Trunk muscle involvement in late-onset Pompe disease: Study of thirty patients

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1 Avilble online t Neuromusculr Disorders 22 (2012) S148 S154 Trunk muscle involvement in lte-onset Pompe disese: Study of thirty ptients Aíd Alejldre,b, Jordi Díz-Mner,b, Sbrin Rvgli c,d, Enrico Colli Tibldi e, Frncesco D Amore e, Germán Morís f, Nuri Muels g,b, Jun J. Vílchez g,b, An Grcí-Medin h, Mercedes Usón i, Frncisco A. Mrtínez Grcí j, Isbel Ill,b, Ann Pichiecchio e, Neuromusculr Disorders Unit, Deprtment of Neurology, Universitt Autónom de Brcelon, Hospitl de l Snt Creu i Snt Pu, Brcelon, Spin b Centro de Investigción Biomédic en Red en Enfermeddes Neurodegenertivs CIBERNED, Spin c Deprtment of Helth Sciences nd Neurosciences, University of Pvi, Itly d Clinicl Institute Beto Mtteo, Vigevno, Itly e Neurordiology Deprtment, Ntionl Neurologicl Institute I.R.C.C.S. C.Mondino Foundtion, Pvi, Itly f Deprtment of Neurology, Hospitl Universitrio Centrl de Asturis, Oviedo, Spin g Deprtment of Neurology, Hospitl Universitri I Politècnic L Fe, Vlenci, Spin h Deprtment of Neurology, Hospitl Generl Universitrio Rein Sofí, Murci, Spin i Deprtment of Neurology, Fundción Hospitl Son Lltzer, Plm de Mllorc, Spin j Deprtment of Neurology. Hospitl Universitrio Virgen de l Arrixc, Murci, Spin Abstrct Lte-onset Pompe disese is chrcterized by progressive wekness involving proximl limb nd respirtory muscles. Recently, tretment with enzyme replcement therpy (ERT) hs been introduced prtilly improving ptients prognosis, but stndrd consensus on when to strt ERT is still lcking. There is lso lck of biomrkers relted to the clinicl progression of the disese. Here we used muscle mgnetic resonnce imging (MRI) or computed tomogrphy (CT) to study the bdominl nd prvertebrl muscles of 30 lte-onset Pompe ptients t different stges of disese. We observed selective pttern of muscle dmge, with erly involvement of the Multifidus muscle, followed by the Obliquus internus bdominis nd Longissimus muscle. Some degree of trunk involvement on MRI occurred even in symptomtic ptients. Severity of muscle involvement in MRI correlted with ptients functionl stge. We suggest tht: () the combintion of prvertebrl nd bdominl muscle involvement my serve s useful tool in the dignostic work-up of ptients with clinicl suspicion of Pompe disese; (b) trunk bnormlities pper t very erly stges of disese nd even in symptomtic ptients, possibly nnouncing the onset of the disese nd thus the need for closer clinicl follow-up. Ó 2012 Elsevier B.V. All rights reserved. Keywords: Pompe disese; MRI; Prvertebrl muscles; Abdominl muscles 1. Introduction Corresponding uthor. Address: Deprtment of Neurordiology, Neurologicl Ntionl Institute I.R.C.C.S. C. Mondino Foundtion, 2, Mondino Street, Pvi, Itly. Tel.: ; fx: E-mil ddress: nn.pichiecchio@mondino.it (A. Pichiecchio). Pompe disese, lso known s cid mltse deficiency (AMD) or glycogen storge disese type II (GSD II), is rre utosoml recessive disorder due to deficiency of the lysosoml enzyme cid lph glycosidse (GAA). This deficiency cuses intrlysosoml ccumultion of glycogen /$ - see front mtter Ó 2012 Elsevier B.V. All rights reserved.

