the neuromuscular differential diagnosis of joint...

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

A R T I C L E

The Neuromuscular Differential Diagnosis ofJoint HypermobilityS. DONKERVOORT, C.G. BONNEMANN, B. LOEYS, H. JUNGBLUTH, AND N.C. VOERMANS

Sandra DonSection at the

Dr. CarstenSection in theconcern clinica

Prof.dr. BartUniversity Medinvolvement. H

Dr. Heinz Juand King's Coneurodevelopm

Dr. Nicol VNetherlands. Hthe neuromusc

**CorrespoNetherlands. E

DOI 10.100Article first

� 2015 Wil

Joint hypermobility is the defining feature of various inherited connective tissue disorders such as Marfansyndrome and various types of Ehlers–Danlos syndrome and these will generally be the first conditions to beconsidered by geneticists and pediatricians in the differential diagnosis of a patient presenting with suchfindings. However, several congenital and adult-onset inherited myopathies also present with jointhypermobility in the context of often only mild-to-moderate muscle weakness and should, therefore, beincluded in the differential diagnosis of joint hypermobility. In fact, on the molecular level disorders within bothgroups represent different ends of the same spectrum of inherited extracellular matrix (ECM) disorders. In thisreview we will summarize the measures of joint hypermobility, illustrate molecular mechanisms these groups ofdisorders have in common, and subsequently discuss the clinical features of: 1) the most common connectivetissue disorders with myopathic or other neuromuscular features: Ehlers–Danlos syndrome, Marfan syndromeand 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 withrecognition of these disorders. © 2015 Wiley Periodicals, Inc.

KEYWORDS: myopathies; hypermobility; inherited connective tissue disorders; extracellular matrix

How to cite this article: Donkervoort S, Bonnemann CG, Loeys B, Jungbluth H, Voermans NC. 2015. TheNeuromuscular Differential Diagnosis of Joint Hypermobility. Am J Med Genet Part C 169C:23–42.

INTRODUCTION

Inherited connective tissue disorderssuch as Ehlers–Danlos syndrome(EDS) and Marfan syndrome are char-acterized by joint hypermobility andfragility of skin, blood vessels, andinternal organs. There may also beassociated mild-to-moderate muscleweakness, muscle hypoplasia, or hypo-tonia indicating clinical overlap with a

kervoort is a board certified geneticNational Institutes of Health, NatioB€onnemann is a pediatric neurologiNeurogenetics Branch at the Neuroll, molecular genetic, and translatioLoeys is pediatricianandclinical geneical Center, Nijmegen, The Nethere contributed to the molecular andngbluth is a Consultant and Reader illege, London, United Kingdom. Hental disorders.

oermans works as an adult neuroer main research interest is inheritedular features of inherited connectivndence to: N.C. Voermans, Departm-mail: nicol.voermans@radboudum2/ajmg.c.31433published online in Wiley Online Lib

ey Periodicals, Inc.

group of inherited myopathies that mayalso feature joint hypermobility and skinchanges and should, therefore, be con-sidered in the differential diagnosis ofthese disorders.

Inherited myopathies represent aclinical spectrum with significant ge-netic and phenotypic heterogeneityranging from severe and sometimesearly fatal disorders to relatively mildconditions compatible with near normal

counselor in the Neurogenetics Branch, Neuromuscnal Institute of Neurological Disorders and Stroke.st and neurgeneticist. He is Chief of the Neuromuscogical Institute of Neurological Disorders, National Inal aspects of early onset neuromuscular disorders.ticistworking in thegeneticsdepartmentsof theUnivlands. Specific interests include connective tissue dclinical delineation of several disease entities, mostn Paediatric Neurology at the Evelina Children's Hospis main research interest is in neurogenetics, in p

logist at the neuromuscular center of the Radbomyopathies, in particular congenital myopathies, fe tissue disorders and muscle ECM disorders.ent of Neurology, 935, Radboud university medicalc.nl

rary (wileyonlinelibrary.com).

life span. Recent advances in the geneticclarification of inherited myopathieshave significantly improved our under-standing of their pathogenesis andenabled classifications of these condi-tions based on both the clinical featuresand the primary genetic and biochem-ical defects. In addition to the pattern ofmuscle weakness, variable presence ofother clinical findings such as centralnervous system or cardiorespiratory

ular and Neurogenetic Disorders of Childhood

ular and Neurogenetic Disorders of Childhoodnstitutes of Health. His main research interests

ersityHospitalAntwerp, BelgiumandRadboudisorders, especially those with cardiovascularprominently Loeys–Dietz syndrome.ital, Guy's & St Thomas' NHS Foundation Trust,articular the genetics of neuromuscular and

ud university medical center, Nijmegen, theascioscapulohumeral muscular dystrophy, and

center, P.O. Box 9101 6500 HB Nijmegen, The

24 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

involvement, cataracts, opthalmoplegia,myotonia, muscle rippling, contrac-tures, and spine rigidity may assist indefining specific phenotype–genotypecorrelations. Significant joint hyper-mobility can be a distinctive clinicalfeature in its own right and may confusethe differential diagnosis, in particular inpatients where muscle weakness is notthe most prominent finding at presenta-tion [Voermans et al., 2008a]. Con-firmatory genetic diagnosis is importantfor providing accurate prognosis, man-agement, recurrence risk, genetic coun-seling, and for the development oftherapeutic strategies.

In this review we will summarizethe measures of joint hypermobility,illustrate molecular mechanisms sharedbetween these groups of disorders, andsubsequently discuss the clinical andgenetic features of the: 1) most commonconnective tissue disorders with myo-pathic or other neuromuscular features(EDS, Marfan, and Loeys–Dietz syn-drome); 2) myopathy and connectivetissue overlap disorders (“muscle extrac-ellular matrix (ECM) disorders”); and 3)myopathies with prominent joint hyper-mobility. As such, this review does notcover all neuromuscular disorders withsome degree of distal hypermobility(such as spinal muscular atrophy, nema-line myopathy, and certain forms ofcongenital muscular dystrophy), butrather concentrates on the connectivetissue and muscle overlap disorders plussome selected myopathies in whichhypermobility is a more consistentfeature. The aim is to assist clinicalgeneticists and other clinicians with therecognition of these disorders.

ASSESSMENT OF JOINTHYPERMOBILITY

Joint hypermobility is defined as abnor-mally increased active and/or passiverange of motion in a joint [Beightonet al., 1998]. Presence of multiplehypermobile joints can be referred toas generalized joint hypermobility andmay be associated with recurrent (sub)luxations.When assessing joint mobility,the large physiological range related tosex, age, and race has to be taken into

account. In fact, generalized jointhypermobility is the severe end of aspectrum of physiological joint mobility.

So far, the nomenclature andclassification of joint hypermobilityused in literature is variable: “hyper-mobility” is the term used in thediagnostic criteria of EDS and Marfansyndrome; in several case reports otherterms are used: “hyperlaxity“, “jointlaxity” and, even less specifically, “hy-perelasticity” and “hyperextensibility.”Furthermore, description of how jointmobility is determined and which jointshave been tested is often lacking. Thismay result in inaccuracy of the clinicaldescription and consequently lead tounder-recognition and underestimationof the presence of joint hypermobility invarious myopathies [Voermans et al.,2009b] We have, therefore, advocatedthe use of the term “hypermobility”assessed by a standardized scale, theBeighton and Bulbena scores (Table I)[Bulbena et al., 1992; Beighton et al.,1998].

CLINICAL ANDMOLECULAR OVERLAP

The pathophysiology of hypermobilityis likely to be multifactorial, comprisingfactors affecting both dynamic jointfunction and connective tissue charac-teristics of the various ECM compart-ments in muscle, the myotendinousjunction, tendon, and joint capsule[Voermans et al., 2008a] as well as thephysical properties of the muscle cellsthemselves. The multifactorial etiologyprobably explains why joint hypermo-bility occurs in both myopathies andinherited connective tissue disorders.

Altered tendon and joint capsulestructure and function may contributeto joint hypermobility in various myo-pathies. This point is illustrated bystudies in zebrafish demonstrating thatloss of selenoprotein-N function causesdisruption of both muscle and myosep-tum architecture [Deniziak et al., 2007],the latter being the connective tissuelayer involved in force transmissionthrough connecting tendons to muscle.Next, type VI collagen is present inbovine tendons, where it may be

involved in organizing the ECM offibrocartilage and provide a survivalfactor for fibrochondrocytes [Carvalhoet al., 2007]; consequently, COL6mutations may alter tendon structureand function. Furthermore, it has beensuggested that RyR1-mediated calciumsignaling plays a role in mechano-trans-duction pathways of fibroblasts in ten-don [Wall and Banes, 2005] andhypothetically, RYR1 mutations maythus alter mechanic tendon function oftendon. However, this has not beeninvestigated in detail and further re-search will be required.

This clinical overlap extends to themolecular level: ECM proteins involvedin the pathophysiology of inheritedconnective tissue disorders (collagens I,III, V, IX, lysylhydroxylase, tenascin-X,fibrillin, fibulin, elastin, and perlecan)are expressed not only in connectivetissue of tendons and joint capsules, butalso of muscle (endo-, peri-, andepimysium). Its structure and functionmay be altered as a consequence ofmutations in any of these genes [Voer-mans et al., 2008a; Hubmacher andApte, 2013]. Clinicians and researchersdealing with myopathies and inheritedconnective tissue disorders should beaware of this overlap. Only a multi-disciplinary approach will allow fullrecognition of the wide variety ofsymptoms present in the spectrum ofECM defects, which has importantimplications for scientific research, di-agnosis, and for the treatment of thesedisorders.

Inherited Connective TissueDisorders With NeuromuscularFeatures

Ehlers–Danlos syndromeEDS is a clinically and geneticallyheterogeneous group of inherited con-nective tissue disorders characterized byvarious combinations of generalizedjoint hypermobility, skin hyperextensi-bility, and tissue fragility. In 1997, sixmain EDS types were defined, thehypermobility type, classical type, andvascular type, and the rare kyphoscoli-otic type, arthrochalasis type, and der-matosparaxis type EDS (Table II)

TABLEI.

Assessm

entofJointHyp

ermobility

Bulbena

scoreDegreeof

mob

ility

bypassivemaneuversin

9joints.

Totalscore:

0–10.H

ypermob

ility:�

5(w

omen)and�4

(men).

BeightonscoreDegreeof

mob

ility

bypassivemaneuversin

5joints.

Totalscore:

0–9Hypermob

ility:score:

�5Upper

extrem

ity:

1)Thu

mb:

passiveappo

sitionof

thethum

bto

theflexo

raspect

oftheforearm

<21

mm;

2)Metacarpo

phalangeal:with

thepalm

ofthehand

restingon

thetable,

thepassive

dorsiflexionof

thefifth

fingeris�9

0°;

3)Elbow

hyperextensio

n:passivehyperextensio

nof

theelbow

�10°;

4)Externalshou

lder

rotatio

n;with

theup

perarm

touching

thebo

dy,andtheelbow

fixed

at90°;theforearm

istakenin

externalrotatio

nto

>85°of

thesagittalplane

(sho

ulderlin

e);Lo

wer

extrem

ity—

supine

position:

5)Hip

abdu

ction:

passivehipabdu

ction�8

5°;

6)Patellarhyperm

obility:ho

ldingwith

onehand

theproxim

alendof

thetib

ia,

thepatella

canbe

moved

wellto

thesid

eswith

theotherhand

;7)

Ank

leandfeet

hyperm

obility:an

excessrangeof

passivedo

rsiflexion

oftheankleeversion

ofthefoot

canbe

prod

uced;

8)Metatarsoph

alangeal:do

rsalflexion

ofthetoeover

thediaphysis

ofthefirst

metatarsalis�9

0°;Lo

wer

extrem

ity—pron

epo

sition:

9)Kneehyperflexion

:kn

eeflexion

allowstheheel

tomakecontactwith

thebu

ttock.

