Nicol C Voermans and Peter A Huijing

Introduction

Fascia-related disorders are defined as disorders resulting from altered stiffness or compliance of the fascia. Stiffness is defined as the actual change in force for a given change in length (i.e., ΔF/Δl). Compliance is the inverse of stiffness (i.e., Δl/ΔF). Increased compliance of fascia yielding hypermobility occurs in various inherited connective tissue disorders (e.g., Ehlers–Danlos syndrome (EDS), Marfan syndrome, cutis laxa, and osteogenesis imperfecta). These multisystem disorders are characterized by varying involvement of vessels, skin, joints, bones, internal organs, eyes, muscle, and the peripheral and central nervous system.

This chapter will focus on changes in muscle function related to increased fascia compliance in Marfan syndrome and, particularly, EDS. After a short clinical description of these disorders, a description of neuromuscular involvement in both will be given, and then a discussion of results of studies regarding effects of increased fascial compliance on muscle characteristics in EDS.

Clinical features of EDS and Marfan syndrome

EDS is a clinically and genetically heterogeneous group of inherited connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. In a minority of patients, EDS is caused by changes in extracellular matrix molecules collagen types I, III, V, lysyl hydroxylase, and tenascin-X (TNX); however, in most patients the genetic background remains unresolved (Beighton et al. 1998). The revised classification of EDS into six major types is based on clinical and biochemical features (Beighton et al. 1998). These types are: the classical, hypermobility, vascular, kyphoscoliotic, arthrochalasia, and dermatosparaxis types. The hypermobility type is most common in EDS, followed by the classical type. Together, they account for approximately 90% of all cases (Steinmann et al. 2002). The vascular type is far less common, but is associated with the occurrence of arterial dissections (i.e., tears within the wall of blood vessels, which allow blood to separate wall layers) and aneurysms (i.e., localized, blood-filled dilation: balloon-like bulge of a blood vessel caused by disease or weakening of the wall), which may cause severe neurological complications. The kyphoscoliotic, arthrochalasia, and dermatosparaxis types are rare. In 2001, a new autosomal recessive type of EDS caused by deficiency of TNX was identified (Schalkwijk et al. 2001). Subsequently, TNXB gene haploinsufficiency was found to be associated with the hypermobility type of EDS in a minority of patients (Zweers et al. 2003).

Marfan syndrome is another inherited connective-tissue disorder characterized by varying patterns of organ involvement, including the cardiovascular and pulmonary systems, eyes, skeleton, skin, and dura. At least 91% of all Marfan patients fitting clinical diagnostic criteria show mutation in the fibrillin-1 gene (FBN1) on chromosome 15, and 27% of the mutations are spontaneous (Loeys et al. 2004). Many symptoms do not present until puberty or later, and severe complications rarely develop before adulthood. With the availability of elective cardiac surgery and management by expert centers, mean life expectancy of Marfan patients increased from 32 years in 1972 to 41 years in 1993, and probably even further since then, approaching normal life expectancy (Silverman et al. 1995; Pyeritz 2009). Accompanying increasing life expectancy, there is a shift from life-threatening cardiovascular involvement to more chronic and less serious complaints such as ocular and orthopaedic disorders, and possibly, neuromuscular complications (Dean 2007; Hasan et al. 2007; Jones et al. 2007; Ramirez & Dietz 2007; von Kodolitsch & Robinson 2007; Voermans et al. 2009a).

Physical or manual therapy in EDS and Marfan syndrome focuses on reduction of musculoskeletal pain, maintenance of muscle force, increase of joint stability, reduction of scoliosis, and functional improvement (Braverman 1998). We will not discuss these therapeutic options in this chapter.

Neuromuscular involvement in EDS and Marfan syndrome

Overlooked for a long time, neuromuscular involvement in EDS and Marfan syndrome is expected, based on interactions between muscle fibers and extracellular matrix (ECM) molecules (Voermans et al. 2008). Muscle hypotonia, muscle rupture, fatigue, and musculoskeletal pain are included in the diagnostic criteria of EDS (Beighton et al. 1998), and we recently reported mild-to-moderate muscle weakness in EDS patients (Voermans et al. 2009b). Furthermore, muscle involvement in Marfan syndrome has lately received renewed attention, probably due to increasing insight into the role of ECM molecules in muscle pathophysiology (Behan et al. 2003; Cohn et al. 2007; Voermans et al. 2008). We will discuss this in more detail below.

