The neuromuscular differential diagnosis of joint hypermobility

Abstract

Joint hypermobility is the defining feature of various inherited connective tissue disorders such as Marfan syndrome and various types of Ehlers-Danlos syndrome and these will generally be the first conditions to be considered by geneticists and pediatricians in the differential diagnosis of a patient presenting with such findings. However, several congenital and adult-onset inherited myopathies also present with joint hypermobility in the context of often only mild-to-moderate muscle weakness and should, therefore, be included in the differential diagnosis of joint hypermobility. In fact, on the molecular level disorders within both groups represent different ends of the same spectrum of inherited extracellular matrix (ECM) disorders. In this review we will summarize the measures of joint hypermobility, illustrate molecular mechanisms these groups of disorders have in common, and subsequently discuss the clinical features of: 1) the most common connective tissue disorders with myopathic or other neuromuscular features: Ehlers-Danlos syndrome, Marfan syndrome and Loeys-Dietz syndrome; 2) myopathy and connective tissue overlap disorders (muscle extracellular matrix (ECM) disorders), including collagen VI related dystrophies and FKBP14 related kyphoscoliotic type of Ehlers-Danlos syndrome; and 3) various (congenital) myopathies with prominent joint hypermobility including RYR1- and SEPN1-related myopathy. The aim of this review is to assist clinical geneticists and other clinicians with recognition of these disorders.

A framework for the classification of joint hypermobility and related conditions

“…A recent review pointed out the increasing list of hereditary myopathies which typically show JH and, among them Bethlem myopathy, Ullrich congenital myopathy, COL12A1 ‐related myopathy (or Ehlers–Danlos syndrome/myopathy overlap), SEPN1 ‐ and RYR1 ‐related myopathies, MYH7 ‐ and TTN ‐related core myopathies, and limb girdle muscular dystrophy type 2E with joint hyperlaxity and contractures [Donkervoort et al, ]. The underlying cause of JH in these conditions is thought to be multifactorial, including the muscle/tendon complex, the joint capsule and other extracellular matrix components [Donkervoort et al, ]. JH may also be seen in some forms of mitochondrial myopathy [Sugimoto et al, ].…”

Neurological and spinal manifestations of the Ehlers–Danlos syndromes

“…Abnormal extracellular matrix in generalized connective tissue structure suggests molecular overlap between inherited connective tissue disorders and certain congenital myopathies, awareness of which may be helpful in recognition of these rare disorders [Voermans et al, ; Donkervoort et al, ].…”

Marfan syndrome: Report of a complex phenotype due to a 15q21.1 contiguos gene deletion encompassing FBN1, and literature review

“…The patient reported herein had a clinical diagnosis of MFS according to the revised Ghent criteria, in addition he had a dysmorphic facial appearance (i.e., reduced head circumference relative to his height, small ears, widely spaced eyes, broad nasal bridge, prominent columella), and neuromuscular/neuropsychiatric involvement. The clinical picture of MFS may include the presence of myopathic signs, that is, muscle hypoplasia, muscle cramps, and generalized muscle weakness [Donkervoort et al, ]; however, lower limb dystonic posturing, immature behavior, and a deficit in praxis and spatial organization with motor clumsiness have not been previously described in patients with MFS.…”