2 A. Alejldre et l. / Neuromusculr Disorders 22 (2012) S148 S154 S149 in severl tissues such s skeletl muscle, crdic muscle or liver [1]. Different clinicl ptterns hve been described, rnging from rpidly progressive infntile forms to slowly progressive dult-onset phenotypes [2]. In generl, lteonset Pompe disese is chrcterized by wekness of the proximl limb nd xil muscles ssocited with respirtory muscles involvement [3]. However, mny different clinicl presenttions hve been reported, rnging from predominnt respirtory involvement to exclusive limb muscles wekness. Clinicl nd muscle biopsy findings cn be unspecific in Pompe disese, so tht muscle imging cn become helpful dignostic tool [1]. Computed tomogrphy (CT) studies in dult ptients hve shown tht the disese spreds over the yers from trunk to extremities [4] with selective muscle involvement found in the thighs [5]. The most recent therpeutic progress in Pompe disese hs been enzymtic replcement therpy (ERT) with recombinnt humn GAA (rh-gaa), which hs proved to be effective in both infntile nd dult forms [6,7]. Although long-term follow-up dt in treted ptients re still lcking, ERT seems to improve muscle wekness nd to stbilize the disese. The response to rh-gaa my be less robust in more dvnced phses of the disese [8] nd this emphsizes the need for prompt dignosis nd erly tretment initition. Becuse of the high costs of the tretment there hve been controversil discussions bout when the therpy should be strted [9]. Considering tht prvertebrl muscles re involved t n erly disese stge, we decided: (1) to study both the posterior nd nterior trunk muscles in 30 lte-onset Pompe ptients by muscle imging in order to evlute their degree of involvement in lrge cohort of ptients t different functionl stges; (2) to investigte whether there is correltion between our clinicl nd imging dt. 2. Mteril nd methods 2.1. Clinicl dt A group of 30 dult-onset Pompe ptients undergoing regulr follow-up ssessments t our centres ws recruited from April 2006 to July Pompe disese dignosis ws bsed on <30% reduction versus controls of GAA ctivity in peripherl blood lymphocytes/muscle, nd ws confirmed by moleculr nlysis of the GAA gene (Tble 1). Muscle MRI ws performed s prt of the ssessment nd ptients were clssified into 4 groups ccording to the following functionl stges: Asymptomtic: no muscle wekness or respirtory involvement, the only bnorml finding ws hyperckemi. Mild involvement: ptients were ble to wlk nd climb up stirs without help, musculr wekness ws detected on clinicl exmintion. Moderte involvement: ptients needed ids (bnister, crutch, stick) to climb up stirs, hd difficulties to stnd up from chir or required non-invsive ventiltion t night. Severe involvement: ptients were unble to wlk more thn 10 m without help or required non-invsive mechnicl ventiltion during the dy. We collected the following dt from ech ptient: (1) demogrphics (ge, sex); (2) clinicl fetures (ge t onset, ge t dignosis, disese durtion t the time of imging, presence of hyperlordosis, bdominl or prvertebrl muscle wekness, presence of lumbr pin, percentge of vitl cpcity in sitting position, nd need for respirtory support); (3) therpeutic dt (ERT tretment t time of MRI, time from tretment onset to MRI); (4) muttions found in the GAA gene Muscle MRI Muscle MRI ws performed by 1.5T MR scnner (1.5T Philips Inter nd 1.5T Philips Achiev XR Reles) nd ws used to obtin T1-weighted spin-echo xil imges from the mid-dorsl segment to the scrum using the sme prmeters (TR = 300 ms, TE = 10 ms, thickness = 10 mm). The imging protocol took 45 min. Five ptients were investigted using muscle CT scn. They did not tolerte the MRI protocol due to severe respirtory wekness. CT xil imges were performed t the sme level with the sme thickness. None of the ptients of this series hd repeted studies. Two independent observers blind to clinicl informtion exmined ll the scns nd evluted prvertebrl (specificlly Multifidus, Longissimus, Iliocostl Lumborum, Qudrtus Lumborum nd Illiopsos) nd bdominl (specificlly Rectus, Trnsversus, Obliquus Externus, Obliquus Internus ) muscles (Fig. 1). Muscle trophy ws evluted by the Mercuri scle [10] Sttistics We performed Person test to correlte the functionl stge (scored 1 4) in every ptient with the degree of muscle involvement (scored s the verge vlue of the Mercuri s scle of ll the muscles). It ws considered significnt if P ws lower thn Results All ptients (17 women nd 13 men) hd lte-onset form of the disese. All but 5 were symptomtic. Men ge t MRI ws 46 yers (±16.7 SD); men ge t disese onset ws 29 yers (±12.9 SD); men dely in dignosis ws 10 yers (±8.4 SD) nd verge durtion of the symptoms t the time of imging ws 7 yers (±12).