General:Presence

orabsenceof

ecchym

oses

(one

pointforthe

presence

ofecchym

oses).One

pointforeach

hyperm

obile

joint

General:

1)Dorsiflexion

ofthelittle

fingersbeyond

90°;on

epo

intforeach

hand

;2)

Apposition

ofthethum

bsto

theflexo

raspect

oftheforearm;on

epo

intforeach

hand

;3)

Hyperextensionof

theelbowsbeyond

10°;

onepo

intforeach

elbow;

4)Hyperextensionof

thekn

eesbeyond

10°;

onepo

intforeach

knee;

5)Fo

rwardflexion

ofthetrun

kwith

kneesfully

extend

edso

that

thepalm

sof

thehand

restflaton

theflo

or;on

epo

int.One

pointforeach

hyperm

obile

joint

Beightonscore

Gon

iometer

used

for

measurementof

jointmob

ility

The

Bulbena

scoreinclud

eson

eitem

onthepresence

orabsenceof

ecchym

oses,w

hich

areun

common

inmyopathiesandmay

thereforebe

areason

ablediscriminator

todistinguish

betw

een“muscular”

hyperm

obility

and“conn

ectivetissue”

hyperm

obility.F

urthermore,in

youn

gerpatientstheBeightonscoreislessreliableandtheBulbena

scoreismoreuseful.

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 25

TABLEII.Overview

ofInherited

Connective

TissueDisordersan

dConge

nital

Myo

pathiesWithJointHyp

ermobility

Diso

rder

Mod

eof

inheritanceProtein

involved

Gene

Muscleinvolvem

ent

Hypermob

ility/

Dislocation/

Con

tractures

Associatedsymptom

s

Inheritedconn

ectivetissuedisorderswith

neurom

uscularfeatures

Classic

type

(I/II)AD

CollagenV

Unk

nown

COL5A

1/A2

Musclehypo

tonia,

delayedgrossmotor

developm

ent,fatig

ue

Generalized

joint

hyperm

obility

with

rrecurring

joint

dislo

catio

ns(sho

ulder,patella,

tempo

romandibu

lar

joints)

Skin

hyperextensib

ility,easybruisin

g,velvetyskin,wideningof

scars

Hypermob

ility

type

(III)

AD

Tenascin-X

;Unk

nown

TNXB

Musculoskeletalpain

Generalized

joint

hyperm

obility

with

recurringjoint

dislo

catio

ns(sho

ulder,patella,

tempo

romandibu

lar

joints)

Easybruisin

g,velvetyskin

Vascular

type

(IV)AD

CollagenIII

COL3A

1Tend

onandmuscle

rupture

Distaljoint

hyperm

obility

(hands/fingers),

tend

onandmuscle

rupture

Thin,

translu

cent

skin,extensive

bruisin

g.arterial/intestin

al/uterine

fragility

orrupture,

characteristic

facialappearance,

acrogeria,club

foot,varicose

veins,

arteriovenou

s,carotid

-caverno

usfistula,

pneumo(hemo)

thorax,ging

ival

recession

Kypho

scoliotic

type

(VIA

)AR

Lysyl

hydroxylase

PLOD

Severe

muscle

hypo

toniaat

birth,

delayedgrossmotor

developm

ent

Distaljoint

hyperm

obility

Scoliosis,scleralfragility

andruptureof

theocular

glob

e,arterialrupture,

osteop

enia,

marfano

idhabitus,microcornea

Musculocontractural

(VIB)AR

Dermatan-4-

sulfo

transferase

CHST

14Severe

muscle

hypo

toniaat

birth,

delayedgrossmotor

developm

ent.

Distaljoint

hyperm

obility

Scoliosis


TABLEII.(Continued)

Diso

rder

Mod

eof

inheritanceProtein

involved

Gene

Muscleinvolvem

ent

Hypermob

ility/

Dislocation/

Con

tractures

Associatedsymptom

s

Aarthrochalasiatype

(VIIA)AD

CollagenI

COL1A

1Po

lyhydram

nios,

bilateralclub

foot,

congenital

hypo

tonia,

delayedgrossmotor

developm

ent

Arthrog

rypo

sis,

bilateralhip

dislo

catio

n,and

hyperm

obility

ofthe

shou

lders,elbows,

andkn

ees

Facialdysm

orph

icfeatures,skin

hyperextensib

ility

EDSwith

prog

ressive

kyph

oscolio

sis,

myopathyand

hearinglossFK

506-

bind

ingprotein14

FKBP1

4Severe

muscle

hypo

toniaat

birth,

delayedgrossmotor

developm

ent

Distaljoint

hyperm

obility

Scoliosis,sensorineuronalhearingloss

Tenascin-X

deficient

type

AR

Tenascin-X

TNXB

Muscleweakn

ess

Generalized

joint

hyperm

obility

Skin

hyperextensib

ility,easy

bruisin

g,velvetyskin

Marfansynd

romeAD

Fibrillin

FBN1

Musclehypo

plasia,

musclecram

ps,easy

fatig

ability,

generalized

muscle

weakn

ess

Distaljoint

hyperm

obility

(DIP/

PIP/

MCPjoints,

wrists),

contractures

(elbow

s)

Ascending

aortadilatatio

nandrupture,

arachn

odactyly,scoliosis

/spo

ndylolisthesis,

pectus

excavatum,h

ighpalate,typical

facialappearance

Loeys–Dietz

synd

rome

AD

TGFB

R1/2SM

AD3

TGFB

2/3

Musclehypo

tonia

Jointhyperm

obility,

contractures

(cam

ptod

actyly,club

foot)

Hypertelorism

,cleftpalate/bifiduvula,

widespreadarterialandaortic

aneurysm

with

arterialtortuo

sity

Myopathyandconn

ectivetissueoverlapsynd

romes

UllrichCon

genital

myopathy(U

CMD)

AD/A

RCollagenVI

COL6A

1/A2/A3

Hypoton

ia,delayed

motor

mileston

es,

profou

ndmuscle

weakn

ess.

Onset

in1stdecade;

wheelchairbo

und.

Distaljoint

hyperm

obility,

(MCPjoints,PIP,

andDIP

joints),

contractures

(proximaljoints)

Earlyrespiratoryfailu

re,d

ermalfeatures

(hyperkeratosis,softvelvetyskin,

andatend

ency

tokeloid

or“cigarette

paper“

scar

form

ation

Bethlem

myopathy

(BM)AD

Collagen

VI

COL6A

1/A2/A3

Hypoton

ia,delayed

motor

mileston

es,

redu

cedfetal

movem

ents,

mild

muscle

weakn

ess

(proximal>distal,

extensors >

flexo

rs)

Onset

in1stor

2nd

decade

Distaljoint

hyperm

obility

(DIP

joints),flexion

contractures

(fingers,wrists,

elbows,andankles)

Respiratory

failu

re


TABLEII.(Continued)

Diso

rder

Mod

eof

inheritanceProtein

involved

Gene

Muscleinvolvem

ent

Hypermob

ility/

Dislocation/

Con

tractures

Associatedsymptom

s

CollagenVIlook

-alike

synd

romes

AR

Unk

nown/AR

Candidate

proteins:

Integrin

alfa9Activin

AIIBreceptor

Laminin

receptor

1

Candidate

region

s:ITGA9

ACVR2B

LAMR13p23-p21

Con

genitalhypo

tonia,

delayedmotor

mileston

es,

redu

cedfetal

movem

ents,

generalized

muscle

weakn

ess

(proximal>distal)

Distaljoint

hyperm

obility,

proxim

alcontractures

Early

respiratoryfailu

re,mild

tomod

eratementalretardation,

decreasedpu

lmon

aryvitalcapacity,

scoliosis

CollagenXII

related

myopathy/EDS

overlap

synd

romeAR

Collagen12

COL12

A1

Generalized

muscle

weakn

essMild

facial

weakn

ess,and

absent

deep

tend

onreflexesInability

tostandor

ambu

late

independ

ently

Widespreadjoint

hyperm

obility

atbirthcombinedwith

proxim

alcontractures

and

prog

ressive

kyph

oscolio

sis

Higharched

palate

Myopathieswith

striking

jointhyperm

obility

Multi-minicoredisease

(MmD)AR

Seleno

protein

N“classic

MmD”

SEPN

1Hypoton

ia,redu

ced

fetalmovem

ents,

delayedmotor

mileston

es,

muscleweakn

ess

(axial>proxim

al>

distal)

Distaljoint

hyperm

obility

(MCP);to

alesser

degree

inall

otherlim

bjoints

Respiratory

failu

re>>

muscle

weakn

ess,spinalrigidity,scoliosis,

second

arycardiac(right

ventricular)

involvem

ent

AR

Ryano

dine

receptor

“MmD

subgroup

s”RYR1

Hypoton

ia,redu

ced

fetalmovem

ents,

delayedmotor

mileston

es,

muscleweakn

ess

(axial>proxim

al>distal)Su

bgroup

with

severe

hipgirdleweakn

ess.

Subgroup

with

markeddistal

weakn

essand

wastin

g,predom

inantly

thehand

sDistaljoint

hyperm

obility

(MCP),to

alesser

degree

inall

otherlim

bjoints

Oph

thalmop

legia,mild

respiratoryinvolvem

ent,mild

facialmuscleweakn

ess


TABLEII.(Continued)

Diso

rder

Mod

eof

inheritanceProtein

involved

Gene

Muscleinvolvem

ent

Hypermob

ility/

Dislocation/

Con

tractures

Associatedsymptom

s

Centralcore

disease

(CCD)AD/(AR)

Ryano

dine

receptor

RYR1

Muscleweakn

esswith

prom

inent

involvem

entof

hip

girdle

andaxial

muscles,

mild

facialweakn

ess,

rare

bulbar

involvem

ent.

Generalized

hyperm

obility,

congenital

hipdislo

catio

ncommon

(Mitralvalveprolapse),malignant

hypertherm

ia

Other

core

myopathies

Myosin

heavychain7

Titin

MYH7TTN

Prog

ressivemuscle

weakn

essMild

facial

weakn

ess

Distalcontractures

(MYH7)

Pron

ounced

distalhyperm

obility

(TTN)

Severe

respiratoryim

pairment(M

YH7)

Limbgirdle

muscular

dystroph

y2Ewith

jointhyperlaxity

and

contractures

(LGMD2E

þ)AR

b-

sarcoglycan

SCGB:

Prog

ressivelim

bgirdle

muscleweakn

ess,

onset0–5years,

delayedmotor

mile

ston

es,

facialweakn

ess

Distaljoint

hyperm

obility

(MCP

andPIPjoints),

contractures

(DIP

joints)

Tachycardia,arrhythm

ia,chestpain,

scoliosis,no

cturnaldyspnea

Con

genitalmyasthenic

synd

rome

TO

BEADDED

AD:autosom

aldo

minantinheritance;

AR:autosom

alrecessiveinheritance.


