Thesis defense Nicol Voermans (Donders Series 64)

22 September 2011

Promotors: Prof.dr. B.G.M. van Engelen, Prof.dr. B.C. Hamel, Prof.dr. A. de Haan

Neuromuscular features of Ehlers-Danlos syndrome and Marfan syndrome - expanding the phenotype of inherited connective tissue disorders and investigating the role of the extracellular matrix in muscle

Ehlers-Danlos syndrome (EDS) and Marfan syndrome are two of the most frequent inherited connective tissue disorders, characterized by joint hypermobility, tissue fragility and easy bruising, skin hyperextensibility, and / or arterial aneurysmata with ruptures. Neuromuscular features have been reported in incidental cases, and are generally ascribed to reduced physical activity.

Inspired by patients referred to us and by recent developments in neuromuscular research, we presented an overview of the clinical and molecular continuum of the inherited connective tissue disorders and certain myopathies. Next, we studied the occurrence and nature of neuromuscular features in EDS and Marfan syndrome, and showed that both disorders are associated with mild neuromuscular features, with signs of myopathy and polyneuropathy in EDS; and signs of myopathy, polyneuropathy, and lumbosacral radiculopathy in Marfan syndrome. Furthermore, we showed that severe fatigue and chronic pain are highly prevalent among EDS patients. The five possible determinants involved in fatigue in EDS are sleep disturbances, concentration problems, social functioning, self efficacy concerning fatigue, and pain severity. Pain is related to hypermobility, dislocations, and previous surgery and associated with moderate to severe impairment in daily functioning. Finally, we investigated the pathophysiological mechanisms of muscle weakness in EDS in order to explore the role of the extracellular matrix in muscle function. The result showed that muscle weakness in EDS is not caused by reduced physical activity but results from (1) alterations of the series elastic component of the myotendinous pathways (due to increased compliance of connective tissue of muscle and tendon); (2) a reduction of myofascial force transmission (due to increased compliance of connective tissue between muscles and fascia), due to which muscles act more independently; and (3) a failure to maximally voluntarily activate the muscles.

This study will probably increase awareness of the various neuromuscular features of these and other inherited connective tissue disorders among clinicians and researchers, and thus improve the clinical recognition of these symptoms. The results of the studies on fatigue and pain could form a starting point for the development of an effective cognitive behavioral intervention for fatigue in EDS. Treatment of pain should be a prominent aspect of the symptomatic management of EDS. The results have also raised new research questions, e.g. what is the occurrence of neuromuscular symptoms in other inherited connective tissue disorders; which pathophysiological mechanisms cause peripheral nerve dysfunction in EDS and Marfan syndrome; how do ECM defects in various types of EDS result in intracellular - both myopathic and axonal – changes; and why is central activation capacity reduced in EDS.