American Journal of Medical Part C (Seminars in ) 169C:23–42 (2015) ARTICLE

The Neuromuscular of

S. DONKERVOORT, C.G. BONNEMANN, B. LOEYS, H. JUNGBLUTH, AND N.C. VOERMANS

Joint hypermobility is the defining feature of various inherited disorders such as 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 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 (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) and connective tissue overlap disorders (muscle extracellular matrix (ECM) disorders), including 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. © 2015 Wiley Periodicals, Inc.

KEY WORDS: myopathies; hypermobility; inherited connective tissue disorders; extracellular matrix How to cite this article: Donkervoort S, Bonnemann CG, Loeys B, Jungbluth H, Voermans NC. 2015. The Neuromuscular Differential Diagnosis of Joint Hypermobility. Am J Med Genet Part C 169C:23–42.

INTRODUCTION group of inherited myopathies that may life span. Recent advances in the genetic also feature joint hypermobility and skin clarification of inherited myopathies Inherited connective tissue disorders changes and should, therefore, be con- have significantly improved our under- such as Ehlers–Danlos syndrome sidered in the differential diagnosis of standing of their pathogenesis and (EDS) and Marfan syndrome are char- these disorders. enabled classifications of these condi- acterized by joint hypermobility and Inherited myopathies represent a tions based on both the clinical features fragility of skin, blood vessels, and clinical spectrum with significant ge- and the primary genetic and biochem- internal organs. There may also be netic and phenotypic heterogeneity ical defects. In addition to the pattern of associated mild-to-moderate muscle ranging from severe and sometimes muscle weakness, variable presence of weakness, muscle hypoplasia, or hypo- early fatal disorders to relatively mild other clinical findings such as central tonia indicating clinical overlap with a conditions compatible with near normal nervous system or cardiorespiratory

Sandra Donkervoort is a board certified genetic counselor in the Neurogenetics Branch, Neuromuscular and Neurogenetic Disorders of Childhood Section at the National Institutes of Health, National Institute of Neurological Disorders and Stroke. Dr. Carsten Bonnemann€ is a pediatric neurologist and neurgeneticist. He is Chief of the Neuromuscular and Neurogenetic Disorders of Childhood Section in the Neurogenetics Branch at the Neurological Institute of Neurological Disorders, National Institutes of Health. His main research interests concern clinical, molecular genetic, and translational aspects of early onset neuromuscular disorders. Prof.dr. Bart Loeys is pediatrician and clinical geneticist working in the genetics departments of the University Hospital Antwerp, Belgium and Radboud University Medical Center, Nijmegen, The Netherlands. Specific interests include connective tissue disorders, especially those with cardiovascular involvement. He contributed to the molecular and clinical delineation of several disease entities, most prominently Loeys–Dietz syndrome. Dr. Heinz Jungbluth is a Consultant and Reader in Paediatric Neurology at the Evelina Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, and King's College, London, United Kingdom. His main research interest is in neurogenetics, in particular the genetics of neuromuscular and neurodevelopmental disorders. Dr. Nicol Voermans works as an adult neurologist at the neuromuscular center of the Radboud university medical center, Nijmegen, the Netherlands. Her main research interest is inherited myopathies, in particular congenital myopathies, fascioscapulohumeral muscular dystrophy, and the neuromuscular features of inherited connective tissue disorders and muscle ECM disorders. **Correspondence to: N.C. Voermans, Department of Neurology, 935, Radboud university medical center, P.O. Box 9101 6500 HB Nijmegen, The Netherlands. E-mail: [email protected] DOI 10.1002/ajmg.c.31433 Article first published online in Wiley Online Library (wileyonlinelibrary.com).

ß 2015 Wiley Periodicals, Inc. 24 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE involvement, , opthalmoplegia, account. In fact, generalized joint involved in organizing the ECM of myotonia, muscle rippling, contrac- hypermobility is the severe end of a fibrocartilage and provide a survival tures, and spine rigidity may assist in spectrum of physiological joint mobility. factor for fibrochondrocytes [Carvalho defining specific phenotype–genotype So far, the nomenclature and et al., 2007]; consequently, COL6 correlations. Significant joint hyper- classification of joint hypermobility may alter structure mobility can be a distinctive clinical used in literature is variable: “hyper- and function. Furthermore, it has been feature in its own right and may confuse mobility” is the term used in the suggested that RyR1-mediated calcium the differential diagnosis, in particular in diagnostic criteria of EDS and Marfan signaling plays a role in mechano-trans- patients where muscle weakness is not syndrome; in several case reports other duction pathways of in ten- the most prominent finding at presenta- terms are used: “hyperlaxity“, “joint don [Wall and Banes, 2005] and tion [Voermans et al., 2008a]. Con- laxity” and, even less specifically, “hy- hypothetically, RYR1 mutations may firmatory genetic diagnosis is important perelasticity” and “hyperextensibility.” thus alter mechanic tendon function of for providing accurate prognosis, man- Furthermore, description of how joint tendon. However, this has not been agement, recurrence risk, genetic coun- mobility is determined and which investigated in detail and further re- seling, and for the development of have been tested is often lacking. This search will be required. therapeutic strategies. may result in inaccuracy of the clinical This clinical overlap extends to the In this review we will summarize description and consequently lead to molecular level: ECM involved the measures of joint hypermobility, under-recognition and underestimation in the pathophysiology of inherited illustrate molecular mechanisms shared of the presence of joint hypermobility in connective tissue disorders ( I, between these groups of disorders, and various myopathies [Voermans et al., III, V, IX, lysylhydroxylase, -X, subsequently discuss the clinical and 2009b] We have, therefore, advocated , fibulin, , and perlecan) genetic features of the: 1) most common the use of the term “hypermobility” are expressed not only in connective connective tissue disorders with myo- assessed by a standardized scale, the tissue of and joint capsules, but pathic or other neuromuscular features Beighton and Bulbena scores (Table I) also of muscle (endo-, peri-, and (EDS, Marfan, and Loeys–Dietz syn- [Bulbena et al., 1992; Beighton et al., epimysium). Its structure and function drome); 2) myopathy and connective 1998]. may be altered as a consequence of tissue overlap disorders (“muscle extrac- mutations in any of these [Voer- ellular matrix (ECM) disorders”); and 3) mans et al., 2008a; Hubmacher and CLINICAL AND myopathies with prominent joint hyper- Apte, 2013]. Clinicians and researchers MOLECULAR OVERLAP mobility. As such, this review does not dealing with myopathies and inherited cover all neuromuscular disorders with The pathophysiology of hypermobility connective tissue disorders should be some degree of distal hypermobility is likely to be multifactorial, comprising aware of this overlap. Only a multi- (such as spinal muscular atrophy, nema- factors affecting both dynamic joint disciplinary approach will allow full line myopathy, and certain forms of function and connective tissue charac- recognition of the wide variety of congenital muscular dystrophy), but teristics of the various ECM compart- symptoms present in the spectrum of rather concentrates on the connective ments in muscle, the myotendinous ECM defects, which has important tissue and muscle overlap disorders plus junction, tendon, and joint capsule implications for scientific research, di- some selected myopathies in which [Voermans et al., 2008a] as well as the agnosis, and for the treatment of these hypermobility is a more consistent physical properties of the muscle cells disorders. feature. The aim is to assist clinical themselves. The multifactorial etiology geneticists and other clinicians with the probably explains why joint hypermo- Inherited Connective Tissue recognition of these disorders. bility occurs in both myopathies and Disorders With Neuromuscular inherited connective tissue disorders. Features Altered tendon and joint capsule ASSESSMENT OF JOINT structure and function may contribute Ehlers–Danlos syndrome HYPERMOBILITY to joint hypermobility in various myo- EDS is a clinically and genetically Joint hypermobility is defined as abnor- pathies. This point is illustrated by heterogeneous group of inherited con- mally increased active and/or passive studies in zebrafish demonstrating that nective tissue disorders characterized by range of motion in a joint [Beighton loss of selenoprotein-N function causes various combinations of generalized et al., 1998]. Presence of multiple disruption of both muscle and myosep- joint hypermobility, skin hyperextensi- hypermobile joints can be referred to tum architecture [Deniziak et al., 2007], bility, and tissue fragility. In 1997, six as generalized joint hypermobility and the latter being the connective tissue main EDS types were defined, the may be associated with recurrent (sub) layer involved in force transmission hypermobility type, classical type, and luxations. When assessing joint mobility, through connecting tendons to muscle. vascular type, and the rare kyphoscoli- the large physiological range related to Next, type VI collagen is present in otic type, arthrochalasis type, and der- sex, age, and race has to be taken into bovine tendons, where it may be matosparaxis type EDS (Table II) RIL MRCNJUNLO EIA EEISPR SMNR NMDCLGNTC)25 GENETICS) MEDICAL IN (SEMINARS C PART GENETICS MEDICAL OF JOURNAL AMERICAN ARTICLE