[Beighton et al., 1998]. A clinicallydistinct form results from tenascin-X(TNX) deficiency due to recessivemutations in the TNXB gene [Schalk-wijk et al., 2001]. The list of otherapparently more rare subtypes is grad-ually expanding (Table III) [Castori andVoermans, 2014; Sobey, 2014]. Hyper-mobility is present in all forms of EDSbut mostly pronounced in the hyper-mobility, classical, and TNX-deficienttype. In the vascular type, joint hyper-mobility is usually limited to the digits,whereas in the kyphoscoliotic type bothfingers, wrists, toes, and ankles areseverely affected. Proximal contracturesmay develop later in the course of thedisease in this latter type (Fig. 1).

EDS is associated with a variety ofneuromuscular features, initially docu-mented in case reports and generallyconsidered secondary to exercise avoid-ance prompted by joint hypermobility[Bertin et al., 1989; Beighton et al.,1998; Palmeri et al., 2003]. Musclehypotonia, delayed motor milestones,fatigue, musculoskeletal pain, andmuscle rupture are included in thediagnostic criteria [Beighton et al.,1998].

Over the last years these neuro-muscular findings have been acknowl-edged as a primary aspect of the EDSphenotype. The first physiological studyof muscle weakness in EDS was per-formed by Bilkey et al. in 1981demonstrating that muscle weaknesswas primarily due to reduced jointproprioception and the tendency forminor subluxations, which in combina-tion was thought to result in a differentlearned motor pattern [Bilkey et al.,1981]. In 2009, Voermans et al. per-formed a prospective study in 40genetically or biochemically confirmedpatients with EDS (vascular, classic,hypermobile, and TNXB-deficientEDS), showing that mild-to-moderateneuromuscular involvement is commonin these disorders [Voermans et al.,2009c] and may include complaints ofmyalgia and limited exercise endurance,andmild-to-moderate muscleweakness,reduction of vibration sense, and mildmobility impairment on examination.Nerve conduction studies demonstrated

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, CYP21BAssociation with Gilles de la Tourette syndrome AD HDCAssociation with parodontitis AD UnknownAssociation with periventricular heterotopia XLD FLNABrittle cornea syndrome type 1 AR ZNF469Brittle cornea syndrome type 2 AR PRDM5Cardiac-valvular AR COL1A2Classic with arterial rupture AD COL1A1Ehlers–Danlos syndrome/osteogenesis imperfecta overlap AD COL1A1, COL1A2Ehlers–Danlos syndrome-like due to 6q27 deletion Sporadic/AD Not applicableKyphoscoliotic with myopathy and deafness AR FKBP14Musculocontractural, type 1 AR CHST14Musculocontractural, type 2 AR DSEOverlap phenotype due to COL3A1/COL5A2/MSTN haploinsufficiency AD COL3A1, COL5A2, MSTN (deletion)Progeroid AR B4GALT7Spondylocheirodysplasia AR SLC39A13Tenascin X-deficient AR, AD (?) TNXB

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


an associated axonal sensory polyneur-opathy in a minority of patients, andneedle electromyography showed mildmyopathic features with a mixed patternof smaller and broader motor unit actionpotentials. Muscle biopsies showed mildmyopathic changes (increased internalnuclei and fiber size variation) in 25% ofEDS patients, with a lower density andshorter length of collagen fibrils in theECM on electron microscopy (EM).Creatine kinase (CK) was only mildlyelevated in 10% of patients (range 40–681U/L). These clinical and histopa-thological findings confirmed that mild-to-moderate neuromuscular involve-ment is part of the EDS spectrum andthat a muscle biopsy to investigate a co-existent myopathy or neuropathy is notnecessarily indicated if otherwise diag-nostic EDS features are present.

Recently, a patient with TNX-deficient EDS presenting with a pre-dominantly myopathic phenotype wasreported [Penisson-Besnier et al., 2013].Clinical features included progressiveaxial and proximal limb muscle weak-ness, subclinical cardiac involvement,minimal skin hyperextensibility, no jointabnormalities, and a history of easybruising. Muscle biopsy revealed mild

myopathic changes, but no dystrophicfeatures were observed, correspondingto previous reports [Voermans et al.,2007b]. The absence of Ullrich con-genital muscular dystrophy (UCMD) orBethlem myopathy (BM) myopathyfeatures (no typical contractures, noskin features, only mild muscle MRIfeatures of collagen VI myopathies, andno fibrosis on muscle biopsy) appearedto suggest that the different ECMprotein defects have different impacton muscle structure: collagen VI defi-ciency gives rise to progressive increaseof endomysial connective tissue,whereas TNX deficiency producesmuscle “softness” but no endomysialfibrosis. This points to a different role ofthese and other ECM proteins impli-cated in EDS in muscle ECM develop-ment and functioning (Tables II and III).

Furthermore, EDS may present inthe neonatal period with significanthypotonia and should, therefore, beconsidered in the initial differential diag-nosis of the floppy infant syndrome [Yiset al., 2008; Voermans et al., 2008b].Among the different subtypes of EDS,congenitalmuscle involvement is probablymost pronounced in the kyphoscolitictype (EDS VIA), due to autosomal-

recessive (AR) PLOD1 mutations (mis-sense and splice site mutations, deletions,and duplications). PLOD1 encodes lysylhydroxylase, a catalyzing enzyme essentialfor the formation of hydroxylysine incollagens and collagen-like proteins,which are critical for the binding ofcarbohydrates, and therefore the stabilityof collagen cross links. Infants with thisEDS type can be born with significanthypotonia, failure to thrive, delayedmotordevelopment, wrist, and hip dislocation,congenital, or early onset kyphoscoliosis.Other manifestations include ophthalmo-logic findings (scleral fragility, rupture ofthe ocular globe, microcornea) joint andskin hypermobility, marfanoid habitus,and contractures. Vascular complicationsincluding stroke and spontaneous arterialrupture have been reported [Brinckmannet al., 1998; Ha et al., 1994].

Additionally, recessive loss of functionmutations inCHST14, encoding derma-tin-4-sulfotransferase 1, result in muscu-locontractural EDS (EDS kyphoscoliotictype VIB) with a clinical spectrum thatincludes significant congenital hypotonia,gross motor delay, muscle hypoplasia withprogressive joint hypermobility, as well asprogressive earlyonset kyphoscoliosis, jointcontractures, club feet, characteristic facial

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


features, thin, and bruisable skin, atrophicscarring, and variable ocular involvement(Fig. 2) [Shimizu et al., 2011;Dundar et al.,2009]. Congenital bilateral thumb adduc-tion may be a distinctive clinical finding[Kosho et al., 2010; Miyake et al., 2010;Malfait et al., 2010]. In one familyautosomal recessive mutations in thedermatan sulphate epimerase (DSE) werefound in a family with multisystemicmusculocontractural, type 2 [Mulleret al., 2013].

Mutations in FKBP14 cause asubtype of EDS that resemblesCHST14 disorders. Patients present

with severe congenital muscle hypoto-nia, progressive scoliosis, joint hyper-mobility, and hyperelastic skin, butunlike patients with CHST14, thesepatients also have sensorineural hearingimpairment [Baumann et al., 2012;Murray et al., 2014]. CK levels rangedfrom normal to mildly elevated (range60–300 IU/L), nerve conduction stud-ies are normal, electromyography isnormal in infancy but may show amyopathic pattern in adolescence andadulthood. Muscle biopsies may show aspectrum of histopathological featuresranging from non-specific increased

fiber size variability to more pro-nounced changes with fiber atrophyand proliferation of fatty tissue. Electronmicroscopy may show focal rearrange-ment of myofibrils with irregular Z-lines. Muscle MRI was normal in onepatient but showed fatty replacement ofmuscle tissue, predominantly affectedthe rectus femoris, and vastus lateraliswith relative sparing of the adductorcompartment. FKBP14 is an ER proteinthat may have a catalytic functionthrough accelerating cis-trains isomer-ization of peptidyl-propyl bonds.FKBP14 loss-of-function fibroblast


analysis showed disturbed distributionand impaired assembly of several ECMcomponents specifically collagen type Iand III and fibronectin.

Dominant de-novo mutations inCOL1A1 are a rare cause of EDS andhave been reported in a girl with severeEDS VIIA of the arthrochalasia type[Nuytinck et al., 2000; Giunta et al.,2008] Pregnancy in this case wascomplicated by polyhydramnios andbilateral clubfoot noted on prenatalultrasound. At birth she was noted tohave hypotonia, arthrogryposis, bilateralhis dislocation and hypermobility of theshoulders, elbows, and knees. At age1 year she had facial dysmorphicfeatures, delayed motor milestones,severe hypotonia, and skin and jointhypermobility. Genetic analysis of theCOL1A1 gene showed a heterozygousmissense affecting the splice acceptorsite resulting in skipping of exon 6. Theheterozygous Arg134Cys mutation inCOL1A1 mutation has been identifiedin two unrelated patients with an EDS/osteogenesis imperfect (OI) overlap

Figure 2. Finger extensor weakness in h(VIB) type EDS. Proximal and distal muscle atpatients. The first patient has been reported i

condition characterized by osteopenia,soft, and doughy skin with hyperexten-sibility, infrarenal aortic, and arterialaneurysms, joint hypermobility, pectusexcavatum and easy bruising [Malfaitet al., 2013]. Interestingly, mutations inthe Gly-X-Y triplet repeat of COL1A1gene result in osteogenesis imperfecta,indicating a wide phenotypical spec-trum. These collagen I-related disordersall have a combination of joint hyper-mobility and muscle hypotonia anddelay in motor development.

The study of Voermans et al. alsodemonstrated a correlation betweenresidual TNX levels and the degree ofneuromuscular involvement, pointing ata dose-effect relation between the ECMdefect and muscle dysfunction. Thisphenomenon was subsequently sup-ported by physiological studies inTNXB-deficient patients and tnxbknock-out mice [Voermans et al.,2009c; Huijing et al., 2010; Gerritset al., 2013]. These studies showed areduction of force transmission betweenindividual muscles and the surrounding

ands of 25-year-old (A, B) and 18-year-old (F) frophy in arms and lower legs (C), dropping feet (En [Voermans et al., 2012] at age of 23.

fascia (“myofascial force transmission”)probably due to increased compliance(i.e., reduced elasticity) of the connec-tive tissue surrounding the individualmuscles. As a result, TNX-deficientmuscles appear less capable of trans-mitting forces in other ways than viamyotendinous force transmission andtherefore function more independently.Such altered function probably requiresadapted patterns of muscular coordina-tion to allow effective physiologicalmovements [Huijing et al., 2010]. Theincreased compliance of muscle ECMmay also play a role in muscle weaknessin other EDS types.

Marfan syndromeMarfan syndrome is characterized byocular, skeletal, and cardiovascular man-ifestations and due to dominantly in-herited mutations in the fibrillin-1(FBN1) gene. FBN1 encodes fibrillin-1, an ubiquitously expressed majorcomponent of ECM microfibrils withan important role for elastin depositionin elastic fibers. Variable expression in

emale patients with Musculocontractural) and hyperkeratosis pillari (G) in the same


Marfan syndrome is the rule, butcomplete non-penetrance has onlyrarely been documented. About 25%of mutations are dominantly acting de-novo mutation. Joint hypermobility isusually most pronounced in distal jointsand often accompanied by arachnodac-tyly (Fig. 3), but (congenital) jointcontractures, particularly of the elbow,also occur frequently [Loeys et al.,2010].

