J Neurol (2009) 256:13–27 DOI 10.1007/s00415-009-0105-1 REVIEW JON 3105 N. C. Voermans C. G. Bonnemann B. C. J. Hamel H. Jungbluth B. G. van Engelen Joint hypermobility as a distinctive feature in the differential diagnosis of myopathies Introduction Congenital and adult-onset inherited myopathies repre- sent a wide spectrum of syndromes, ranging from severe and sometimes early fatal disorders to relatively mild conditions compatible with nearly normal life. Recent advances concerning the genetic clarification of inher- ited myopathies have significantly improved our under- standing of their pathogenesis. It has also enabled clas- sifications of these conditions based on both the clinical features and the primary biochemical and genetic de- fects. In addition to the pattern of muscle weakness, other clinical features such as cardiac involvement, myo- Received: 30 June 2008 Accepted: 8 September 2008 Published online: 9 February 2009 N. C. Voermans () · B. G. van Engelen Neuromuscular Centre Nijmegen Dept. of Neurology, 935 Radboud University Nijmegen Medical Centre P.O. Box 9101 6500 HB Nijmegen, The Netherlands Tel.: +31-24/3613396 Fax: +31-24/3541122 E-Mail: n.voermans@neuro.umcn.nl C. G. Bonnemann Dept. of Neurology Children’s Hospital of Philadelphia, USA B. C. J. Hamel Dept. of Human Genetics Radboud University Nijmegen Medical Centre, The Netherlands H. Jungbluth Evelina Children’s Hospital Dept. of Paediatric Neurology- Neuromuscular Service St. Thomas’ Hospital and Clinical Neuroscience Division King’s College London, UK ■ Abstract Congenital and adult- onset inherited myopathies re- present a wide spectrum of syn- dromes. Classification is based upon clinical features and bio- chemical and genetic defects. Joint hypermobility is one of the distinc- tive clinical features that has often been underrecognized so far. We therefore present an overview of myopathies associated with joint hypermobility: Ullrich congenital muscular dystrophy, Bethlem my- opathy, congenital muscular dystrophy with joint hyperlaxity, multi-minicore disease, central core disease, and limb girdle muscular dystrophy 2E with joint hyperlaxity and contractures. We shortly discuss a second group of disorders characterised by both muscular features and joint hyper- mobility: the inherited disorders of connective tissue Ehlers-Danlos syndrome and Marfan syndrome. Furthermore, we will briefly dis- cuss the extent and pattern of joint hypermobility in these myopathies and connective tissue disorders and propose two grading scales commonly used to score the sever- ity of joint hypermobility. We will conclude focusing on the various molecules involved in these dis- orders and on their role and inter- actions in muscle and tendon, with a view to further elucidate the pathophysiology of combined hypermobility and myopathy. Hopefully, this review will contrib- ute to enhanced recognition of joint hypermobility and thus be of aid in differential diagnosis. ■ Key words myopathy · joint hypermobility · Ullrich congenital muscular dystrophy · Bethlem myopathy · Multiminicore Disease (MmD) · Central Core Disease (CCD)