TABLE I. Assessment of Joint Hypermobility

Bulbena score Degree of mobility by passive maneuvers in 9 joints. Beighton score Degree of mobility by passive maneuvers in 5 joints. Total score: 0–10.Hypermobility:5 (women) and 4 (men). Total score: 0–9 Hypermobility: score: 5 Upper extremity: General: 1) Thumb: passive apposition of the thumb to the flexor aspect of the forearm <21 mm; 1) Dorsiflexion of the little fingers beyond 2) Metacarpophalangeal: with the palm of the hand resting on the table, the passive 90°; one point for each hand; dorsiflexion of the fifth finger is 90°; 2) Apposition of the thumbs to the flexor 3) Elbow hyperextension: passive hyperextension of the elbow 10°; aspect of the forearm; one point for each hand; 4) External shoulder rotation; with the upper arm touching the body, and the elbow 3) Hyperextension of the elbows beyond 10°; fixed at 90°; the forearm is taken in external rotation to >85° of the sagittal plane one point for each elbow; (shoulder line); Lower extremity—supine position: 4) Hyperextension of the knees beyond 10°; 5) Hip abduction: passive hip abduction 85°; one point for each knee; 6) Patellar hypermobility: holding with one hand the proximal end of the tibia, 5) Forward flexion of the trunk with knees fully the patella can be moved well to the sides with the other hand; extended so that the palms of the hand rest flat on 7) Ankle and feet hypermobility: an excess range of passive dorsiflexion the floor; one point. One point for each of the ankle eversion of the foot can be produced; hypermobile joint 8) Metatarsophalangeal: dorsal flexion of the toe over the diaphysis of the first metatarsal is 90°; Lower extremity—prone position: 9) Knee hyperflexion: knee flexion allows the heel to make contact with the buttock. General: Presence or absence of ecchymoses (one point for the presence of ecchymoses). One point for each hypermobile joint Beighton score Goniometer used for measurement of joint mobility

The Bulbena score includes one item on the presence or absence of ecchymoses, which are uncommon in myopathies and may therefore be a reasonable discriminator to distinguish between “muscular” hypermobility and “connective tissue” hypermobility. Furthermore, in younger patients the Beighton score is less reliable and the Bulbena score is more useful. 6AEIA ORA FMDCLGNTC ATC(EIASI EIA EEIS ARTICLE GENETICS) MEDICAL IN (SEMINARS C PART GENETICS MEDICAL OF JOURNAL AMERICAN 26

TABLE II. Overview of Inherited Connective Tissue Disorders and Congenital Myopathies With Joint Hypermobility

Disorder Mode of Hypermobility/ inheritance Dislocation/ involved Muscle involvement Associated symptoms Inherited connective tissue disorders with neuromuscular features Classic type (I/II) AD COL5A1/A2 Muscle , Generalized joint Collagen V delayed gross motor hypermobility with Skin hyperextensibility, easy bruising, Unknown development, rrecurring joint velvety skin, widening of scars dislocations (shoulder, patella, temporomandibular joints) Hypermobility type (III) TNXB Musculoskeletal pain Generalized joint Easy bruising, velvety skin AD Tenascin-X; hypermobility with Unknown recurring joint dislocations (shoulder, patella, temporomandibular joints) Vascular type (IV) AD COL3A1 Tendon and muscle Distal joint Thin, translucent skin, extensive Collagen III rupture hypermobility bruising. arterial/intestinal/uterine (hands/fingers), fragility or rupture, tendon and muscle characteristic facial appearance, rupture acrogeria, clubfoot, varicose veins, arteriovenous, carotid-cavernous fistula, pneumo(hemo) thorax, gingival recession Kyphoscoliotic type PLOD Severe muscle Distal joint , scleral fragility and rupture of (VIA) AR Lysyl hypotonia at birth, hypermobility the ocular globe, arterial rupture, hydroxylase delayed gross motor , development marfanoid habitus, microcornea Musculocontractural CHST14 Severe muscle Distal joint Scoliosis (VIB) AR hypotonia at birth, hypermobility Dermatan-4- delayed gross motor sulfotransferase development. TABLE II. (Continued) 27 GENETICS) MEDICAL IN (SEMINARS C PART GENETICS MEDICAL OF JOURNAL AMERICAN ARTICLE