Although Marfan himself consid-ered muscle involvement integral to hissyndrome, neuromuscular features havereceived little attention until recently.Gradually, muscle fatigue and, to a lesserextent, muscle weakness, muscle hypo-plasia, myalgia, and cramps are beingrecognized as neuromuscular Marfanfeatures [Grahame and Peyritz, 1995;Behan et al., 2003; Jones et al., 2007].

A systematic observational studyon neuromuscular features in 10 pa-tients with Marfan syndrome showedthat various neuromuscular symptomsoccur frequently and consist of a mildmyopathy or polyneuropathy or both,which was more pronounced in theolder patients [Voermans et al., 2009a].The four oldest patients in this cohort(>50 years) reported muscle weaknessand had functional impairments. Fivepatients had a mild-to-moderate re-duction of vibration sense. Nerveconduction studies showed a mildaxonal sensory polyneuropathy infour patients. The muscle biopsiesobtained in two patients showedmyopathic changes in a 56-year-oldfemale patient, and was normal in a 32-year-old male. In addition, signs of alumbosacral radiculopathy were foundin four patients, which were associatedwith dural ectasia and spinal meningealcysts. Although these findings werefound in a small cohort of patients,they indicate a need to increase theawareness of neuromuscular involve-ment and radicular symptoms that maybecome more pronounced over time inMarfan syndrome patients [Voermanset al., 2009a].

The abundant expression of fibril-lin-1 in the skeletal muscle endomysiumand perimysium suggests a causal linkbetween muscle symptoms and the

FBN1 mutation [Zhang et al., 1995]In addition to its structural role in ECM,fibrillin-1 is also involved in regulatingTGF-b signaling via LTBP binding andthus influences muscle function. In-creased TGF-b signaling has beensuggested to suppress the muscle regen-erating capacity of the satellite cells[Hubmacher and Apte, 2013].

Loeys–Dietz syndrome (LDS)LDS is a Marfan-related condition firstdescribed by Loeys et al. [2005]. Thepatients present with a typical triad ofhypertelorism, cleft palate/bifid uvulawith widespread arterial/aortic aneur-ysm and arterial tortuosity. Skeletalfeatures shared with Marfan syndromeinclude pectus deformity, scoliosis,arachnodactyly but also joint hyper-mobility with camptodactyly, and clubfoot have described. Cervical spineinstability has also been observedfrequently [Erkula et al., 2010]. Thecondition is caused by mutations ofgenes encoding for components of theTGF-b signaling, such as TGF-breceptors 1 and 2 [Loeys et al., 2005],the actual cytokines TGFB2 [Lindsayet al., 2012] and TGFB3 [Bertoli-Avella et al., 2014] or the downstreameffector SMAD3 [van de Laar et al.,2011], and these are now classified asLDS types 1–5 [MacCarrick et al.,2014], all with some degree of muscleinvolvement such as hypotonia, re-duced muscle mass, and delayed motordevelopment

Myopathy and Connective TissueOverlap Disorders

Collagen VI-related dystrophies andmyopathies (COL 6-RD)Collagen VI is an important ECMcomponent and forms a microfibrillarnetwork that is closely associated withthe muscle cell and the surroundingbasement membrane. It is also found inthe interstitial space of many othertissues including tendon, skin, cartilage,and intervertebral discs. In muscle it ispredominantly produced by the inter-stitial fibroblasts. The exact mechanismand the downstream effects of collagenVI deficiency on muscle cells are

incompletely understood and may in-volve myofiber apoptosis as well asimpaired autophagy [Grumati et al.,2010]. In tendon, collagen VI is pre-sumably synthesized by the residenttendon fibroblast population, and as-sumes a distinctly pericellular orienta-tion around these cells, and as such itmay represent a survival factor for thesecells.

Autosomal dominant (AD) andrecessive (AR) mutations (includinglarger deletions) in each of the threecollagen 6 genes COL6A1, COL6A2,and COL6A3 cause a spectrum ofmyopathies associated with a jointhypermobility, contractures, and char-acteristic skin findings. Dominant mu-tations in the COL6 genes affectcollagen VI microfibril formation,resulting in disengagement of collagenVI from the basal lamina. Severe de-novo dominant-negative COL6 mu-tations lead to UCMD, whereas theintermediate and BM phenotype canbe caused by less severe dominant-negative mutations, or less commonlyby COL6 recessive mutations[B€onnemann, 2011]. Recessive nullmutations lead to a complete absenceof collagen VI in the matrix and asevere UCMD phenotype. Approxi-mately 5–10% of patients with a clinicaldiagnosis of COL6-RD do not have amutation in COL6A1–3 and it ispossible that their disease is caused byan unknown gene. Two related but lessfrequent phenotypes have been addedto this spectrum: an AD limb-girdlemuscular dystrophy phenotype and anAR myosclerosis phenotype reportedin one family with mutations inCOL6A2 [Merlini et al., 2008;Scacheri et al., 2002]; however, jointhypermobility is not a prominentfeature in these latter two phenotypes.

The clinical hallmarks of UCMDare profound muscle weakness of earlyonset with respiratory insufficiency asdisease progresses, with proximal jointcontractures and striking hypermobil-ity of mostly distal joints (toes, ankles,fingers, and wrists) [Lampe andBushby, 2005]. Posteriorly protrudingcalcanei are commonly seen (Fig. 4).Affected children typically either

Figure 3. Hypermobility of distal interphalangeal joints and wrist in a 28-year-old male Marfan patient (A, B); arachnodactyly withpositive 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 walkindependently or do so only for alimited period of time. Congenital hipdislocations and kyphosis may bepresent at birth, and spinal rigidity,scoliosis, and variable proximal con-tractures develop early in the course ofthe disease. The distal hypermobilitycan gradually give way to marked longfinger flexion contractures and tightAchilles tendons. Respiratory failurein the first or second decade is acommon cause of death unless treatedwith nocturnal respiratory support.Cardiac involvement has not beendocumented to date [van der Kooiet al., 2006].

In BM, muscle weakness has apredominant proximal pattern and amilder course. Although often mildlysymptomatic at birth or in infancy,symptoms typically manifest within thefirst or second decades, with frequently ahistory of neonatal hypotonia or torti-collis, delayedmotor milestones, or evendecreased fetal movements [Jobsis et al.,1996]. On the other hand some adult

patients are only verymildly affected andremain unaware of weakness [Lampeand Bushby, 2005]. In childhood, thecontractures may be preceded by hyper-mobility in the same joint, and be of astrikingly dynamic nature, appearing,and disappearing in various joints [Jobsiset al., 1996]. However, nearly all patientseventually show flexion contractures ofthe fingers, wrists, elbows, and ankles,and those may contribute to the degreeof overall disability as much as theassociated weakness. Strikingly, hyper-mobility of distal interphalangeal jointscan remain present (Fig. 5). Progressionis slow and occasionally results in thepatient being wheelchair-bound onlyafter 25–40 years [Lampe and Bushby,2005]. Respiratory failure can be part ofthe clinical spectrum and may evenoccur in ambulatory patients [Foleyet al., 2013]. To date, there has beenno evidence of cardiac involvement inBM [van der Kooi et al., 2006].

COL6-RD patients across thespectrum have distinct patterns ofmuscle involvement on MRI: the

vastus muscles often show a rim ofabnormal signal at the muscle periph-ery, with relative sparing of the centralpart (giving it a striped appearance),whereas the rectus femoris often showsa central area of abnormal signalknown as the “central shadow” phe-nomenon [Merlini et al., 2008]. At calflevel appearances are more variable buta significant proportion of patients withboth BM and UCMD also show a rimof abnormal signal at the periphery ofsoleus and gastrocnemii [Mercuri et al.,2005; B€onnemann et al., 2014].Muscle biopsy in UCMD patientsdemonstrates variable pathology, rang-ing from non-specific mild myopathicchanges in particular early in the courseto a more dystrophic appearance[Schessl et al., 2008]. Early findingsemphasize atrophic rather than dystro-phic changes. Additionally, variation infiber size, type 1 fiber predominance,an increase in endomysial connectivetissue, increased numbers of internalnuclei, and focal areas of necrosis, alongwith other evidence of muscle fiber

Figure 4. Severely affected 16-month-old male UCMD patient with joint hypermobility in hands (A), prominent calcaneus, and softskin (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 maleUCMDpatient (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 offibers containing fetal myosin can befound [Pepe et al., 2002]. Immuno-fluorence analysis for collagen VIlocalization in UCMD biopsies mayshow dramatic reduction or absence ofimmunofluorescence in severe reces-sive patients, or a mislocalization in thedominant negative cases. The latter isbest seen in staining protocols incor-porating double labeling of the base-ment membrane (using for instancecollagen IV or perlecan as a marker)along with collagen VI. In BM, musclebiopsy generally demonstrates a non-specific myopathy with fiber-size var-iation, few necrotic and regenerativefibers, and a mild increase in con-nective tissue. Standard collagen VIimmunohistochemistry is often unin-formative but may show mislocaliza-tion of collagen VI on double staining.In contrast, immunofluorescence label-ing of collagen VI in skin fibroblastcultures allows detecting even verysubtle alterations in collagen VI inCOL6-RD patient fibroblasts and is

highly predictive of COL6A mutations[Ishikawa et al., 2002; Lampe andBushby, 2005].

Collagen-6 look-like disordersMercuri et al. [2004] reported five caseswith congenital muscular dystrophy(CMD) associated with short stature,proximal contractures, rigidity of thespine, and distal joint hypermobility aswell as early respiratory failure and mildto moderate cognitive disability (CMDwith joint hyperlaxity). Hypermobilitywas present in distal fingers, toes, andankles but the expression of collagen VIwas confirmed to be normal on musclebiopsies in all five patients; in addition,in one informative family linkage to anyof the three COL6 gene loci could beexcluded [Mercuri et al., 2004].

In addition, Tetreault et al. [2006]reported 14 cases affected by autosomalrecessive congenital muscular dystrophy(CMD) with distal joint hypermobility.All patients presented with musclehypotonia at birth, generalized slowlyprogressive muscle weakness, and prox-

imal contractures predominantly affect-ing ankle, knees, and shoulders co-existing with distal hypermobility,mainly observed in the fingers, wrists,toes, elbows, and cervical spine. Nospinal rigidity was observed, but a mildto severe scoliosis was a frequent finding.Pulmonary vital capacity was usuallydiminished. CK was normal or onlymildly increased, with muscle biopsyshowing only non-specific myopathicfeatures. Genetic studies excluded mu-tations in the three genes coding forcollagen VI subunits and suggestedlinkage to a region on chromosome3p23–21.This linkage was not found incases with a similar phenotype in othercenters, indicating genetic heterogene-ity [Tetreault et al., 2006].