3 S150 A. Alejldre et l. / Neuromusculr Disorders 22 (2012) S148 S154 Tble 1 Clinicl nd genetic dt of ptients nlyzed. Functionl scle ccording to functionl impirment (see Section 2). Ptient Gender Age (yers) Age t onset (yers) Age of dignosis (yers) Time to dignosing (yers) Functionl scle t time of MRI Muttion Mechnicl ventiltion 1 Femle Asymptomtic IVS 13TG IVS GA No 100 No 2 Mle Asymptomtic IVS 13TG 525 del T No 95 No 3 Mle 26 3 Asymptomtic IVS 13TG not found No 100 No 4 Mle Asymptomtic IVS 13 TG 525 del T No 100 No 5 Mle Asymptomtic IVS 13 TG deltg No 90 No 6 Femle Mild IVS 13 TG 525 del T Yes 93 Yes 7 Mle Mild IVS 13TG 875GA Yes 82 Yes 8 Femle Mild CG No 93 No 9 Mle Mild IVS 13 TG 2014 CT No 84 Yes 10 Femle Mild IVS 13 TG No 72 Yes 1697del 11 Mle Mild IVS 13 TG Del exon 18 No 93 Yes 12 Mle Mild IVS 13 TG 525 del T No 87 Yes 13 Femle Moderte IVS 13 TG No 80 Yes 2600_2604delTGCT 14 Femle Moderte IVS 13 TG 2014 CT No 71 Yes 15 Femle Moderte IVS 13TG No 69 Yes 236_246delCCACACAGTGC 16 Femle Moderte IVS 13TG 1192DupC No 82 Yes 17 Femle Moderte IVS 13TG 875GA No 70 No 18 Femle Moderte IVS 13 TG 525 del T Yes 49 Yes 19 Femle Moderte IVS 13 TG 525 del T Yes 32 Yes 20 Femle Moderte IVS 13 TG delEx18 Yes 55 Yes 21 Mle Moderte IVS 13 TG IVS1076-1G>C No 58 Yes 22 Mle Moderte IVS 13 TG 2298_2301 No 73 Yes delinsaaagta 23 Femle Moderte IVS 13 TG 1297 GA No 80 Yes 24 Mle Severe IVS 71195GA 1856GA No 44 Yes 25 Mle Severe IVS 13 TG 1465 GA Yes 15 Yes 26 Femle Severe IVS 13 TG 2237GA Yes 23 Yes 27 Femle Severe IVS 13 TG 2237GA Yes 51 Yes 28 Mle Severe IVS 13 TG IVS1076-1G>C Yes 43 Yes 29 Femle Severe IVS 13 TG 1561GA No 85 Yes 30 Femle Severe IVS 13 TG 784 GA No 92 No Ptients were symptomtic or they were dignosed due to fmily study; therefore ge t onset nd time to dignosing were unknown. CV% Tretment We clssified 5 ptients s symptomtic (16.6%), 7 s mildly ffected (23.3%), 11 s modertely ffected (36.6%), nd 7 s severely ffected (23.3%) (Tble 1). Eleven out of thirty (36%) ptients complined of chronic lumbr pin. Thirteen (43%) ptients showed trunk wekness when sked to rise the trunk from prone position, nd 14/30 (46%) ptients hd hyperlordosis on clinicl exmintion. Eighteen out of thirty (60%) ptients were unble to rise from the supine position, possibly indicting bdominl wekness; nine ptients (30%) needed respirtory support t the time of the scn. Twenty-two (73.3%) ptients were treted with ERT, with men time from tretment onset to MRI of 0.9 yers (1.2 SD). The group of symptomtic ptients included 4 men nd 1 womn. Men ge t MRI ws 30 yers (21.5 SD). Only one ptient complined of occsionl lumbr pin. Dignosis ws reched s prt of the investigtion for symptomtic hyperckemi in 5 ptients nd through fmily screening in ptient 2. MRI nlysis of this group showed mild trophy in t lest one muscle (Tble 2). The Multifidus muscle ws the most frequently ffected, reching grde 2 on the Mercuri scle in 4 out of 5 ptients, followed by the Obliquus Internus muscle, reching grde 2 nd 3 on Mercuri scle, respectively in 2 out of 5 ptients. Mildly ffected ptients (4 men nd 3 women) hd men ge of 37 yers (9.1 SD) nd men disese durtion of 8 yers (8.6 SD). 3 ptients complined of chronic lumbr pin, four hd trunk wekness while 6 ptients hd hyperlordosis. Men vitl cpcity in sitting position ws 85 ± 7.7% in this group. Two ptients needed nocturnl ventiltion due to episodes of nocturnl pne. Six ptients re now on ERT, only in one of them the tretment hd been strted 3 yers fter performing the scn. Rdiologicl studies showed different degrees of involvement of ll prvertebrl nd bdominl muscles, but the Obliquus Internus nd Longissimus muscles were completely trophic in ll but one ptient. The Multifidus muscle ws involved in ll these ptients except in one of them. Conversely, the Obliquus Externus, Qudrtus Lumborum nd Illiopsos muscles were spred in most ptients in this group.