Disorder Mode of Hypermobility/ inheritance Protein Dislocation/ involved Gene Muscle involvement Contractures Associated symptoms Aarthrochalasia type COL1A1 Polyhydramnios, Arthrogryposis, Facial dysmorphic features, skin (VIIA) AD Collagen I bilateral clubfoot, bilateral hip hyperextensibility congenital dislocation, and hypotonia, hypermobility of the delayed gross motor shoulders, elbows, development and knees EDS with progressive FKBP14 Severe muscle Distal joint Scoliosis, sensorineuronal hearing loss , hypotonia at birth, hypermobility myopathy and delayed gross motor hearing loss FK506- development binding protein 14 Tenascin-X deficient TNXB Muscle weakness Generalized joint Skin hyperextensibility, easy bruising, type AR Tenascin-X hypermobility velvety skin Marfan syndrome AD FBN1 Muscle hypoplasia, Distal joint Ascending dilatation and rupture, Fibrillin muscle cramps, easy hypermobility (DIP/ , scoliosis fatigability, PIP/MCP joints, /, generalized muscle wrists), , high palate, typical weakness contractures (elbows) facial appearance Loeys–Dietz syndrome TGFBR1/2 SMAD3 Muscle hypotonia Joint hypermobility, Hypertelorism, cleft palate/bifid uvula, AD TGFB2/3 contractures widespread arterial and aortic (, club with arterial tortuosity foot) Myopathy and connective tissue overlap syndromes Ullrich Congenital COL6A1/A2/A3 Hypotonia, delayed Distal joint Early respiratory failure, dermal features myopathy (UCMD) motor milestones, hypermobility, (, soft velvety skin, AD/AR Collagen VI profound muscle (MCP joints, PIP, and a tendency to keloid or “cigarette weakness. and DIP joints), paper“ scar formation Onset in 1st decade; contractures wheelchair bound. (proximal joints) COL6A1/A2/A3 Hypotonia, delayed Distal joint Respiratory failure (BM) AD Collagen motor milestones, hypermobility (DIP VI reduced fetal joints), flexion movements, contractures mild muscle (fingers, wrists, weakness elbows, and ankles) (proximal > distal, extensors > flexors) Onset in 1st or 2nd decade 8AEIA ORA FMDCLGNTC ATC(EIASI EIA EEIS ARTICLE GENETICS) MEDICAL IN (SEMINARS C PART GENETICS MEDICAL OF JOURNAL AMERICAN 28

TABLE II. (Continued)

Disorder Mode of Hypermobility/ inheritance Protein Dislocation/ involved Gene Muscle involvement Contractures Associated symptoms Collagen VI look-alike Candidate regions: ITGA9 Congenital hypotonia, Distal joint Early respiratory failure, mild to syndromes AR ACVR2B LAMR1 3p23-p21 delayed motor hypermobility, moderate mental retardation, Unknown/AR milestones, proximal decreased pulmonary vital capacity, Candidate proteins: reduced fetal contractures scoliosis Integrin alfa 9 Activin movements, A IIB generalized muscle receptor 1 weakness (proximal > distal) Collagen XII related COL12A1 Generalized muscle Widespread joint High arched palate myopathy / EDS weakness Mild facial hypermobility at overlap weakness, and birth combined with syndrome AR absent deep tendon proximal Collagen 12 reflexes Inability to contractures and stand or ambulate progressive independently kyphoscoliosis Myopathies with striking joint hypermobility Multi-minicore disease SEPN1 Hypotonia, reduced Distal joint Respiratory failure>> muscle (MmD) AR fetal movements, hypermobility weakness, spinal rigidity, scoliosis, Selenoprotein delayed motor (MCP); to a lesser secondary cardiac (right ventricular) N “classic MmD” milestones, degree in all involvement muscle weakness other limb joints (axial > proximal > distal) AR Ryanodine receptor RYR1 Hypotonia, reduced (axial > proximal > distal) Subgroup “MmD subgroups” fetal movements, with severe hip girdle weakness. delayed motor Subgroup with marked distal milestones, weakness and wasting, predominantly muscle weakness the hands Distal joint Ophthalmoplegia, mild hypermobility respiratory involvement, mild (MCP), to a lesser facial muscle weakness degree in all other limb joints ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 29

[Beighton et al., 1998]. A clinically ) distinct form results from tenascin-X (TNX) deficiency due to recessive MYH7 mutations in the TNXB gene [Schalk- wijk et al., 2001]. The list of other apparently more rare subtypes is grad- ually expanding (Table III) [Castori and Voermans, 2014; Sobey, 2014]. Hyper- mobility is present in all forms of EDS but mostly pronounced in the hyper- mobility, classical, and TNX-deficient hyperthermia scoliosis, nocturnal dyspnea type. In the vascular type, joint hyper- Severe respiratory impairment ( (), malignant , , , mobility is usually limited to the digits, whereas in the kyphoscoliotic type both fingers, wrists, toes, and ankles are severely affected. Proximal contractures may develop later in the course of the disease in this latter type (Fig. 1). EDS is associated with a variety of ) Pronounced

) neuromuscular features, initially docu- Dislocation/ Contractures Associated symptoms mented in case reports and generally Hypermobility/ TTN MYH7 distal hypermobility ( ( hypermobility, congenital hip dislocation common hypermobility (MCP and PIP joints), contractures (DIP joints) considered secondary to exercise avoid- Distal contractures Generalized Distal joint ance prompted by joint hypermobility

) [Bertin et al., 1989; Beighton et al., 1998; Palmeri et al., 2003]. Muscle hypotonia, delayed motor milestones, fatigue, musculoskeletal pain, and Continued ( muscle rupture are included in the diagnostic criteria [Beighton et al., 5 years, – 1998]. Over the last years these neuro- weakness Mild facial weakness muscle weakness, onset 0 prominent involvement of hip girdle and axial muscles, mild facial weakness, rare bulbar involvement. delayed motor mile stones, facial weakness muscular findings have been acknowl- TABLE II. Progressive muscle Progressive limb girdle TO BE ADDED Muscle weakness with edged as a primary aspect of the EDS phenotype. The first physiological study of muscle weakness in EDS was per- formed by Bilkey et al. in 1981 demonstrating that muscle weakness was primarily due to reduced joint and the tendency for minor , which in combina- tion was thought to result in a different learned motor pattern [Bilkey et al., 1981]. In 2009, Voermans et al. per- formed a prospective study in 40 MYH7 TTN SCGB: RYR1 genetically or biochemically confirmed patients with EDS (vascular, classic, hypermobile, and TNXB-deficient

- EDS), showing that mild-to-moderate b neuromuscular involvement is common in these disorders [Voermans et al., )AR

þ 2009c] and may include complaints of and limited exercise endurance, and mild-to-moderate muscle weakness, reduction of vibration sense, and mild dystrophy 2 E with joint hyperlaxity and contractures (LGMD2E heavy chain 7 sarcoglycan (CCD) AD/(AR) Ryanodine receptor syndrome Limb girdle muscular Other core myopathies Central core disease Disorder Mode of inheritance Protein involved Gene Muscle involvement Congenital myasthenic AD: autosomal dominant inheritance; AR: autosomal recessive inheritance. mobility impairment on examination. Nerve conduction studies demonstrated 30 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

TABLE III. Rare Variants of Ehlers–Danlos Not Included in the 1998 Diagnostic Criteria

