Abdullin A, Martin P, Santoleri S, Koistinaho J, Silman I, Giniatullin R, Fox MA, Heikkinen A, Pihlajaniemi T (2017) Collagen XIII secures pre- and postsynaptic integrity of the neuromuscular synapse. Hum Mol Genet 26:2076–2090CrossRefGoogle Scholar
- 6.Logan CV, Cossins J, Rodriguez Cruz PM, Parry DA, Maxwell S, Martinez-Martinez P, Riepsaame J, Abdelhamed ZA, Lake AV, Moran M, Robb S, Chow G, Sewry C, Hopkins PM, Sheridan E, Jayawant S, Palace J, Johnson CA, Beeson D (2015) Congenital myasthenic syndrome type 19 Is caused by mutations in COL13A1, encoding the atypical non-fibrillar collagen type XIII alpha1 chain. Am J Hum Genet 97:878–885CrossRefGoogle Scholar
- 8.Nicholl DJ, Hilton-Jones D, Palace J, Richmond S, Finlayson S, Winer J, Weir A, Maddison P, Fletcher N, Sussman J, Silver N, Nixon J, Kullmann D, Embleton N, Beeson D, Farrugia ME, Hill M, McDermott C, Llewelyn G, Leonard J, Morris M (2010) Open letter to prime minister David Cameron and health secretary Andrew Lansley. BMJ 341:c6466CrossRefGoogle Scholar
- 9.Raspall-Chaure M, Del Toro-Riera M, Gratacos M, Cuenca-Leon E, Ferrer I, Indo Y, Roig-Quilis M, Macaya-Ruiz A (2005) Congenital insensitivity to pain with anhidrosis associated with congenital myasthenic syndrome. Rev Neurol 41:218–222Google Scholar