Arq Neu ro p siq u iat r 2003;61(4):946-949
M YOPATHY OF DISTAL LOWER LIM BS
Th e clin ical varian t o f Miyo sh i
Crist iane N. Soares
1, M arcos R.G. de Freit as
1, Osvaldo J.M . Nasciment o
2,
Lenilda Ferreira da Silva
1, Andréa R. de Freit as
3, Lineu C. Werneck
4ABSTRACT - Miyoshi d istal d ystrop hy is a rare m yop athy characterized b y an autosom al recessive p attern of inheritance and it is p revalent in Jap an. Onset of d isease is in early ad ult life w ith w eakness and atrop hy of the leg m uscles. Recently g ene linkag e to chrom osom e 2p 12-14 has b een estab lished . We rep ort three sisters, b orn of consang uineous p arents. All of them noticed w eakness and atrop hy of leg m uscles, and could not w alk on their heels. In all of them the creatine kinase concentrations w ere very hig h. The electrom yog rap hy show ed m yop athic p atterns and the m uscle b iop sy d isclosed d ystrop hic chang es and an ab sence of d ysferlin. There are few cases rep orted of Miyoshi d istal d ystrop hy in Latin Am erica. The Miyoshi m yop athy m ay b e d istinct am ong the hered itary d istal m yop athies.
KEY WORDS: d istal m uscular d ystrop hy, m yop athy, Miyoshi m yop athy, d ysferlin.
M iopatia distal dos membros inferiores: variante de M iyoshi
RESUMO - A d ist ro fia m u scu lar d e Miyo sh i é d o en ça rara, d escrit a in icialm en t e n o Jap ão e d e h eran ça autossôm ica recessiva. Caracteriza-se p or fraq ueza e atrofia m uscular acom etend o inicialm ente e às vezes exclusivam ente a m usculatura d o com p artim ento p osterior d as p ernas, com evolução lentam ente p rog ressiva. Recentem ente verificou-se alteração g enética no crom ossom o 2p -12-14. Referim os a três p acientes d o sexo fem inino, irm ãs e filhas d e p ais consang üíneos d e p rim eiro g rau. Tod as ap resentaram com o sintom a inicial fraq ueza nas p ernas com d ificuld ad e p ara and ar, sob retud o na p onta d os p és. A flexão d orsal d os p és estava p reservad a. Tod as exib iam níveis elevad os d e creatinog uinase. A eletrom iog rafia em tod as m ostrou p ad rão m iop ático. A b ióp sia m uscular revelou alteração d a d isferlina. Poucos casos d e m iop atia d e Miyoshi são relatados na Am érica Latina. Realçam os seus critérios diagnósticos necessários para o diagnóstico desta afecção d entre as m iop atias g eneticam ente d eterm inad as.
PALAVRAS-CHAVE: d istrofia m uscular d istal, m iop atia, m iop atia d e Miyoshi, d isferlina.
Dep art am en t o d e Neu ro lo g ia, Ho sp it al Un iversit ário An t o n io Ped ro , Un iversid ad e Fed eral Flu m in en se (UFF), Nit eró i, Brasil: 1Méd ica Resid en te;2Pro fesso r Tit u lar d e Neu ro lo g ia; 3Neu ro lo g ist a;4Ch efe d e Dep art am en t o d e Neu ro lo g ia d o Ho sp it al d e Clín icas d a Un iversid a-d e Fea-d eral a-d o Paran á, Cu rit ib a PR, Brasil.
Received 10 Feb ru ary 2003, received in fin al fo rm 11 Ju n e 2003. Accep t ed 4 Ju ly 2003.
Dra. Crist iane N. Soares - Rua Aureliano Cout inho 81/605 - 25625-000 Pet rópolis RJ - Brasil. E-mail: [email protected] Myo p at h ies u su ally p resen t w eakn ess an d p ro
xi-m al atrop hy1,2, involving m ainly p elvic and escap ular
m u scles. Ho w ever, t h ere is a g ro u p o f rare m yo p a-t h ies w ia-t h d ifferen a-t ch araca-t erisa-t ics a-t h aa-t affeca-t sp e-cially d ist al m u scles. Th ey can b e id en t ified b y t h e follow ing features: autosom ic d om inant or recessive g en et ic in h erit an ce, early o r lat e o n set d ist al m u scle atrop hy, increased creatine kinase (CK) and ab norm al m u scles b io p sy1,3.