Rare variant Inheritance Gene(s) Association with 21a-hydroxylase deficiency AR TNXB, CYP21B Association with Gilles de la Tourette syndrome AD HDC Association with parodontitis AD Unknown Association with periventricular heterotopia XLD FLNA Brittle cornea syndrome type 1 AR ZNF469 Brittle cornea syndrome type 2 AR PRDM5 Cardiac-valvular AR COL1A2 Classic with arterial rupture AD COL1A1 Ehlers–Danlos syndrome/ overlap AD COL1A1, COL1A2 Ehlers–Danlos syndrome-like due to 6q27 deletion Sporadic/AD Not applicable Kyphoscoliotic with myopathy and deafness AR FKBP14 Musculocontractural, type 1 AR CHST14 Musculocontractural, type 2 AR DSE Overlap phenotype due to COL3A1/COL5A2/MSTN AD COL3A1, COL5A2, MSTN (deletion) Progeroid AR B4GALT7 Spondylocheirodysplasia AR SLC39A13 -deficient AR, AD (?) TNXB

AD, autosomal dominant; AR, autosomal recessive; XLD, X-linked dominant.

an associated axonal sensory polyneur- myopathic changes, but no dystrophic recessive (AR) PLOD1 mutations (mis- opathy in a minority of patients, and features were observed, corresponding sense and splice site mutations, deletions, needle electromyography showed mild to previous reports [Voermans et al., and duplications). PLOD1 encodes lysyl myopathic features with a mixed pattern 2007b]. The absence of Ullrich con- hydroxylase, a catalyzing enzyme essential of smaller and broader motor unit action genital muscular dystrophy (UCMD) or for the formation of hydroxylysine in potentials. Muscle biopsies showed mild Bethlem myopathy (BM) myopathy collagens and collagen-like proteins, myopathic changes (increased internal features (no typical contractures, no which are critical for the binding of nuclei and fiber size variation) in 25% of skin features, only mild muscle MRI carbohydrates, and therefore the stability EDS patients, with a lower density and features of collagen VI myopathies, and of collagen cross links. Infants with this shorter length of collagen fibrils in the no on muscle biopsy) appeared EDS type can be born with significant ECM on electron microscopy (EM). to suggest that the different ECM hypotonia, failure to thrive, delayed motor Creatine kinase (CK) was only mildly protein defects have different impact development, wrist, and hip dislocation, elevated in 10% of patients (range 40– on muscle structure: collagen VI defi- congenital, or early onset kyphoscoliosis. 681 U/L). These clinical and histopa- ciency gives rise to progressive increase Other manifestations include ophthalmo- thological findings confirmed that mild- of endomysial connective tissue, logic findings (scleral fragility, rupture of to-moderate neuromuscular involve- whereas TNX deficiency produces the ocular globe, microcornea) joint and ment is part of the EDS spectrum and muscle “softness” but no endomysial skin hypermobility, marfanoid habitus, that a muscle biopsy to investigate a co- fibrosis. This points to a different role of and contractures. Vascular complications existent myopathy or neuropathy is not these and other ECM proteins impli- including stroke and spontaneous arterial necessarily indicated if otherwise diag- cated in EDS in muscle ECM develop- rupture have been reported [Brinckmann nostic EDS features are present. ment and functioning (Tables II and III). et al., 1998; Ha et al., 1994]. Recently, a patient with TNX- Furthermore, EDS may present in Additionally, recessive loss of function deficient EDS presenting with a pre- the neonatal period with significant mutations in CHST14, encoding derma- dominantly myopathic phenotype was hypotonia and should, therefore, be tin-4-sulfotransferase 1, result in muscu- reported [Penisson-Besnier et al., 2013]. considered in the initial differential diag- locontractural EDS (EDS kyphoscoliotic Clinical features included progressive nosis of the floppy infant syndrome [Yis type VIB) with a clinical spectrum that axial and proximal limb muscle weak- et al., 2008; Voermans et al., 2008b]. includes significant congenital hypotonia, ness, subclinical cardiac involvement, Among the different subtypes of EDS, gross motor delay, muscle hypoplasia with minimal skin hyperextensibility, no joint congenital muscle involvement is probably progressive joint hypermobility, as well as abnormalities, and a history of easy most pronounced in the kyphoscolitic progressive early onset kyphoscoliosis, joint bruising. Muscle biopsy revealed mild type (EDS VIA), due to autosomal- contractures, club feet, characteristic facial ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 31

Figure 1. Remarkable distal joint hypermobility (metacarpophalangeal and metatarsophalangeal joints) in a 4-year-old male patient with the kyphoscoliotic type of Ehlers–Danlos syndrome (A and B); elbow contractures and mild knee contractures in a 16-year-old male patient with the kyphoscoliotic type of Ehlers–Danlos syndrome (C) [Voermans et al., 2009].

features, thin, and bruisable skin, atrophic with severe congenital muscle hypoto- fiber size variability to more pro- scarring, and variable ocular involvement nia, progressive scoliosis, joint hyper- nounced changes with fiber atrophy (Fig. 2) [Shimizu et al., 2011; Dundar et al., mobility, and hyperelastic skin, but and proliferation of fatty tissue. Electron 2009]. Congenital bilateral thumb adduc- unlike patients with CHST14, these microscopy may show focal rearrange- tionmaybeadistinctiveclinicalfinding patients also have sensorineural hearing ment of myofibrils with irregular Z- [Kosho et al., 2010; Miyake et al., 2010; impairment [Baumann et al., 2012; lines. Muscle MRI was normal in one Malfait et al., 2010]. In one family Murray et al., 2014]. CK levels ranged patient but showed fatty replacement of autosomal recessive mutations in the from normal to mildly elevated (range muscle tissue, predominantly affected dermatan sulphate epimerase (DSE)were 60–300 IU/L), nerve conduction stud- the rectus femoris, and vastus lateralis found in a family with multisystemic ies are normal, electromyography is with relative sparing of the adductor musculocontractural, type 2 [Muller normal in infancy but may show a compartment. FKBP14 is an ER protein et al., 2013]. myopathic pattern in adolescence and that may have a catalytic function Mutations in FKBP14 cause a adulthood. Muscle biopsies may show a through accelerating cis-trains isomer- subtype of EDS that resembles spectrum of histopathological features ization of peptidyl-propyl bonds. CHST14 disorders. Patients present ranging from non-specific increased FKBP14 loss-of-function 32 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE analysis showed disturbed distribution condition characterized by osteopenia, (“myofascial force transmission”) and impaired assembly of several ECM soft, and doughy skin with hyperexten- probably due to increased compliance components specifically collagen type I sibility, infrarenal aortic, and arterial (i.e., reduced elasticity) of the connec- and III and fibronectin. , joint hypermobility, pectus tive tissue surrounding the individual Dominant de-novo mutations in excavatum and easy bruising [Malfait muscles. As a result, TNX-deficient COL1A1 are a rare cause of EDS and et al., 2013]. Interestingly, mutations in muscles appear less capable of trans- have been reported in a girl with severe the Gly-X-Y triplet repeat of COL1A1 mitting forces in other ways than via EDS VIIA of the arthrochalasia type gene result in osteogenesis imperfecta, myotendinous force transmission and [Nuytinck et al., 2000; Giunta et al., indicating a wide phenotypical spec- therefore function more independently. 2008] Pregnancy in this case was trum. These collagen I-related disorders Such altered function probably requires complicated by polyhydramnios and all have a combination of joint hyper- adapted patterns of muscular coordina- bilateral clubfoot noted on prenatal mobility and muscle hypotonia and tion to allow effective physiological ultrasound. At birth she was noted to delay in motor development. movements [Huijing et al., 2010]. The have hypotonia, arthrogryposis, bilateral The study of Voermans et al. also increased compliance of muscle ECM his dislocation and hypermobility of the demonstrated a correlation between may also play a role in muscle weakness shoulders, elbows, and knees. At age residual TNX levels and the degree of in other EDS types. 1 year she had facial dysmorphic neuromuscular involvement, pointing at features, delayed motor milestones, a dose-effect relation between the ECM Marfan syndrome severe hypotonia, and skin and joint defect and muscle dysfunction. This Marfan syndrome is characterized by hypermobility. Genetic analysis of the phenomenon was subsequently sup- ocular, skeletal, and cardiovascular man- COL1A1 gene showed a heterozygous ported by physiological studies in ifestations and due to dominantly in- missense affecting the splice acceptor TNXB-deficient patients and tnxb herited mutations in the fibrillin-1 site resulting in skipping of exon 6. The knock-out mice [Voermans et al., (FBN1) gene. FBN1 encodes fibrillin- heterozygous Arg134Cys in 2009c; Huijing et al., 2010; Gerrits 1, an ubiquitously expressed major COL1A1 mutation has been identified et al., 2013]. These studies showed a component of ECM with in two unrelated patients with an EDS/ reduction of force transmission between an important role for elastin deposition osteogenesis imperfect (OI) overlap individual muscles and the surrounding in elastic fibers. Variable expression in