4 A. Alejldre et l. / Neuromusculr Disorders 22 (2012) S148 S154 S151 Fig. 1. MRI involvement of trunk muscles. Norml bdominl nd prvertebrl muscles slice (): Psos muscle (1), Rectus (2), Obliquus Externus (3), Obliquus Internl (4), Trnsversus (5), Qudrtus Lumborum (6), Multifidus muscle (7), Longissimus muscle (8), Iliocostl Lumborum (9). Asymptomtic. ptient number 1 (b). Mild clinicl stge ptient number 10 (c). Moderte clinicl stge ptient number 13 (d). Severe clinicl stge ptient number 27 (e). The group with moderte disese severity included 2 men nd 9 women with men ge of 50 yers (11.2 SD) nd men durtion of disese of 19 yers (7.3 SD). Five ptients complined of lumbr pin, 5 hd trunk wekness while 5 other ptients hd hyperlordosis. Men vitl cpcity in sitting position ws 62% (16.1 SD) nd 3 ptients needed respirtory support. Nine ptients were on ERT tretment (men tretment durtion to MR time ws 1.2 yers). Imging showed involvement of ll prvertebrl nd bdominl muscles. Specificlly, t this stge the Trnsversus, Obliquus Internus, Rectus, Ilicostl, Iliopsos nd Longissimus muscles were completely trophic. The Obliquus Externus, Multifidus nd Illiopsos muscles were less trophic. Finlly, 3 men nd 4 women were clssified s severely ffected. The men ge ws 65 yers (9.9 SD) nd men durtion of disese ws 28 yers (13.3 SD). Three ptients complined of lumbr pin, five hd trunk wekness nd one hd hyperlordosis. The men vitl cpcity in sitting position ws 42% (28.9 SD) nd 4 ptients needed noninvsive mechnicl ventiltion. Six ptients were on ERT tretment (time from tretment strt to MRI ws 1.1 yers (0.9 SD). Imging studies showed complete trophy of ll muscles. We nlysed if ny correltion could be estblished between the functionl stge nd the degree of muscle involvement using the Person test. We found positive significnt correltion (p < 0.001) showing tht with worse functionl stge there ws greter degree of muscle involvement on MRI. 4. Discussion Pompe disese s metbolic muscle disese hs received lot of rdiologic ttention in the lst few yers, especilly in reltion to the recent ERT introduction [4,5,8,11,12]. Musculr imging, especilly muscle MRI, hs proved to be relible in ssessing both the pttern nd the severity of muscle dmge in severl different muscle disorders [13 16]. In prticulr, CT studies demonstrted tht Pompe disese in dult ptients spreds over the yers from trunk to extremities with xil nd thigh muscles being more severely ffected thn lower leg nd shoulder girdle muscles [4]. Specificlly, posterior lumbr prspinl nd Psos muscles were demonstrted to be severely trophic in ll ptients [4,11] so tht it ws suggested to consider Pompe disese in ny cse of otherwise unexplined prspinl muscle trophy [11]. A study in 11 ptients showed selective dmge in different thigh muscles over time [5], while nother study performed with whole-body MRI in 20 ptients lso observed involvement of the subscpulr nd tongue muscles [17]. A recent report hs suggested tht routine EMG ssessment of these ptients should include lumbr prvertebrl exmintion, which is ffected t erly stges of the disese [12,18]. Recent reports bout typicl cses of Pompe disese reveled by rigid spine syndrome hve rised further interest in trying to elucidte the pttern nd extent of trunk involvement in these ptients [19,20]. However, clinicl symptoms nd signs of trunk involvement re often vgue nd unspecific (pin, subtle posturl chnges) nd my be esily overlooked. Moreover, these muscles re difficult to ssess cliniclly. A rough clinicl evlution my be bsed on the bility to rise from the supine position or to rise the trunk from the prone position, but these re complex movements involving severl muscle groups nd their clinicl ssessment my be further hmpered in the presence of concomitnt respirtory dysfunction. Tking into ccount the erly involvement of trunk muscles, we decided to crefully study both prvertebrl