Collagen XII related myopathy/EDSoverlap syndromeRecent findings show that collagen XIImutations cause an EDS/myopathyoverlap syndrome associated withmuscle weakness and joint hypermobil-ity in mice and humans [Hicks et al.,

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


2014; Zou et al., 2014]. Collagen XII,the largest member of the fibril-associ-ated collagens with interrupted triplehelix (FACIT) family, assembles fromthree identical a-chains encoded by theCOL12A1 gene. Collagen XII binds tocollagen I-containing fibrils via itscollagenous domain, whereas its largenon-collagenous arms interact withother matrix proteins such as TNX. Indense connective tissues and bone,collagen XII is thought to regulateorganization and mechanical propertiesof collagen fibril bundles [Chiquet et al.,2014].

TheEDS/myopathyoverlappheno-type was observed in two non-relatedfamilieswithahomozygousrecessiveloss-of-function mutation and a de novodominant mutation in collagen XII(COL12A1), respectively [Zou et al.,2014]. The two siblings who werehomozygous for the loss-of-functionmutationshowedwidespreadjointhyper-mobility at birth combinedwith general-ized muscle weakness, proximal

contractures, and progressive kyphosco-liosis. Both siblings had mild facial weak-ness, high palate, and absent deep tendonreflexes.Motordevelopmentwasdelayed,both siblings were able to get into sittingposition, but unable to stand or ambulateindependently.CKandnerveconductionvelocitieswerenormal, themusclebiopsywas myopathic with variability in fiberdiameter, there was no evidence ofdegeneration or regeneration.

A de novo missense mutation inCOL12A1 was identified in a boy withweakness and joint hyperlaxity andproximal joint contractures, noted inthe first year of life. He had delayedmotor development and started walkingshortly before age 2 years. He had mildkyphosis; his contractures improvedover time. Muscle ultrasound of thethigh showed increased echogenicity.Nerve conduction studies were normal.Muscle biopsy was consistent with amyopathy, there was mild variability infiber diameter without evidence ofdegeneration of regeneration.

Around the same time, Hicks et al.[2014] identified dominantly actingCOL12A1 missense mutations infive individuals from two familieswith a clinical phenotype resemblingBethlem myopathy. Symptoms startedin childhood with generalized weak-ness with some improvement in ado-lescence followed by some progressionof weakness later in life. Patients hadpredominant proximal weakness, con-tractures, hypertrophic scarring, andjoint hyperlaxity. Pulmonary functiontesting was reduced in some. CK levelsranged from normal to moderatelyelevated (1800U/L). MRI imagingshowed severe atrophy of the rectusfemoris and selective involvement ofthe femoral quadriceps, adductor andthe medial gastrocnemium. A centralshadow, typically seen in COL6-RDwas not observed. One of theCOL12A1 mutation identified was asubstitution of a conserved glycineresidue in the Gly-X-Y motif of thetriple helix domain, a common hotspot


for mutations in collagen disorders ingeneral [Butterfield et al., 2013].Dermal fibroblasts showed intracellularretention of Collagen XII and a subtlereduction in TNX [Hicks et al., 2014].A mouse model with inactivation ofthe COL12A1 gene shows decreasedgrip strength, delay in fiber-typetransition and deficiency in passiveforce generation. Corresponding tostudies of TNX deficiency, these ob-servations indicate a role for a matrix-based passive force-transducing elasticelement in the evolution of weaknessin these disorders. In general, the EDS/myopathy overlap phenotype empha-sizes the emerging importance of themuscle ECM in the pathogenesis ofmuscle disease [Voermans et al., 2008a;Zou et al., 2014].

Myopathies With Striking JointHypermobility

RYR1 and SEPN1 related myopathiesThe congenital myopathies with cores—Multi-minicore Disease (MmD) andCentral Core Disease (CCD)—areamong the most common congenitalmyopathies [Jungbluth et al., 2011;Maggi et al., 2013]. They are clinicallyand genetically heterogeneous and asso-ciated with variable characteristic ab-normalities on oxidative stains that giverise to the cores. MmD and CCD due tothe skeletal muscle ryanodine receptor(RyR1) gene (RYR1) mutations may beassociated with marked generalizedhypermobility not infrequently result-ing in joint dislocations [Gamble et al.,1988], whereas MmD due to recessivemutations in the selenoprotein N(SEPN1) gene often features distalhypermobility in the upper limbs andmay give rise to “marfanoid” features.

The skeletal muscle RyR1 plays acrucial role in excitation-contraction(E–C) coupling by releasing Ca2þ fromsarcoplasmic reticulum (SR) stores. Twomajor hypotheses have been formulatedconcerning the pathogenesis of RYR1-related core myopathies, depletion ofsarcoplasmic reticulum calcium storeswith resulting increase in cytosoliccalcium levels (“leaky channel” hypoth-esis), and disturbance of excitation-

contraction coupling (E–C uncouplinghypothesis) [Treves et al., 2008]. Whilstprimary RyR1 malfunction seems to bethe main molecular mechanism under-lying dominantly inherited RYR1-re-lated myopathies, recessive RYR1-related myopathies appear to be morevariable with loss of calcium conduc-tance, probably mediated by markedRyR1 protein reduction, a relativelycommon observation [Wilmshurst et al.,2010; Klein et al., 2012; Zhou et al.,2013].

Selenoprotein-N, is a glycoproteinlocalized in the endoplasmic reticulumand involved in various antioxidantdefense systems and several metabolicpathways. SEPN1 is highly expressedduring development [Castets et al.,2009] with a more specific role inmyogenesis suggested by abundant ex-pression in fetal muscle precursor cellsand the observation of disturbed satellitecell function in the sepn1 �/� knock-out mouse [Castets et al., 2011]. Theclose functional and spatial relationshipbetween selenoprotein N and RyR1reported in animal models [Deniziaket al., 2007] and a structural motif similarto those found in calcium-bindingproteins [Moghadaszadeh et al., 2001]suggest a role in calcium homeostasis,suggesting a molecular basis for theclinico-pathological overlap betweenSEPN1- andRYR1-relatedmyopathies.

Multiminicore disease (MmD)The “classic” (but probably not mostcommon) phenotype of MmD is asso-ciated with autosomal-recessive muta-tions in SEPN1 and is characterized bypredominantly axial muscle weakness,spinal rigidity, early scoliosis, and respi-ratory impairment. Some patients mayexhibit a “marfanoid” habitus witharachnodactyly but ocular and cardio-vascular features ofMarfan syndrome aretypically absent. In contrast, autosomal-recessive mutations in the skeletalmuscle ryanodine receptor (RYR1)gene have been associated with a widerrange of clinical features comprisingexternal ophthalmoplegia, distal weak-ness and wasting or predominant hipgirdle involvement resembling CCD[Ferreiro et al., 2012]. In the latter

forms, there may also be a histopatho-logic continuum with CCD due todominant RYR1 mutations, reflectingthe common genetic background [Zhouet al., 2007]. Although multi minicoresare a classic pathophysiological findingofRYR1 and SEPN1-related myopathy,biopsies can show a spectrum of findingsconsistent with congenital myopathies[Bharucha-Goebel et al., 2013].

All phenotypes may be associatedwith contractures (either arthrogryposisin early-onset forms or predominantAchilles tendon tightness of later onsetin milder cases) and/or joint hyper-mobility, mostly pronounced in thehands (Fig. 6). If present, distal hyper-mobility tends to be more severe inpatients with recessive RYR1 mutationsthan in those with SEPN1 mutations,but may be present in both and is oftenassociated with atrophy of intrinsic handmuscles, hand hypotonia, and moderateweakness. Patellar and knee dislocationsmay be a feature [Gamble et al., 1988].In the majority of patients, weakness isstatic or only slowly progressive, withthe degree of respiratory impairmentbeing the most important prognosticfactor particularly in SEPN1-relatedforms.

The diagnosis of MmD is basedon the presence of suggestive clinicalfeatures and the finding of multiplecores on histochemical muscle biopsystains. Muscle MRI may aid genetictesting as patterns of selective muscleinvolvement are distinct dependingon whether the mutations are in theSEPN1 [Mercuri et al., 2010] or theRYR1 gene [Jungbluth et al., 2004;Klein et al., 2011]. Mutational analysisof the RYR1 or the SEPN1 gene willbe required to confirm the geneticdiagnosis. Management is mainlysupportive and in particular has toaddress the risk of marked respiratoryimpairment in SEPN1-related MmDand the possibility of malignant hy-perthermia susceptibility in RYR1-related forms for the patient andcarrier relatives.

Central core disease (CCD)Central core disease (CCD) is causedmainly by dominant but also less

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 (metacarpophalangealjoints) 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-tions and typically presents in infancywith hypotonia or developmental delayand predominantly hip girdle and axialmuscle weakness. Facial, bulbar, andrespiratory involvement is minimal orabsent. Progression is slow and almost allpatients achieve the ability to walkindependently, except the most severeneonatal cases, and those with verysevere orthopedic complications; how-ever, marked clinical variability, evenwithin the same family, has beenreported. Orthopedic complicationsare common in CCD and comprisecongenital dislocation of hips, scoliosis,and foot deformities including talipesequinovarus and pes planus [Gambleet al., 1988]. Many patients have strikingjoint hypermobility, occasionally asso-ciated with patellar instability. Achillestendon tightness occurs but other con-tractures are rare.

The term CCD refers to thecharacteristic, well-defined reduction

of oxidative enzyme activity in thecenter of the muscle fiber reflectingthe absence of mitochondria in this area.Serum CK is usually normal in CCDbut may occasionally be mildly elevated,mainly in patients with additional exer-tional myalgia and muscle cramps.Muscle ultrasound shows a strikingincrease in echo intensity but relativesparing of the rectus femoris within thethigh, corresponding to a similarlyconsistent pattern of selective muscleinvolvement on muscle MRI, whichmay assist in differentiating RYR1-related CCD from other myopathieswith overlapping histopathologicalfeatures.

Genetic diagnosis is established bysequencing of the RYR1 gene, bearingin mind that not infrequently twodominant RYR1 mutations may berunning in the same family and thatRYR1 variants of uncertain significanceare not uncommon [Klein et al., 2012].Accurate genetic diagnosis and familial

segregation testing is of importance soappropriate precautions can be taken formalignant hyperthermia. The functionalconsequences of autosomal-recessiveand dominant RYR1 mutations havebeen outlined in the paragraph onMmD above.

Other core myopathiesCores on muscle biopsy are a non-specific finding and apart from SEPN1-and RYR1-related myopathies havebeen recognized in a number of othergenetic backgrounds. The most com-mon forms among this group areMYH7-related MmD [Cullup et al.,2012] often associated with distal con-tractures as seen in other MYH7-relatedmyopathies [Lamont et al., 2014] andTTN-related core myopathies [Chau-veau et al., 2014] with highly variableclinic-pathological presentation, includ-ing pronounced distal hypermobility[Oates et al., 2014]. In contrast to theSEPN1- and RYR1-related forms,


primary cardiac involvement is verycommon in MYH7- and TTN-relatedcore myopathies [Romero et al., 2014].