Figure 2. Finger extensor weakness in hands of 25-year-old (A, B) and 18-year-old (F) female patients with Musculocontractural (VIB) type EDS. Proximal and distal muscle atrophy in arms and lower legs (C), dropping feet (E) and hyperkeratosis pillari (G) in the same patients. The first patient has been reported in [Voermans et al., 2012] at age of 23. ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 33

Marfan syndrome is the rule, but FBN1 mutation [Zhang et al., 1995] incompletely understood and may in- complete non- has only In addition to its structural role in ECM, volve myofiber as well as rarely been documented. About 25% fibrillin-1 is also involved in regulating impaired [Grumati et al., of mutations are dominantly acting de- TGF-b signaling via LTBP binding and 2010]. In tendon, collagen VI is pre- novo mutation. Joint hypermobility is thus influences muscle function. In- sumably synthesized by the resident usually most pronounced in distal joints creased TGF-b signaling has been tendon fibroblast population, and as- and often accompanied by arachnodac- suggested to suppress the muscle regen- sumes a distinctly pericellular orienta- tyly (Fig. 3), but (congenital) joint erating capacity of the satellite cells tion around these cells, and as such it contractures, particularly of the elbow, [Hubmacher and Apte, 2013]. may represent a survival factor for these also occur frequently [Loeys et al., cells. 2010]. Loeys–Dietz syndrome (LDS) Autosomal dominant (AD) and Although Marfan himself consid- LDS is a Marfan-related condition first recessive (AR) mutations (including ered muscle involvement integral to his described by Loeys et al. [2005]. The larger deletions) in each of the three syndrome, neuromuscular features have patients present with a typical triad of collagen 6 genes COL6A1, COL6A2, received little attention until recently. hypertelorism, cleft palate/bifid uvula and COL6A3 cause a spectrum of Gradually, muscle fatigue and, to a lesser with widespread arterial/aortic aneur- myopathies associated with a joint extent, muscle weakness, muscle hypo- ysm and arterial tortuosity. Skeletal hypermobility, contractures, and char- plasia, myalgia, and cramps are being features shared with Marfan syndrome acteristic skin findings. Dominant mu- recognized as neuromuscular Marfan include pectus deformity, scoliosis, tations in the COL6 genes affect features [Grahame and Peyritz, 1995; arachnodactyly but also joint hyper- collagen VI formation, Behan et al., 2003; Jones et al., 2007]. mobility with camptodactyly, and club resulting in disengagement of collagen A systematic observational study foot have described. Cervical spine VI from the basal lamina. Severe de- on neuromuscular features in 10 pa- instability has also been observed novo dominant-negative COL6 mu- tients with Marfan syndrome showed frequently [Erkula et al., 2010]. The tations lead to UCMD, whereas the that various neuromuscular symptoms condition is caused by mutations of intermediate and BM phenotype can occur frequently and consist of a mild genes encoding for components of the be caused by less severe dominant- myopathy or polyneuropathy or both, TGF-b signaling, such as TGF-b negative mutations, or less commonly which was more pronounced in the receptors 1 and 2 [Loeys et al., 2005], by COL6 recessive mutations older patients [Voermans et al., 2009a]. the actual cytokines TGFB2 [Lindsay [Bonnemann,€ 2011]. Recessive null The four oldest patients in this cohort et al., 2012] and TGFB3 [Bertoli- mutations lead to a complete absence (>50 years) reported muscle weakness Avella et al., 2014] or the downstream of collagen VI in the matrix and a and had functional impairments. Five effector SMAD3 [van de Laar et al., severe UCMD phenotype. Approxi- patients had a mild-to-moderate re- 2011], and these are now classified as mately 5–10% of patients with a clinical duction of vibration sense. Nerve LDS types 1–5 [MacCarrick et al., diagnosis of COL6-RD do not have a conduction studies showed a mild 2014], all with some degree of muscle mutation in COL6A1–3 and it is axonal sensory polyneuropathy in involvement such as hypotonia, re- possible that their disease is caused by four patients. The muscle biopsies duced muscle mass, and delayed motor an unknown gene. Two related but less obtained in two patients showed development frequent phenotypes have been added myopathic changes in a 56-year-old to this spectrum: an AD limb-girdle female patient, and was normal in a 32- muscular dystrophy phenotype and an Myopathy and Connective Tissue year-old male. In addition, signs of a AR myosclerosis phenotype reported Overlap Disorders lumbosacral radiculopathy were found in one family with mutations in in four patients, which were associated Collagen VI-related dystrophies and COL6A2 [Merlini et al., 2008; with and spinal meningeal myopathies (COL 6-RD) Scacheri et al., 2002]; however, joint . Although these findings were Collagen VI is an important ECM hypermobility is not a prominent found in a small cohort of patients, component and forms a microfibrillar feature in these latter two phenotypes. they indicate a need to increase the network that is closely associated with The clinical hallmarks of UCMD awareness of neuromuscular involve- the and the surrounding are profound muscle weakness of early ment and radicular symptoms that may . It is also found in onset with respiratory insufficiency as become more pronounced over time in the interstitial space of many other disease progresses, with proximal joint Marfan syndrome patients [Voermans tissues including tendon, skin, , contractures and striking hypermobil- et al., 2009a]. and intervertebral discs. In muscle it is ity of mostly distal joints (toes, ankles, The abundant expression of fibril- predominantly produced by the inter- fingers, and wrists) [Lampe and lin-1 in the stitial fibroblasts. The exact mechanism Bushby,2005].Posteriorlyprotruding and perimysium suggests a causal link and the downstream effects of collagen calcanei are commonly seen (Fig. 4). between muscle symptoms and the VI deficiency on muscle cells are Affected children typically either 34 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