5 S152 A. Alejldre et l. / Neuromusculr Disorders 22 (2012) S148 S154 Tble 2 MRI nlysis nd quntifiction of trunk muscle involvement. Ptient MRI dte Time onset- MRI yrs Time tretment- MRI b Trnsversus Obliquus Internl Obliquus Externl Rectus Multifidus muscle Longissimus muscle Ilio-costl lumborum Qudrtus lumborum /06/27 b NA /02/18 b /03/16 b /12/10 b /07/ NA NA NA NA /09/ /02/06 1 b /08/ NA /12/ NA /05/ /10/ /06/ /12/ NA NA NA NA /06/ /02/ NA NA NA NA /06/01 b /01/ NA /05/ /08/ NA NA /08/ /01/ /09/ NA NA NA NA /06/ /04/ NA NA NA NA /04/ NA NA NA NA /04/ NA NA /08/ NA NA /06/ NA 4 3 NA /05/29 42 b Age t onset is unknown becuse ptients were symptomtic or dignosed due to fmily study. b These ptients were not under tretment with ERT. NA: not ccessible. CT: computerized tomogrphy. Psos muscle nd bdominl muscles in 30 lte-onset Pompe ptients, evluting nine muscles of the lumbr prvertebrl re nd the nterior bdominl muscles. We found tht ll our ptients, including symptomtic ones, hd some degree of trunk muscle trophy, suggesting tht MRI is ble to find muscle chnges in trunk muscles before ptients notice ny symptom (Fig. 2). Although cler pttern of involvement could not be found, distribution of the dmge in different muscles over time ws observed. Specificlly, the Multifidus nd the Obliquus Internus muscles were commonly the first muscles ffected, followed by the Longissimus, the Trnsversus nd the Rectus muscles nd eventully the Iliocostl Lumborum, Qudrtus Lumborum, Illiopsos nd Obliquus Externus muscles. Our results suggest tht the presence of both prvertebrl nd bdominl muscle trophy on muscle MRI of ptients with prominent wekness of the pelvic girdle muscles or symptomtic hyperckemi could be suggestive of lte-onset Pompe disese nd potentilly shorten the well known problem of the dignostic dely. Prvertebrl trophy is not uncommon nd my be seen in other metbolic myopthies (i.e. glycogenosis V), in musculr dystrophies (e.g. fcio-scpulo-humerl musculr dystrophy -FSHD-, lminopthies), in mitochondril myopthies (e.g. NADH-CoQ reductse deficiency), in congenitl myopthies, s for exmple in SEPN-1 or dynmin-2 relted myopthies or in substntil percentge of ptients with low bck pin s well [11,21 25]. However, their ssocition with bdominl muscle trophy, s we observed in our cohort of ptients, is not commonly seen in other diseses, s fr s we know. The ssocition of bdominl nd prvertebrl wekness is clinicl chrcteristic feture of FSHD, where it is frequent to find hyperlordosis, lumbr pin nd prominent symmetric bdomen [26]. However, the presence of fcil wekness, cler

6 A. Alejldre et l. / Neuromusculr Disorders 22 (2012) S148 S154 S153 Fig. 2. Schemtic representtion of medin MRI or CT muscle score ccording to Mercuri scle of ech functionl group of ptients. symmetric muscle involvement nd distl nterior wekness distinguishes Pompe from FSHD phenotypes. It is relevnt to note tht from the imging point of view trunk trophy should be ssocited with other rdiologic fetures suggestive of lte-onset Pompe disese, such s the selective loction of thigh muscles deteriortion of gret dductor muscle nd posterior comprtment muscles nd the chrcteristic spring of lower leg muscles [5], in order to strengthen the dignostic suspect. Cliniclly, we observed tht only one third of our Pompe ptients complined of lumbr pin tht could be permnent or fluctuting, especilly relted to wlking or stnding up for hours, nd did not seem to correlte with disese severity nor with the severity of trunk involvement on imging. Rther, we found good correltion between motor functionl stge nd trunk muscle trophy, with the exception of