Limb girdle muscular dystrophy 2 E withjoint hyperlaxity and contractures(LGMD2E þ)Kaindl et al. reported a family with asevere and progressive limb-girdle mus-cular dystrophy with joint hypermobil-ity, contractures, and cardiorespiratorysymptoms comprising chest pain, tachy-cardia, arrhythmias, and dyspnea [Kaindlet al., 2005]. Muscle weakness presentedin the first decade, with delayed motormilestones and a progressive Duchenne-like muscular dystrophy including facialweakness, resulting in loss of ambulationaround the age of 10 years. Hyper-mobility was most pronounced inproximal interphalangeal joints and inmetacarpophalangeal joints, contrastingwith contractures in the distal interpha-langeal joints and, to a lesser extent, inknees and elbows. CK levels wereelevated to 50 times of normal values.Genetic analysis revealed a homozygousmicrodeletion of approximately 400KBon chromosome 4q11-q12, a regioncontaining the b-sarcoglycan gene,whose pathogenetic role in this con-dition was further supported by my-opathic changes on muscle biopsy andimmunohistochemical studies showingcomplete absence of sarcoglycan A andB immunoreactivity. Some degree ofjoint hypermobility in these patientsmay be related to the muscle weaknessand hypotonia. However, since b-sarcoglycan is not expressed in tendonsor connective tissue, and hypermobilityis not a common feature in otherpatients with b-sarcoglycan mutations,joint hypermobility, and contracturesmay also result from a contiguous genesyndrome.

CONCLUDING REMARKS

This review has focused on the overlapbetween connective tissue disorders andthe congenital myopathies associatedwith joint hypermobility and skinfeatures, emphasizing that some of theprimary myopathies are an importantconsideration in the differential diag-

nosis of generalized joint hypermobility.Findings of joint hypermobility andmuscle involvement should be evaluatedin context of the patient’s overallphenotypic presentation to allow foraccurate diagnosis.

The pattern of distribution of jointhypermobility, its dynamic nature aswell as the co-existence of hypermo-bility with dislocations and contracturesoccur both in the myopathies andinherited connective tissue disordersdiscussed. Congenital myopathies aremore often accompanied by distal ratherthan generalized hypermobility (distaland proximal interphalangeal and meta-carpophalangeal joints of hands, distalinterphalangeal joints of feet, wrists, andankles), and one frequently finds con-genital hip dislocation (in particular inCOL6 and RYR1 related conditions.Another very distinctive feature inCOL6 related dystrophies is a coex-istence of pronounced distal joint hyper-mobility with prominent andprogressive joint contractures, whichtypically occur in the shoulders, elbows,hips, knees, and Achilles tendons, butalso in the finger flexors, so that thereboth evidence of joint hyper mobility aswell as contractures in the hands andfingers.

We expect that this reviewwill assistclinical geneticists and other specialistswithout primary neuromuscular exper-tise to better recognize these myopathiesamong patients presenting with jointhypermobility and muscle weakness,which is of importance for the clinicalassessment but also (and increasingly) forthe interpretation of whole exomesequencing results of uncertainsignificance.

REFERENCES

Baumann M, Giunta C, Krabichler B,R€uschendorf F, Zoppi N, Colombi M,Bittner RE, Quijano-Roy S, Muntoni F,Cirak S, Schreiber G, Zou Y, Hu Y, RomeroNB, Carlier RY, Amberger A, DeutschmannA, Straub V, Rohrbach M, Steinmann B,Rost�asy K, Karall D, B€onnemann CG,Zschocke J, Fauth C. 2012. Mutations inFKBP14 cause a variant of Ehlers-Danlossyndrome with progressive kyphoscoliosis,myopathy, and hearing loss. Am J HumGenet 90:201–16.

B€onnemann CG, Brockmann K, Hanefeld F.2003. Muscle ultrasound in Bethlem myo-pathy. Neuropediatrics 34:335–336.

B€onnemann CG. 2011. The collagen VI-relatedmyopathies: muscle meets its matrix. NatRev Neurol 7:379–390.

Behan WM, Longman C, Petty RK, Comeglio P,Child AH, Boxer M, Foskett P, HarrimanDG. 2003. Muscle fibrillin deficiency inMarfan’s syndrome myopathy. J NeurolNeurosurg Psychiatry 74:633–638.

Beighton P, De Paepe A, Steinmann B, TsipourasP, Wenstrup RJ. 1998. Ehlers-Danlos syn-dromes: revised nosology, Villefranche,1997. Ehlers-Danlos National Foundation(USA) and Ehlers-Danlos Support Group(UK). Am J Med Genet 77:31–37.

Bertin P, Treves R, Julia A, Gaillard S, sproges-Gotteron R. 1989. Ehlers-Danlos syn-drome, clotting disorders and musculardystrophy. Ann Rheum Dis 48:953–956.

Bertoli-Avella AM, Gillis E, Morisaki H, Verha-gen JMA, de Graaf BM, van de Beek G,Gallo E, Kruithof BPT, Venselaar H, MyersL, Laga S, Doyle AJ, Oswald G, vanCappellen GWA, Yamanaka I, van derHelm RM, Beverloo B, de Klein A, PardoL, Lammens M, Evers C, Devriendt K,Dumoulein M, Timmermans J, Bruggen-wirth HT, Verheijen F, Rodrigus I, BaynamG, Kempers M, Saenen J, Van Craenen-broeck EM, Minatoya K, Matsukawa R,Tsukube T, Kubo N, Hofstra R, GoumansMJ, Bekkers Roos-Hesselink, van de LaarIMBH, Dietz HC, Van Laer L, Morisaki T,WesselsMW, Loeys BL. 2014.Mutations in aTGFb ligand, TGFB3, cause syndromicaortic aneurysms and dissections. JACC inrevision.

Bharucha-Goebel DX, Santi M, Medne L,Zukosky K, Dastgir J, Shieh PB, WinderT, Tennekoon G, Finkel RS, Dowling JJ,Monnier N, B€onnemann CG. 2013. Severecongenital RYR1-associated myopathy:The expanding clinicopathologic andgenetic spectrum. Neurology 80:1584–1589.

Bilkey WJ, Baxter TL, Kottke FJ, Mundale MO.1981. Muscle formation in Ehlers-Danlossyndrome. Arch Phys Med Rehabil 62:444–448.

B€onnemann C, Voermans NC. 2012. Chapter 70:ECM-related myopathies and musculardystrophies. In: Hill J, editor. Fundamentalbiology and mechanisms of disease.pp 979–993.

B€onnemann CG, Wang CH, Quijano-Roy S,Deconinck N, Bertini E, Ferreiro A,Muntoni F7, Sewry C, B�eroud C, MathewsKD, Moore SA, Bellini J, Rutkowski A,North KN. Members of InternationalStandard of Care Committee for CongenitalMuscular Dystrophies. 2014. Diagnosticapproach to the congenital muscular dystro-phies. Neuromuscul Disord 24:289–311.

Bosman FT, Stamenkovic I. 2003. Functionalstructure and composition of the extracel-lular matrix. J Pathol 200:423–428.

Brinckmann J, AScil Y, Feshchenko S, Katzer E,Brenner R, Kulozik A, K€ugler S. 1998.Ehlers-Danlos syndrome type VI: lysylhydroxylase deficiency due to a novel pointmutation (W612C). Arch Dermatol Res290:181–6.


Bulbena A, Duro JC, Porta M, Faus S, Vallescar R,Martin-Santos R. 1992. Clinical assessmentof hypermobility of joints: Assemblingcriteria. J Rheumatol 19:115–122.

Bushby KM, Collins J, Hicks D. 2014. Collagentype VI myopathies. Adv Exp Med Biol802:185–199.

Butterfield RJ1, Foley AR, Dastgir J, Asman S,Dunn DM, Zou Y, Hu Y, Donkervoort S,Flanigan KM, Swoboda KJ, Winder TL,Weiss RB, B€onnemann CG. 2013. Positionof glycine substitutions in the triple helix ofCOL6A1, COL6A2, and COL6A3 iscorrelated with severity and mode ofinheritance in collagen VI myopathies.Hum Mutat 34:1558–1567.

Carvalho HF, Felisbino SL, Keene DR, Vogel KG.2006. Identification, content, and distribu-tion of type VI collagen in bovine tendons.Cell Tissue Res 325:315–324.

Castets P, Maugenre S, Gartioux C, RederstorffM, Krol A, Lescure A, Tajbakhsh S,Allamand V, Guicheney P. 2009. Seleno-protein N is dynamically expressed duringmouse development and detected early inmuscle precursors. BMC Dev Biol 9:46.

Castets P, Bertrand AT, Beuvin M, Ferry A, LeGrand F, Castets M, Chazot G, RederstorffM, Krol A, Lescure A, Romero NB,Guicheney P, Allamand V. 2011. Satellitecell loss and impaired muscle regeneration inselenoprotein N deficiency. Hum MolGenet 20:694–704.

Castets P, Lescure A, Guicheney P, Allamand V.2012. Selenoprotein N in skeletal muscle:From diseases to function. J Mol Med (Berl)90:1095–1107.

Castori M, Voermans NC. 2014. Neurologicalmanifestations of Ehlers-Danlos syndrome-(s): A review. Iran J Neurol 13:190–208.

Chauveau C, Bonnemann CG, Julien C, Kho AL,Marks H, Talim B, Maury P, Arne-Bes MC,Uro-Coste E, Alexandrovich A, Vihola A,Schafer S, Kaufmann B, Medne L, H€ubnerN, Foley AR, Santi M, Udd B, Topaloglu H,Moore SA, Gotthardt M, Samuels ME,Gautel M, Ferreiro A. 2014. Recessive TTNtruncating mutations define novel forms ofcore myopathy with heart disease. HumMolGenet 23:980–991.

Chiquet M, Birk DE, Bonnemann CG, KochM. 2014. Collagen XII: Protecting boneand muscle integrity by organizingcollagen fibrils. Int J Biochem Cell Biol53:51–54.

Cullup T, Lamont PJ, Cirak S, Damian MS,WallefeldW, GoodingR, Tan SV, Sheehan J,Muntoni F, Abbs S, Sewry CA, Dubowitz V,Laing NG, Jungbluth H. 2012. Mutations inMYH7 cause Multi-minicore Disease(MmD) with variable cardiac involvement.Neuromuscul Disord 22:1096–1104.

Deniziak M, Thisse C, Rederstorff M, HindelangC, Thisse B, Lescure A. 2007. Loss ofselenoprotein N function causes disruptionof muscle architecture in the zebrafishembryo. Exp Cell Res 313:156–167.

D€undar M, M€uller T, Zhang Q, Pan J, SteinmannB, Vodopiutz J, Gruber R, Sonoda T,Krabichler B, Utermann G, Baenziger JU,Zhang L, Janecke AR. 2009. Loss ofdermatan-4-sulfotransferase 1 function re-sults in adducted thumb-clubfoot syndrome.Am J Hum Genet 85:873–82.

Erkula G, Sponseller PD, Paulsen LC, Oswald GL,Loeys BL, Dietz HC. 2010. Musculoskeletalfindings of Loeys-Dietz syndrome. J BoneJoint Surg Am 92:1876–1883.

Ferreiro A, Quijano-Roy S, Pichereau C, Mog-hadaszadeh B, Goemans N, B€onnemann C,Jungbluth H, Straub V, Villanova M, LeroyJP, Romero NB, Martin JJ, Muntoni F, VoitT, Estournet B, Richard P, FardeauM, FoleyAR, Bonnemann CG. 2012. Spontaneouskeloid formation in patients with Bethlemmyopathy. Neurology 79:2158.