Miyoshi m yop athy involves m ainly d istal and p os-t e rio r le g m u scle s, w ios-t h a n e a rly o n se os-t a n d a n au t o so m ic recessive in h erit an ce. Th is m yo p at h y w as first d escrib ed in Jap an , in 1967, b y Miyo sh i an d co l.2,4. It o ccu rs m ain ly in yo u n g ad u lt s b et w een
15-30 years o ld .1,3, w it h o u t sex p referen ce1. It h as an
autosom ic recessive transm ission, w ith com p lete p e-n et rae-n ce. Difficu lt y ie-n t ip t o eie-n g ae-n d clim b ie-n g st airs is t h e in it ial sym p t o m , w it h in vo lvem en t o f g ast ro c-n em iu s ac-n d so leu s m u scles2,5. Th ere is a slo w ly p ro
-g ressive w eakn ess an d t h e p ro xim al m u scles m ay b e involved lately3,6,7. The CK is usually high1,3-6. The
elec-t ro m yo g rah y (EMG) sh o w s a m yo p aelec-t ic p aelec-t elec-t ern an d t h e m u scle s b io p sy re ve a ls d yst ro p h ic ch a n g e s without the p resence of rim m ed vacuoles1,4. Recently
it h as b een sh o w n t h at d ysferlin , o n e o f t h e co m p o -n e-n t s o f m u scu lar fib er m em b ra-n e is d ecreased o r ab sen t . Bejao u i an d co l.1 st u d ied 20 p ed ig rees w it h
Arq Neu ro p siq u iat r 2003;61(4) 947
In t h is d iso rd er t h ere is in vo lvem en t o f ch ro m o so m e 2p 12-14. It h as b een also d escrib ed in USA, It aly, Spain, Germ any, The Netherlands4, Africa1 and Brazil2.
In Jap an it s in cid en ce is ap p ro xim at ely fro m 1 case t o 4 4 0 0 0 0 in h a b it a n t s1, w h ich is s im ila r t o
h yp ercalem ic p erio d ic p aralysis1,3.
We d escrib e three sisters w ith Miyoshi m yop athy, w h o se u n affect ed p aren t s are first d eg ree co u sin s. Th e m u scle b io p sy sh o w ed ab sen ce o f d ysferlin .
CASES
Case 1. Th is is a 30 year o ld fem ale. Sh e is t h e o ld est o f t h ree sist ers a n d m a n ifest ed w ea kn ess o f lo w er lim b s at t h e ag e o f 12 years, w it h d ifficu lt y t o ru n an d clim b stairs. She had p rog ressive w eakness and atrop hy of low er lim b s an d at t h e ag e o f 25 sh e co u ld n eit h er w alk n o r st an d w it h o u t aid . Th ere w ere w eakn ess an d at ro p h y o f t h e calves (t h e p o st erio r p art o f t h e leg s). Th e p ro xim al m u scles w ere rela t ively sp a red . Do rsa l flexio n o f t h e feet w as p reserved as w ell as t h e st ren g t h o f u p p er lim b s. Th e
Fig 3. A-Dysf erlin: normal cont rol (100x). B-Case 3. Def iciency of dysf erlin (100x).
948 Arq Neu ro p siq u iat r 2003;61(4)
t en d o n reflexes w ere p resen t a n d sym m et ric. Th e CK w a s 2850U/l, ald alo se 273U/l, LDH 747U/l. Th e EMG sh o w ed a m yo p at h ic p at t ern . Th e m u scle b io p sy sh o w ed u n sp ecific m yo p at h y ch aract erized b y ro u n d fib ers o f d ifferen t sizes, rare im ag es o f n ecro sis, fib ro sis an d co re cen t ralizat io n .