Figure 3. Hypermobility of distal interphalangeal joints and wrist in a 28-year-old male Marfan patient (A, B); arachnodactyly with positive thumb sign and wrist sign in a 27-year-old male Marfan patient (lower images (C, D) [Voermans et al., 2009].

never achieve the ability to walk patients are only very mildly affected and vastus muscles often show a rim of independently or do so only for a remain unaware of weakness [Lampe abnormal signal at the muscle periph- limited period of time. Congenital hip and Bushby, 2005]. In childhood, the ery, with relative sparing of the central dislocations and may be contractures may be preceded by hyper- part (giving it a striped appearance), presentatbirth,andspinalrigidity, mobility in the same joint, and be of a whereas the rectus femoris often shows scoliosis, and variable proximal con- strikingly dynamic nature, appearing, a central area of abnormal signal tractures develop early in the course of and disappearing in various joints [Jobsis known as the “central shadow” phe- the disease. The distal hypermobility et al., 1996]. However, nearly all patients nomenon [Merlini et al., 2008]. At calf can gradually give way to marked long eventually show flexion contractures of level appearances are more variable but finger flexion contractures and tight the fingers, wrists, elbows, and ankles, a significant proportion of patients with Achilles tendons. Respiratory failure and those may contribute to the degree both BM and UCMD also show a rim in the first or second decade is a of overall disability as much as the of abnormal signal at the periphery of common cause of death unless treated associated weakness. Strikingly, hyper- soleus and gastrocnemii [Mercuri et al., with nocturnal respiratory support. mobility of distal interphalangeal joints 2005; Bonnemann€ et al., 2014]. Cardiac involvement has not been can remain present (Fig. 5). Progression Muscle biopsy in UCMD patients documented to date [van der Kooi is slow and occasionally results in the demonstrates variable pathology, rang- et al., 2006]. patient being wheelchair-bound only ing from non-specific mild myopathic In BM, muscle weakness has a after 25–40 years [Lampe and Bushby, changes in particular early in the course predominant proximal pattern and a 2005]. Respiratory failure can be part of to a more dystrophic appearance milder course. Although often mildly the clinical spectrum and may even [Schessl et al., 2008]. Early findings symptomatic at birth or in infancy, occur in ambulatory patients [Foley emphasize atrophic rather than dystro- symptoms typically manifest within the et al., 2013]. To date, there has been phic changes. Additionally, variation in first or second decades, with frequently a no evidence of cardiac involvement in fiber size, type 1 fiber predominance, history of neonatal hypotonia or torti- BM [van der Kooi et al., 2006]. an increase in endomysial connective collis, delayed motor milestones, or even COL6-RDpatientsacrossthe tissue, increased numbers of internal decreased fetal movements [Jobsis et al., spectrum have distinct patterns of nuclei, and focal areas of necrosis, along 1996]. On the other hand some adult muscle involvement on MRI: the with other evidence of muscle fiber ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 35

Figure 4. Severely affected 16-month-old male UCMD patient with joint hypermobility in hands (A), prominent calcaneus, and soft skin (B). 21-Year old male UCMD patient with significant proximal contractures showing preserved hypermobility of fingers (C). Prominent calcaneus with ankle contractures in 2-year-old male UCMD patient (D) [Voermans et al., 2009]. Distal joint hypermobility (E) and abnormal spontaneous hypertrophic scar in a 18-year-old UCMD patient (F) [Donkervoort et al., 2014].

regeneration such as the presence of highly predictive of COL6A mutations imal contractures predominantly affect- fibers containing fetal myosin can be [Ishikawa et al., 2002; Lampe and ing ankle, knees, and shoulders co- found [Pepe et al., 2002]. Immuno- Bushby, 2005]. existing with distal hypermobility, fluorence analysis for collagen VI mainly observed in the fingers, wrists, localization in UCMD biopsies may Collagen-6 look-like disorders toes, elbows, and cervical spine. No show dramatic reduction or absence of Mercuri et al. [2004] reported five cases spinal rigidity was observed, but a mild immunofluorescence in severe reces- with congenital muscular dystrophy to severe scoliosis was a frequent finding. sive patients, or a mislocalization in the (CMD) associated with , Pulmonary vital capacity was usually dominant negative cases. The latter is proximal contractures, rigidity of the diminished. CK was normal or only best seen in staining protocols incor- spine, and distal joint hypermobility as mildly increased, with muscle biopsy porating double labeling of the base- well as early respiratory failure and mild showing only non-specific myopathic ment membrane (using for instance to moderate cognitive disability (CMD features. Genetic studies excluded mu- collagen IV or perlecan as a marker) with joint hyperlaxity). Hypermobility tations in the three genes coding for along with collagen VI. In BM, muscle was present in distal fingers, toes, and collagen VI subunits and suggested biopsy generally demonstrates a non- ankles but the expression of collagen VI linkage to a region on chromosome specific myopathy with fiber-size var- was confirmed to be normal on muscle 3p23–21.This linkage was not found in iation, few necrotic and regenerative biopsies in all five patients; in addition, cases with a similar phenotype in other fibers, and a mild increase in con- in one informative family linkage to any centers, indicating genetic heterogene- nective tissue. Standard collagen VI of the three COL6 gene loci could be ity [Tetreault et al., 2006]. immunohistochemistry is often unin- excluded [Mercuri et al., 2004]. formative but may show mislocaliza- In addition, Tetreault et al. [2006] Collagen XII related myopathy/EDS tion of collagen VI on double staining. reported 14 cases affected by autosomal In contrast, immunofluorescence label- recessive congenital muscular dystrophy Recent findings show that collagen XII ing of collagen VI in skin fibroblast (CMD) with distal joint hypermobility. mutations cause an EDS/myopathy cultures allows detecting even very All patients presented with muscle overlap syndrome associated with subtle alterations in collagen VI in hypotonia at birth, generalized slowly muscle weakness and joint hypermobil- COL6-RD patient fibroblasts and is progressive muscle weakness, and prox- ity in mice and humans [Hicks et al., 36 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

Figure 5. Finger flexor contractures (proximal interphalangeal joint) (A) and hypermobility in metacarpophalangeal and distal interphalangeal joint in female adolescent with Bethlem myopathy (B). Achilles tendon contractures (C), elbow contractures (D) and abnormal, atrophic scarring in 49-year-old female patient with Bethlem myopathy.