Foley AR, Quijano-Roy S, Collins J, Straub V,McCallum M, Deconinck N, Mercuri E,Pane M, D’Amico A, Bertini E, North K,RyanMM,Richard P, Allamand V, Hicks D,Lamand�e S, Hu Y, Gualandi F, Auh S,Muntoni F, B€onnemann CG. 2013. Naturalhistory of pulmonary function in collagenVI-related myopathies. Brain 136:3625–3633.

Gamble JG, Rinsky LA, Lee JH. 1988. Ortho-paedic aspects of central core disease. J BoneJoint Surg Am 70:1061–1066.

Gerrits KH, Voermans NC, de Haan A, vanEngelen BG. 2013. Neuromuscular proper-ties of the thigh muscles in patients withEhlers-Danlos syndrome. Muscle Nerve47:96–104.

Grahame R, Pyeritz RE. 1995. The Marfansyndrome: Joint and skin manifestations areprevalent and correlated. Br J Rheumatol34:126–131.

Grumati P, Coletto L, Sabatelli P, Cescon M,Angelin A, Bertaggia E, Blaauw B, UrciuoloA, Tiepolo T, Merlini L, Maraldi NM,Bernardi P, Sandri M, Bonaldo P. 2010.Autophagy is defective in collagen VImuscular dystrophies, and its reactivationrescues myofiber degeneration. Nat Med16:1313–1320.

Guicheney P. 2002. Mutations of the selenopro-tein N gene, which is implicated in rigidspine muscular dystrophy, cause the classicalphenotype of multiminicore disease: Re-assessing the nosology of early-onset myo-pathies. Am J Hum Genet 71:739–749.

Ha VT, Marshall MK, Elsas LJ, Pinnell SR,Yeowell HN. 1994. A patient with Ehlers-Danlos syndrome type VI is a compoundheterozygote for mutations in the lysylhydroxylase gene. J Clin Invest 93:1716–21.

Hicks D, Farsani GT, Laval S, Collins J, Sarkozy A,Martoni E, Shah A, Zou Y, Koch M,B€onnemann CG, Roberts M, Lochm€ullerH, Bushby K, Straub V. 2014. Mutations inthe collagen XII gene define a new form ofextracellular matrix-related myopathy. HumMol Genet 23:2353–2363.

Hubmacher D, Apte SS. 2013. The biology of theextracellular matrix: Novel insights. CurrOpin Rheumatol 25:65–70.

Huijing PA, Voermans NC, Baan GC, Buse TE,van Engelen BG, de Haan A. 2010. Musclecharacteristics and altered myofascial forcetransmission in tenascin-X-deficient mice, amouse model of Ehlers-Danlos syndrome. JAppl Physiol 109:986–995.

Ishikawa H, Sugie K, Murayama K, Ito M,Minami N, Nishino I, Nonaka I. 2002.Ullrich disease: collagen VI deficiency: EMsuggests a new basis for muscular weakness.Neurology 59:920–923.

Jobsis GJ, Keizers H, Vreijling JP, de VM Speer,Wolterman RA, Baas F, Bolhuis PA. 1996.Type VI collagen mutations in Bethlemmyopathy, an autosomal dominant myopa-thy with contractures. Nat Genet 14:113–115.

Jones KB, Sponseller PD, Erkula G, Sakai L,Ramirez F, Dietz HC, 3rd, Kost-Byerly S,Bridwell KH, Sandell L. 2007. Symposiumon the musculoskeletal aspects of Marfansyndrome: Meeting report and state of thescience. J Orthop Res 25:413–422.

Jungbluth H, M€uller CR, Halliger-Keller B,Brockington M, Brown SC, Feng L,Chattopadhyay A, Mercuri E, Manzur AY,Ferreiro A, Laing NG, Davis MR, RoperHP, Dubowitz V, Bydder G, Sewry CA,Muntoni F. 2002. Autosomal recessiveinheritance of RYR1 mutations in a con-genital myopathy with cores. Neurology59:284–287.

Jungbluth H, Davis MR, M€uller C, Counsell S,Allsop J, Chattopadhyay A, Messina S,Mercuri E, Laing NG, Sewry CA, BydderG, Muntoni F. 2004. Magnetic resonanceimaging of muscle in congenital myopathiesassociated with RYR1 mutations. Neuro-muscul Disord 14:785–790.

Jungbluth H, Zhou H, Sewry CA, Robb S, TrevesS, Bitoun M, Guicheney P, Buj-Bello A,Bonnemann C, Muntoni F. 2007. Centro-nuclear myopathy due to a de novodominant mutation in the skeletal muscleryanodine receptor (RYR1) gene. Neuro-muscul Disord 17:338–345.

Jungbluth H. 2007. Multi-minicore Disease.Orphanet J Rare Dis 2:31.

Jungbluth H, Sewry CA, Muntoni F. 2011. Coremyopathies. Semin Pediatr Neurol 18:239–249.

Kaindl AM, Jakubiczka S, Lucke T, Bartsch O,Weis J, Stoltenburg-Didinger G, Aksu F,Oexle K, Koehler K, Huebner A. 2005.Homozygous microdeletion of chromo-some 4q11-q12 causes severe limb-girdlemuscular dystrophy type 2E with jointhyperlaxity and contractures. Hum Mutat26:279–280.

Klein A, Jungbluth H, Clement E, Lillis S, Abbs S,Munot P, Pane M, Wraige E, Schara U,Straub V, Mercuri E, Muntoni F. 2011.Muscle magnetic resonance imaging incongenital myopathies due to ryanodinereceptor type 1 gene mutations. ArchNeurol 68:1171–1179.

Klein A, Lillis S, Munteanu I, Scoto M, Zhou H,Quinlivan R, Straub V, Manzur AY, RoperH, Jeannet PY, Rakowicz W, Jones DH,Jensen UB, Wraige E, Trump N, Schara U,Lochmuller H, Sarkozy A, Kingston H,Norwood F, Damian M, Kirschner J, Long-man C, Roberts M, Auer-Grumbach M,Hughes I, Bushby K, Sewry C, Robb S,Abbs S, Jungbluth H, Muntoni F. 2012.Clinical and genetic findings in a largecohort of patients with ryanodine receptor 1gene-associated myopathies. Hum Mutat33:981–988.

van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM,Hoedemaekers YM, Willemsen R, Sever-ijnen LA, Venselaar H, Vriend G, PattynamaPM, Coll�eeM,Majoor-Krakauer D, Polder-mans D, Frohn-Mulder IM, Micha D,


Timmermans J, Hilhorst-Hofstee Y,Bierma-Zeinstra SM, Willems PJ, KrosJM, Oei EH, Oostra BA, Wessels MW,Bertoli-Avella AM. 2011. Mutations inSMAD3 cause a syndromic form of aorticaneurysms and dissections with early-onsetosteoarthritis. Nat Genet. 43:121–126.

Lamont PJ, Wallefeld W, Hilton-Jones D, Udd B,Argov Z, Barboi AC, Bonneman C, BoycottKM, Bushby K, Connolly AM, Davies N,Beggs AH, Cox GF, Dastgir J, DeChene ET,Gooding R, JungbluthH,Muelas N, PalmioJ, Penttil€a S, Schmedding E, Suominen T,Straub V, Staples C, Van den Bergh PY,Vilchez JJ, Wagner KR, Wheeler PG,Wraige E, Laing NG. 2014. Novel muta-tions widen the phenotypic spectrum ofslow skeletal/b-cardiac myosin (MYH7)distal myopathy. Hum Mutat 35:868–879.

Lampe AK, Bushby KM. 2005. Collagen VIrelated muscle disorders. J Med Genet42:673–685.

Lindsay ME, Schepers D, Bolar NA, Doyle JJ,Gallo E, Fert-Bober J, KempersMJ, FishmanEK, Chen Y, Myers L, Bjeda D, Oswald G,Elias AF, Levy HP, Anderlid BM, Yang MH,Bongers EM, Timmermans J, BravermanAC, CanhamN,Mortier GR, Brunner HG,Byers PH, Van Eyk J, Van Laer L, DietzHC, .2012. Loss-of-functionmutations in TGFB2cause a syndromic presentation of thoracicaortic aneurysm. Nat Genet 44:922–927.

Loeys BL, Chen J, Neptune ER, Judge DP,Podowski M, Holm T, Meyers J, Leitch CC,Katsanis N, Sharifi N, Xu FL, Myers LA,Spevak PJ, Cameron DE, De Backer J,Hellemans J, Chen Y, Davis EC, Webb CL,Kress W, Coucke P, Rifkin DB, De PaepeAM, Dietz HC. 2005. A syndrome of alteredcardiovascular, craniofacial, neurocognitiveand skeletal development caused by muta-tions in TGFBR1 or TGFBR2. Nat Genet37:275–281.

Loeys BL, Dietz HC, Braverman AC, CallewaertBL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, MilewiczDM, Pyeritz RE, Sponseller PD, Words-worth P, De Paepe AM. 2010. The revisedGhent nosology for the Marfan syndrome. JMed Genet 47:476–485.

MacCarrick G, Black JH, 3rd, Bowdin S, El-Hamamsy I, Frischmeyer-Guerrerio PA,Guerrerio AL, Sponseller PD, Loeys B,Dietz HC, 3rd. 2014. Loeys-Dietz syn-drome: A primer for diagnosis and manage-ment. Genet Med 16:576–587.

Maggi L, Scoto M, Cirak S, Robb SA, Klein A,Lillis S, Cullup T, Feng L,Manzur AY, SewryCA, Abbs S, Jungbluth H, Muntoni F. 2013.Congenital myopathies—clinical featuresand frequency of individual subtypes diag-nosed over a 5-year period in the UnitedKingdom. Neuromuscul Disord 23:195–205.

Malfait F, Symoens S, Goemans N, Gyftodimou Y,Holmberg E, L�opez-Gonz�alez V,Mortier G,Nampoothiri S, Petersen MB, De Paepe A.2013. Helical mutations in type I collagenthat affect the processing of the amino-propeptide result in an Osteogenesis Im-perfecta/Ehlers-Danlos Syndrome overlapsyndrome. Orphanet J Rare Dis 8:78.

Mercuri E, Yuva Y, Brown SC, Brockington M,Kinali M, Jungbluth H, Feng L, Sewry CA,

Muntoni F. 2002. Collagen VI involvementin Ullrich syndrome: A clinical, genetic, andimmunohistochemical study. Neurology58:1354–1359.

Mercuri E, Lampe A, Straub V, Yuva Y, LongmanC, Wright M, Brown S, Sewry C, Bonne-mann C, Kinali M, Brockington M, HausserI, Hilton JD, Voit T, Bushby K, Muntoni F.2004. Congenital muscular dystrophy withshort stature, proximal contractures anddistal laxity. Neuropediatrics 35:224–229.

Mercuri E, Lampe A, Allsop J, Knight R, Pane M,KinaliM, Bonnemann C, Flanigan K, LapiniI, Bushby K, Pepe G, Muntoni F. 2005.Muscle MRI in Ullrich congenital musculardystrophy and Bethlem myopathy. Neuro-muscul Disord 15:303–310.

Mercuri E, Clements E, Offiah A, Pichiecchio A,Vasco G, Bianco F, Berardinelli A, ManzurA, Pane M, Messina S, Gualandi F, Ricci E,Rutherford M, Muntoni F. 2010. Musclemagnetic resonance imaging involvement inmuscular dystrophies with rigidity of thespine. Ann Neurol 67:201–208.