the erly stges of disese, when the sensitivity of muscle imging seems to overtke the limits of the clinicl evlution. We did not find significnt differences in the pttern of muscle involvement between ERT treted nd untreted ptients. However we did not conduct follow-up studies to determine chnges in the progression of the disese. A prospective study is needed to investigte how ERT ffects MRI chnges in Pompe disese. This my be importnt from therpeutic perspective. In fct, due to its high cost, there is controversy bout when ERT should be initited [9]. Whether trunk involvement my serve s n indictor of the proper time to strt ERT is not the im of this study, s follow-up nd efficcy dt re needed. However, detection of trunk bnormlities my help to reduce the time between first subtle clinicl symptoms ccompnying the onset of the disese nd the dignosis. They my wrn the clinicin bout disese onset nd thus the need for stricter clinicl follow-up. In conclusion, our study demonstrted tht MRI study of trunk muscles in lte-onset Pompe ptients cn be useful in the dignostic work-up nd potentil good tool to guge the rte of disese progression nd monitor response to therpy. Further studies will demonstrte whether MRI could lso be used s helpful biomrker in order to decide when ERT tretment hs to be strted. 5. Conflict of interest None. Acknowledgements We thnk Mry Brdon for her English support nd the ptients, without whom this study would not hve been possible, for their ptience. References [1] Bembi B, Cerini E, Dnesino C, et l. Dignosis of glycogenosis type II. Neurology 2008;71:S4 S11. [2] Vn der Ploeg AT, Reuser A. Pompe s disese. Lncet 2008;372: [3] Hgemns ML, Winkel LP, Vn Doorn PA, et l. Clinicl mnifesttion nd nturl course of lte-onset Pompe s disese in 54 Dutch ptients. Brin 2005;128: [4] de Jger AE, vn der Vliet TM, vn der Ree, Oosterink BJ, Loonen MC. Muscle computed tomogrphy in dult-onset cid mltse deficiency. Muscle Nerve 1998;21: [5] Pichiecchio A, Uggetti C, Rvgli S, et l. Muscle MRI in dultonset cid mltse deficiency. Neuromuscul Disord 2004;14:51 5. [6] vn Cpelle CI, Winkel LP, Hgemns ML, et l. Eight yers experience with enzyme replcement therpy in two children nd one dult with Pompe disese. Neuromuscul Disord 2008;18: [7] Klinge L, Strub V, Neudorf U, Voit T. Enzyme replcement therpy in clssicl infntile pompe disese: results of ten-month follow-up study. Neuropeditrics 2005;36:6 11. [8] Rvgli S, Pichiecchio A, Ponzio M, et l. Chnges in skeletl muscle qulities during enzyme replcement therpy in lte-onset type II glycogenosis: temporl nd sptil pttern of mss vs. strength response. J Inherit Metb Dis 2010;33: [9] Cupler EJ, Berger KI, Leshner RT, et l. Consensus tretment recommendtions for lte-onset pompe disese. Muscle Nerve 2012;45: [10] Mercuri E, Pichiecchio A, Counsell S, et l. A short protocol for muscle MRI in children with musculr dystrophies. Eur J Peditr Neurol 2002;6: [11] Cinnmon J, Slonim AE, Blck KS, Gorey MT, Scuderi DM, Hymn RA. Evlution of the lumbr spine in ptients with glycogen storge disese: CT demonstrtion of ptterns of prspinl muscle trophy. AJNR Am J Neurordiol 1991;12: [12] Hobson-Webb LD, Dermey S, Kishnni PS. The clinicl nd electrodignostic chrcteristics of Pompe disese with post-enzyme replcement therpy findings. Clin Neurophysiol 2011;122: [13] Prds C, Lluger J, Diz-Mner J, et l. Redefining dysferlinopthy phenotypes bsed on clinicl findings nd muscle imging studies. Neurology 2010;75: [14] Fischer D, Wlter MC, Kesper K, et l. Dignostic vlue of muscle MRI in differentiting LGMD2I from other LGMDs. J Neurol 2005;252: [15] Wttjes MP, Kley RA, Fischer D. Neuromusculr imging in inherited muscle diseses. Eur Rdiol 2010;20:

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