2014; Zou et al., 2014]. Collagen XII, contractures, and progressive kyphosco- Around the same time, Hicks et al. the largest member of the fibril-associ- liosis. Both siblings had mild facial weak- [2014] identified dominantly acting ated collagens with interrupted triple ness, high palate, and absent deep tendon COL12A1 missense mutations in helix (FACIT) family, assembles from reflexes.Motordevelopmentwasdelayed, five individuals from two families three identical a-chains encoded by the both siblings were able to get into sitting with a clinical phenotype resembling COL12A1 gene. Collagen XII binds to position, but unable to stand or ambulate Bethlem myopathy. Symptoms started collagen I-containing fibrils via its independently.CKandnerveconduction in childhood with generalized weak- collagenous domain, whereas its large velocitieswerenormal,themusclebiopsy ness with some improvement in ado- non-collagenous arms interact with was myopathic with variability in fiber lescence followed by some progression other matrix proteins such as TNX. In diameter, there was no evidence of of weakness later in life. Patients had dense connective tissues and , degeneration or regeneration. predominant proximal weakness, con- collagen XII is thought to regulate A de novo missense mutation in tractures, hypertrophic scarring, and organization and mechanical properties COL12A1 was identified in a boy with joint hyperlaxity. Pulmonary function of collagen fibril bundles [Chiquet et al., weakness and joint hyperlaxity and testing was reduced in some. CK levels 2014]. proximal joint contractures, noted in ranged from normal to moderately The EDS/myopathyoverlap pheno- the first year of life. He had delayed elevated (1800 U/L). MRI imaging type was observed in two non-related motor development and started walking showed severe atrophy of the rectus familieswithahomozygousrecessiveloss- shortly before age 2 years. He had mild femoris and selective involvement of of-function mutation and a de novo kyphosis; his contractures improved the femoral quadriceps, adductor and dominant mutation in collagen XII over time. Muscle ultrasound of the the medial gastrocnemium. A central (COL12A1), respectively [Zou et al., thigh showed increased echogenicity. shadow, typically seen in COL6-RD 2014]. The two siblings who were Nerve conduction studies were normal. was not observed. One of the homozygous for the loss-of-function Muscle biopsy was consistent with a COL12A1 mutation identified was a mutationshowedwidespreadjointhyper- myopathy, there was mild variability in substitution of a conserved glycine mobility at birth combined with general- fiber diameter without evidence of residue in the Gly-X-Y motif of the ized muscle weakness, proximal degeneration of regeneration. triple helix domain, a common hotspot ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 37 for mutations in collagen disorders in contraction coupling (E–C uncoupling forms, there may also be a histopatho- general [Butterfield et al., 2013]. hypothesis) [Treves et al., 2008]. Whilst logic continuum with CCD due to Dermal fibroblasts showed intracellular primary RyR1 malfunction seems to be dominant RYR1 mutations, reflecting retention of Collagen XII and a subtle the main molecular mechanism under- the common genetic background [Zhou reduction in TNX [Hicks et al., 2014]. lying dominantly inherited RYR1-re- et al., 2007]. Although multi minicores A mouse model with inactivation of lated myopathies, recessive RYR1- are a classic pathophysiological finding the COL12A1 gene shows decreased related myopathies appear to be more of RYR1 and SEPN1-related myopathy, grip strength, delay in fiber-type variable with loss of calcium conduc- biopsies can show a spectrum of findings transition and deficiency in passive tance, probably mediated by marked consistent with congenital myopathies force generation. Corresponding to RyR1 protein reduction, a relatively [Bharucha-Goebel et al., 2013]. studies of TNX deficiency, these ob- common observation [Wilmshurst et al., All phenotypes may be associated servations indicate a role for a matrix- 2010; Klein et al., 2012; Zhou et al., with contractures (either arthrogryposis based passive force-transducing elastic 2013]. in early-onset forms or predominant element in the evolution of weakness Selenoprotein-N, is a glycoprotein Achilles tendon tightness of later onset in these disorders. In general, the EDS/ localized in the endoplasmic reticulum in milder cases) and/or joint hyper- myopathy overlap phenotype empha- and involved in various antioxidant mobility, mostly pronounced in the sizes the emerging importance of the defense systems and several metabolic hands (Fig. 6). If present, distal hyper- muscle ECM in the pathogenesis of pathways. SEPN1 is highly expressed mobility tends to be more severe in muscle disease [Voermans et al., 2008a; during development [Castets et al., patients with recessive RYR1 mutations Zou et al., 2014]. 2009] with a more specific role in than in those with SEPN1 mutations, myogenesis suggested by abundant ex- but may be present in both and is often pression in fetal muscle precursor cells associated with atrophy of intrinsic hand Myopathies With Striking Joint and the observation of disturbed satellite muscles, hand hypotonia, and moderate Hypermobility cell function in the sepn1 / knock- weakness. Patellar and knee dislocations RYR1 and SEPN1 related myopathies out mouse [Castets et al., 2011]. The may be a feature [Gamble et al., 1988]. The congenital myopathies with cores close functional and spatial relationship In the majority of patients, weakness is —Multi-minicore Disease (MmD) and between selenoprotein N and RyR1 static or only slowly progressive, with Central Core Disease (CCD)—are reported in animal models [Deniziak the degree of respiratory impairment among the most common congenital et al., 2007] and a structural motif similar being the most important prognostic myopathies [Jungbluth et al., 2011; to those found in calcium-binding factor particularly in SEPN1-related Maggi et al., 2013]. They are clinically proteins [Moghadaszadeh et al., 2001] forms. and genetically heterogeneous and asso- suggest a role in calcium homeostasis, The diagnosis of MmD is based ciated with variable characteristic ab- suggesting a molecular basis for the on the presence of suggestive clinical normalities on oxidative stains that give clinico-pathological overlap between features and the finding of multiple rise to the cores. MmD and CCD due to SEPN1- and RYR1-related myopathies. cores on histochemical muscle biopsy the skeletal muscle ryanodine receptor stains. Muscle MRI may aid genetic (RyR1) gene (RYR1) mutations may be Multiminicore disease (MmD) testing as patterns of selective muscle associated with marked generalized The “classic” (but probably not most involvement are distinct depending hypermobility not infrequently result- common) phenotype of MmD is asso- on whether the mutations are in the ing in joint dislocations [Gamble et al., ciated with autosomal-recessive muta- SEPN1 [Mercuri et al., 2010] or the 1988], whereas MmD due to recessive tions in SEPN1 and is characterized by RYR1 gene [Jungbluth et al., 2004; mutations in the selenoprotein N predominantly axial muscle weakness, Klein et al., 2011]. Mutational analysis (SEPN1) gene often features distal spinal rigidity, early scoliosis, and respi- of the RYR1 or the SEPN1 gene will hypermobility in the upper limbs and ratory impairment. Some patients may be required to confirm the genetic may give rise to “marfanoid” features. exhibit a “marfanoid” habitus with diagnosis. Management is mainly The skeletal muscle RyR1 plays a arachnodactyly but ocular and cardio- supportive and in particular has to crucial role in excitation-contraction vascular features of Marfan syndrome are address the risk of marked respiratory þ (E–C) coupling by releasing Ca2 from typically absent. In contrast, autosomal- impairment in SEPN1-related MmD sarcoplasmic reticulum (SR) stores. Two recessive mutations in the skeletal and the possibility of malignant hy- major hypotheses have been formulated muscle ryanodine receptor (RYR1) perthermia susceptibility in RYR1- concerning the pathogenesis of RYR1- gene have been associated with a wider related forms for the patient and related core myopathies, depletion of range of clinical features comprising carrier relatives. sarcoplasmic reticulum calcium stores external ophthalmoplegia, distal weak- with resulting increase in cytosolic ness and wasting or predominant hip Central core disease (CCD) calcium levels (“leaky channel” hypoth- girdle involvement resembling CCD Central core disease (CCD) is caused esis), and disturbance of excitation- [Ferreiro et al., 2012]. In the latter mainly by dominant but also less 38 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