Merlini L, Martoni E, Grumati P, Sabatelli P,Squarzoni S, Urciuolo A, Ferlini A, Gua-landi F, Bonaldo P. 2008. Autosomalrecessive myosclerosis myopathy is a collagenVI disorder. Neurology 71:1245–1253.

Miyake N, Kosho T, Mizumoto S, Furuichi T,Hatamochi A, Nagashima Y, Arai E,Takahashi K, Kawamura R, Wakui K,Takahashi J, Kato H, Yasui H, Ishida T,Ohashi H,Nishimura G, ShiinaM, Saitsu H,Tsurusaki Y, Doi H, Fukushima Y, IkegawaS, Yamada S, Sugahara K, Matsumoto N.2010. Loss-of-function mutations ofCHST14 in a new type of Ehlers-Danlossyndrome. Hum Mutat 31:966–74.

Moghadaszadeh B, Petit N, Jaillard C, Brock-ingtonM, Quijano Roy, Merlini S, RomeroL, Estournet N, Desguerre B, Chaigne I,Muntoni D, Topaloglu F, Guicheney H.2001. Mutations in SEPN1 cause congenitalmuscular dystrophy with spinal rigidity andrestrictive respiratory syndrome. Nat Genet29:17–18.

M€uller T, Mizumoto S, Suresh I, Komatsu Y,Vodopiutz J, Dundar M, Straub V, LingenhelA, Melmer A, Lechner S, Zschocke J,Sugahara K, Janecke AR. 2013. Loss ofdermatan sulfate epimerase (DSE) functionresults in musculocontractural Ehlers-Dan-los syndrome. HumMol Genet 22:3761–72.

Murray ML, Yang M, Fauth C, Byers PH. 2014.FKBP14-related Ehlers-Danlos syndrome:expansion of the phenotype to includevascular complications. Am J Med GenetA 164A:1750–5.

Nuytinck L, Freund M, Lagae L, Pierard GE,Hermanns-Le T, De Paepe A. 2000.Classical Ehlers-Danlos syndrome causedby a mutation in type I collagen. Am JHum Genet 66:1398–1402.

Oates EC, Yau KS, Charlton A, Brammah S,Farrar MA, Sampaio H, Lamont PL, MowatD. 2014. G.P.35: Analysis of a large patientcohort with recessive truncating TTNmutations reveals novel clinical featuresand a diverse range of muscle pathologies.Neuromusc Disord 24:805.

Ottenheijm CA, Voermans NC, Hudson BD,Irving T, Stienen GJ, van Engelen BG,Granzier H. 2012. Titin-based stiffening of

muscle fibers in Ehlers-Danlos Syndrome. JAppl Physiol 112:1157–1165.

Palmeri S, Mari F, Meloni I, Malandrini A, ArianiF, Villanova M, Pompilio A, Schwarze U,Byers PH, Renieri A. 2003. Neurologicalpresentation of Ehlers-Danlos syndrometype IV in a family with parental mosaicism.Clin Genet 63:510–515.

Penisson-Besnier I, Allamand V, Beurrier P,Martin L, Schalkwijk J, van Vlijmen-Willems I, Gartioux C, Malfait F, Syx D,Macchi L, Marcorelles P, Arbeille B, Crou�eA, De Paepe A, Dubas F. 2013. Compoundheterozygous mutations of the TNXB genecause primary myopathy. NeuromusculDisord 23:664–669.

Pepe G, de VM Bertini, Bushby K, Vanegas OC,Chu ML, Lattanzi G, Merlini L, Muntoni F,Urtizberea A. 2002. Bethlem myopathy(BETHLEM) 86th ENMC internationalworkshop, 10–11 November 2000, Naar-den, The Netherlands. Neuromuscul Disord12:296–305.

Romero NB, Xie T, Malfatti E, Schaeffer U,B€ohm J, Wu B, Xu F, Boucebci S, Mathis S,Neau JP, Monnier N, Fardeau M, Laporte J.2014. Autosomal dominant eccentric coredisease caused by a heterozygous mutation inthe MYH7 gene. J Neurol NeurosurgPsychiatry 85:1149–1152.

Scacheri PC, Gillanders EM, Subramony SH,Vedanarayanan V, Crowe CA, Thakore N,Bingler M, Hoffman EP. 2002. Novelmutations in collagen VI genes: Expansionof the Bethlem myopathy phenotype. Neu-rology 58:593–602.

Schalkwijk J, ZweersMC, Steijlen PM,DeanWB,Taylor G, van V I, van HBMiller, Bristow J.2001. A recessive form of the Ehlers-Danlossyndrome caused by tenascin-X deficiency.N Engl J Med 345:1167–1175.

Schessl J, Goemans NM,Magold AI, ZouY,HuY,Kirschner J, Sciot R, BonnemannCG. 2008.Predominant fiber atrophy and fiber typedisproportion in early ullrich disease.MuscleNerve 38:1184–1191.

Shimizu K, Okamoto N, Miyake N, Taira K, SatoY, Matsuda K, Akimaru N, Ohashi H,Wakui K, Fukushima Y, Matsumoto N,Kosho T. 2011. Delineation of dermatan 4-O-sulfotransferase 1 deficient Ehlers-Danlossyndrome: observation of two additionalpatients and comprehensive review of 20reported patients. Am J Med Genet A155A:1949–58.

Sobey G. 2014. Ehlers-Danlos syndrome: How todiagnose and when to perform genetic tests.Arch Dis Child Jul 3 Epub ahead of print.

Steinmann B, Royce PM, Superti-Furga A. 2002.The Ehlers-Danlos syndromes. In: Stein-mann B Royce PM, editors. Connectivetissue and its heritable disorders. Wiley-LissInc. Wilmington, DE 19801 p 431–523.

Tetreault M, Duquette A, Thiffault I, Bherer C,Jarry J, Loisel L, Banwell B, D’Anjou G,Mathieu J, Robitaille Y, et al. 2006. A newform of congenital muscular dystrophy withjoint hyperlaxity maps to 3 p23–21. Brain129:2077–2084.

Treves S, Jungbluth H, Muntoni F, Zorzato F.2008. Congenital muscle disorders withcores: The ryanodine receptor calciumchannel paradigm. Curr Opin Pharmacol8:319–326.


van der Kooi AJ, de VoogtWG, Bertini E, MerliniL, Talim FB, Ben Yaou, Urtziberea R, deVisser A. 2006. Cardiac and pulmonaryinvestigations in Bethlem myopathy. ArchNeurol 63:1617–1621.

Voermans NC, Altenburg TM, Hamel BC, deHaan A, van Engelen BG. 2007a. Reducedquantitative muscle function in tenascin-Xdeficient Ehlers-Danlos patients. Neuro-muscul Disord 17:597–602.

Voermans NC, Jenniskens GJ, Hamel BC,Schalkwijk J, Guicheney P, van EngelenBG. 2007b. Ehlers-Danlos syndrome due totenascin-X deficiency: Muscle weakness andcontractures support overlap with collagenVI myopathies. Am J Med Genet A143A:2215–2219.

Voermans NC, Bonnemann CG, Huijing PA,Hamel BC, van Kuppevelt TH, de Haan A,Schalkwijk J, van Engelen BG, JenniskensGJ. 2008a. Clinical and molecular overlapbetween myopathies and inherited connec-tive tissue diseases. Neuromuscul Disord18:843–856.

Voermans NC, van Engelen BG. 2008b. Differ-ential diagnosis of muscular hypotonia ininfants: The kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI). NeuromusculDisord 18:906.author reply 907.

Voermans N, Timmermans J, van Alfen N, PillenS, op den Akker J, Lammens M, Zwarts MJ,van Rooij IA, Hamel BC, van Engelen BG.2009a. Neuromuscular features in Marfansyndrome. Clin Genet 76:25–37.

Voermans NC, Bonnemann CG, Hamel BC,Jungbluth H, van Engelen BG. 2009b. Joint

hypermobility as a distinctive feature in thedifferential diagnosis of myopathies. J Neurol256:13–27.

Voermans NC, van Alfen N, Pillen S, LammensM, Schalkwijk J, Zwarts MJ, van Rooij IA,Hamel BC, van Engelen BG. 2009c. Neuro-muscular involvement in various types ofEhlers-Danlos syndrome. Ann Neurol65:687–697.

Voermans NC, Bonnemann CG, Lammens M,van Engelen BG, Hamel BC. 2009d.Myopathy and polyneuropathy in an ado-lescent with the kyphoscoliotic type ofEhlers-Danlos syndrome. Am J Med GenetA 149A:2311–2316.

Voermans NC, Kempers M, Lammens M, vanAlfen N, Janssen MC, Bonnemann C, vanEngelen BG, Hamel BC. 2012.Myopathy ina 20-year-old female patient with D4ST-1deficient Ehlers-Danlos syndrome due to ahomozygous CHST14 mutation. Am J MedGenet A 158A:850–855.

Wall ME, Banes AJ. 2005. Early responses tomechanical load in tendon: Role for calciumsignaling, gap junctions and intercellularcommunication. J Musculoskelet NeuronalInteract 5:70–84.

Wilmshurst JM, Lillis S, Zhou H, Pillay K,HendersonH,KressW,M€ullerCR,NdondoA, Cloke V, Cullup T, Bertini E, Boenne-mann C, Straub V, Quinlivan R, Dowling JJ,Al-Sarraj S, Treves S, Abbs S, Manzur AY,Sewry CA, Muntoni F, Jungbluth H. 2010RYR1 mutations are a common cause ofcongenital myopathies with central nuclei.Ann Neurol 68:716–726.

Yis U, Dirik E, Chambaz C, Steinmann B,Giunta C. 2008. Differential diagnosisof muscular hypotonia in infants: Thekyphoscoliotic type of Ehlers-Danlossyndrome (EDS VI). Neuromuscul Disord18:210–214.

Zhang H, Hu W, Ramirez F. 1995. Developmen-tal expression of fibrillin genes suggestsheterogeneity of extracellular microfibrils.J Cell Biol 129:1165–1176.

Zhou H, Jungbluth H, Sewry CA, Feng L, BertiniE, Bushby K, Straub V, Roper H, RoseMR,BrockingtonM, Kinali M,Manzur A, RobbS, Appleton R, Messina S, D’Amico A,Quinlivan R, Swash M, M€uller CR, BrownS, Treves S, Muntoni F. 2007. Molecularmechanisms and phenotypic variation inRYR1-related congenital myopathies. Brain130:2024–2036.

Zhou H, Rokach O, Feng L, Munteanu I,Mamchaoui K, Wilmshurst JM, Sewry C,Manzur AY, Pillay K, Mouly V, Duchen M,Jungbluth H, Treves S, Muntoni F. 2013.RyR1 deficiency in congenital myopathiesdisrupts excitation-contraction coupling.Hum Mutat. 34:986–996.

Zou Y, Zwolanek D, Izu Y, Gandhy S,Schreiber G, Brockmann K, Devoto M,Tian Z, Hu Y, Veit G, Meier M, StetefeldJ, Hicks D, Straub V, Voermans NC, BirkDE, Barton ER, Koch M, B€onnemannCG. 2014. Recessive and dominantmutations in COL12A1 cause a novelEDS/myopathy overlap syndrome in hu-mans and mice. Hum Mol Genet23:2339–2352.

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