Recently, mild-to-moderate neuromuscular involvement in a large proportion of EDS patients has been demonstrated (Voermans et al. 2009). Neuromuscular involvement was defined as consistent abnormal findings on questionnaires and/or physical examination, supported by abnormal results of appropriate ancillary investigations. Muscle weakness, myalgia, and rapid fatigability were reported by the majority of patients. Mild-to-moderate muscle weakness (estimated using manual muscle strength testing and with hand-held dynamometry) and mild reduction of vibration sense on physical examination were common (85% and 60%, respectively). Nerve conduction studies revealed axonal polyneuropathy in five patients (13%; predominantly occurring in the TNX-deficient type). Needle electromyography showed mainly myopathic features in nine patients (26%), and a mixed neurogenic–myopathic pattern in most (60%). Muscle ultrasound revealed increased echo intensity (48%) and atrophy (50%). Mild myopathic features (i.e., increased variation of fiber diameter, sporadic isolated atrophic fibers, and a mild increase of internal nuclei) were seen on muscle biopsy of five patients (28%). Creatine kinase was mildly elevated in four patients. Furthermore, patients with complete absence of TNX (i.e., TNX-deficient type EDS) are associated with more severe neuromuscular symptoms than those with reduced TNX serum levels and with reduced staining of TNX within muscle (i.e., hypermobility type EDS caused by TNXB haploinsufficiency). An inverse relation between residual TNX quantity in serum and muscle and degree of neuromuscular involvement is suggested by these results (Voermans et al. 2009b.)They also confirm the findings of previous case reports on neuromuscular symptoms in EDS (Bilkey et al. 1981; Banerjee et al. 1988; Bertin et al. 1989; Takaluoma et al. 2007; Voermans et al. 2007.)

In addition, a recent study on 10 Marfan syndrome patients showed neuromuscular involvement in the majority, albeit with variable severity (Voermans et al. 2009b). Four older patients reported muscle weakness, confirmed by physical examination. Furthermore, five patients had mild-to-moderate reductions of vibration sense, and all older patients reported mild functional impairments. Axonal polyneuropathy was found in four patients and electromyography myopathic and neurogenic changes in all patients, compatible with both myopathy and lumbosacral radiculopathy. Increased echo intensity and atrophy on muscle ultrasound was found in over half of the patients. Muscle biopsies (two patients) showed myopathic changes only in the older, female patient (Voermans et al. 2009a). Review of MR images showed lumbosacral dural ectasia in combination with lumbosacral spinal meningeal cysts in seven patients, with one patient showing an additional thoracolumbar kyphoscoliosis. Creatine kinase was not elevated. Previous cardiovascular complications (endocarditis, mitral-valve prolapse, and aortic root/ascending aorta dilatation) and the medication used (β-blocker) may have contributed to experienced fatigue reported by the Marfan patients. Furthermore, simvastatin, a lipid-lowering drug, can cause myalgia with signs of myopathy, and increases the risk of polyneuropathy (Gaist et al. 2002). However, results of previous studies suggest that cardiovascular disease and side effects cannot fully explain muscle weakness in Marfan patients (Percheron et al. 2007). Results from our study suggest that neuromuscular symptoms in Marfan syndrome are directly associated with moderate-to-mild myopathy and/or polyneuropathy, and the presence of dural ectasia with spinal meningeal cysts was related to lumbosacral radiculopathy. Myopathy in Marfan syndrome might be linked to abnormal fibrillin in muscle connective tissue (endo-, peri- and epimysium) (Behan et al. 2003; Voermans et al. 2009a), which results in excessive transforming growth factor β signaling, which contributes to abnormal muscle-cell development and reactions to injury or inflammation (Neptune et al. 2003; Cohn et al. 2007).

The results regarding inherited connective tissue disorders raise the question whether relatively mild myopathic changes in muscle biopsies in the minority of patients suffice to explain the mild-to-moderate neuromuscular involvement in the majority of EDS and Marfan patients. Non-neuromuscular features of EDS and Marfan syndrome may contribute to various neuromuscular symptoms: e.g., musculoskeletal pain, increased fatigability, and mild impairment may be caused by articular and skeletal problems in EDS (Voermans et al. 2009b). Cardiovascular symptoms and medication in Marfan patients will probably contribute to easy fatigability (Voermans et al. 2009a).

The finding of a close relationship between residual TNX levels and degree of neuromuscular involvement in EDS, and previous studies on the role of fibrillin and excessive transforming growth factor β signaling in Marfan syndrome, suggest another pathophysiological mechanism may take part. The abnormal ECM composition in these disorders may affect muscle physiology (i.e., as a result of increased compliance) or biochemically (i.e., altered signaling by ECM molecules).