Figure 6. MmD patient with distal hypermobility (metacarpophalangeal joints) and atrophy of intrinsic hand and forearm muscles, suggestive of RYR1 involvement, although this has not been genetically confirmed (A and B); wrist and finger (metacarpophalangeal joints) hypermobility in a 22-year-old female MmD patient with a RYR1 mutation (C and D) [Voermans et al., 2009].

commonly by recessive RYR1 muta- of oxidative enzyme activity in the segregation testing is of importance so tions and typically presents in infancy center of the muscle fiber reflecting appropriate precautions can be taken for with hypotonia or developmental delay the absence of mitochondria in this area. malignant hyperthermia. The functional and predominantly hip girdle and axial Serum CK is usually normal in CCD consequences of autosomal-recessive muscle weakness. Facial, bulbar, and but may occasionally be mildly elevated, and dominant RYR1 mutations have respiratory involvement is minimal or mainly in patients with additional exer- been outlined in the paragraph on absent. Progression is slow and almost all tional myalgia and muscle cramps. MmD above. patients achieve the ability to walk Muscle ultrasound shows a striking independently, except the most severe increase in echo intensity but relative Other core myopathies neonatal cases, and those with very sparing of the rectus femoris within the Cores on muscle biopsy are a non- severe orthopedic complications; how- thigh, corresponding to a similarly specific finding and apart from SEPN1- ever, marked clinical variability, even consistent pattern of selective muscle and RYR1-related myopathies have within the same family, has been involvement on muscle MRI, which been recognized in a number of other reported. Orthopedic complications may assist in differentiating RYR1- genetic backgrounds. The most com- are common in CCD and comprise related CCD from other myopathies mon forms among this group are congenital dislocation of hips, scoliosis, with overlapping histopathological MYH7-related MmD [Cullup et al., and foot deformities including talipes features. 2012] often associated with distal con- equinovarus and pes planus [Gamble Genetic diagnosis is established by tractures as seen in other MYH7-related et al., 1988]. Many patients have striking sequencing of the RYR1 gene, bearing myopathies [Lamont et al., 2014] and joint hypermobility, occasionally asso- in mind that not infrequently two TTN-related core myopathies [Chau- ciated with patellar instability. Achilles dominant RYR1 mutations may be veau et al., 2014] with highly variable tendon tightness occurs but other con- running in the same family and that clinic-pathological presentation, includ- tractures are rare. RYR1 variants of uncertain significance ing pronounced distal hypermobility The term CCD refers to the are not uncommon [Klein et al., 2012]. [Oates et al., 2014]. In contrast to the characteristic, well-defined reduction Accurate genetic diagnosis and familial SEPN1- and RYR1-related forms, ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 39 primary cardiac involvement is very nosis of generalized joint hypermobility. Bonnemann€ CG, Brockmann K, Hanefeld F. 2003. Muscle ultrasound in Bethlem myo- common in MYH7- and TTN-related Findings of joint hypermobility and pathy. Neuropediatrics 34:335–336. core myopathies [Romero et al., 2014]. muscle involvement should be evaluated Bonnemann€ CG. 2011. The collagen VI-related in context of the patient’s overall myopathies: muscle meets its matrix. Nat Rev Neurol 7:379–390. Limb girdle muscular dystrophy 2 E with phenotypic presentation to allow for Behan WM, Longman C, Petty RK, Comeglio P, joint hyperlaxity and contractures accurate diagnosis. Child AH, Boxer M, Foskett P, Harriman (LGMD2E þ) The pattern of distribution of joint DG. 2003. Muscle fibrillin deficiency in Marfan’s syndrome myopathy. J Neurol Kaindl et al. reported a family with a hypermobility, its dynamic nature as Neurosurg Psychiatry 74:633–638. severe and progressive limb-girdle mus- well as the co-existence of hypermo- Beighton P, De Paepe A, Steinmann B, Tsipouras cular dystrophy with joint hypermobil- bility with dislocations and contractures P, Wenstrup RJ. 1998. Ehlers-Danlos syn- dromes: revised , Villefranche, ity, contractures, and cardiorespiratory occur both in the myopathies and 1997. Ehlers-Danlos National Foundation symptoms comprising chest pain, tachy- inherited connective tissue disorders (USA) and Ehlers-Danlos Support Group cardia, , and dyspnea [Kaindl discussed. Congenital myopathies are (UK). Am J Med Genet 77:31–37. Bertin P, Treves R, Julia A, Gaillard S, sproges- et al., 2005]. Muscle weakness presented more often accompanied by distal rather Gotteron R. 1989. Ehlers-Danlos syn- in the first decade, with delayed motor than generalized hypermobility (distal drome, clotting disorders and muscular milestones and a progressive Duchenne- and proximal interphalangeal and meta- dystrophy. Ann Rheum Dis 48:953–956. Bertoli-Avella AM, Gillis E, Morisaki H, Verha- like muscular dystrophy including facial carpophalangeal joints of hands, distal gen JMA, de Graaf BM, van de Beek G, weakness, resulting in loss of ambulation interphalangeal joints of feet, wrists, and Gallo E, Kruithof BPT, Venselaar H, Myers around the age of 10 years. 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CK levels were mobility with prominent and Tsukube T, Kubo N, Hofstra R, Goumans MJ, Bekkers Roos-Hesselink, van de Laar elevated to 50 times of normal values. progressive joint contractures, which IMBH, Dietz HC, Van Laer L, Morisaki T, Genetic analysis revealed a homozygous typically occur in the shoulders, elbows, WesselsMW,Loeys BL. 2014. Mutations in a microdeletion of approximately 400 KB hips, knees, and Achilles tendons, but TGFb ligand, TGFB3, cause syndromic aortic aneurysms and dissections. JACC in on chromosome 4q11-q12, a region also in the finger flexors, so that there revision. containing the b-sarcoglycan gene, both evidence of joint hyper mobility as Bharucha-Goebel DX, Santi M, Medne L, whose pathogenetic role in this con- well as contractures in the hands and Zukosky K, Dastgir J, Shieh PB, Winder T, Tennekoon G, Finkel RS, Dowling JJ, dition was further supported by my- fingers. Monnier N, Bonnemann€ CG. 2013. 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