Case 2. A 22-yea r-o ld fem a le p a t ien t . At t h e a g e o f 19 sh e m an ifest ed w eakn ess o f d ist al lo w er lim b s, m ain ly in t h e rig h t o n e, w it h d ifficu lt y t o t ip t o e. Th e p h ysica l exa -m in a t io n sh o w ed -m ild w ea kn ess in flexio n o f t h e feet . Th e an kle jerks w ere ab o lish ed . Th e CK w as 4905U/l, LHD 505 U/l a n d liver fu n ct io n , h em o g ra m , su g a r, crea t in in e were norm al. The EMG showed m yop atic changes: p ositive w aves, in co m p let e recru it m en t an d p o lyp h asic p o t en t ial m otor unities of short lasting and short am p litud e in lower lim b s an d in d elt o id , t ricep s an d b rach io rad ial m u scles in up p er lim b s. The p atient refused to have a m uscular b iop sy as h er t w o sist ers h ad alread y b een t est ed fo r it an d h ad co n firm ed t h e sam e d iag n o sis.
Case 3. An 18-year-old fem ale p atient p resented w eak-n ess o f lo w er lim b s t w o yea rs b efo re. Sh e co u ld eak-n o t ru eak-n an d clim b st airs. Ph ysical exam in at io n revealed w eakn ess in feet flexio n . Th e p at ellar an d an kle reflexes w ere m ild . Her CK w a s 4 0 0 0 U/l, LDH 6 0 0 U/l. Th e EMG sh o w ed in co m p let e recru it m en t o f m o t o r u n it ies an d p o lyp h asic p o t en t ial w it h sh o rt am p lit u d e in g ast ro cn em iu s, q u ad ri-cep s fem o ris, an t erio r t ib ial, t riri-cep s an d b iri-cep s m u scles. Bio p sy sp ecim en w as t aken fro m t h e left rect u s fem u ris m u scle. Cryo st at o r p arafin sect io n s w ere st ain ed w it h h e-m at o xylin an d eo sin (H&ae-mp;E), e-m o d ified Go e-m o ri t rich ro e-m e (GT), NADHt et razo liu m red u ct ase (NADHTR) an d ad en o -sine triphophatase (ATPase). They showed: variation in fiber size (Fig 1A), p resen ce o f so m e n ecro t ic fib ers (Fig 1B), fo cal en larg ed fib ers w it h d isru p t io n o f in t erm yo fib rillar n et w o rk p at t ern (‘m o t h -eat en ’ an d w h o rled fib ers) (Fig 2A) an d p red o m in an ce o f t yp e 1 at ro p h ic fib ers (Fig 2B). Th e in d irect im m u n o flu o rescen ce t est (ep i-ilu m in a t io n ) w a s d o n e w it h d ysfe rlin a n t ib o d y fro m No vo ca st ra , (New cast le u p o n Tyn e, UK.) (100x). Th e d ysferlin an t ib o d y co n cen t rat io n o f w as 1/10. Th e sect io n s w ere o f 4 m icra thick. There was absence of dysferlin in the fiber m em brane (Fig 3). Th e o t h er im m u n o h ist o ch em ical m et h o d s (d yst ro -p h in , lam in in , m ero sin , sarco g lican ) w ere n o rm al.
DISCUSSION
We rep ort three sisters w ith d istal Miyoshi’s m yo-p at h y (MM). All o f t h em h ad t h e sam e yo-p h en o t yyo-p e, however there was a difference in the clinical severity. Th e o ld est sist er w as m o re severely affect ed . In all o f t h em t h e o n set w as in yo u n g ag es, b et w een 12 an d 19. Th e m ain sym p t o m w as d ist al lo w er lim b w eakn ess, w it h d ifficu lt y t o t ip t o e. In t h e o ld est p a-t ien a-t a-t h ere w as a g rad u al evo lu a-t io n an d sh e co u ld n o t w alk w it h o u t aid . Th ere w as a severe at ro p h y in g a st ro n em iu s m u scles. Th is p ro g ressio n h a s b een
d escrib ed in MM an d it is t h e o n ly d ist al m yo p at h y t h at b eg in s in t h e p o st erio r p art o f t h e leg s . Th e p ro xim al lo w er lim b s m u scles m ay b e in vo lved aft er m an y years an d t h e an t erio r t ib ial an d t h e p ero n eal m u scles are alm o st n o rm al8. Ho w ever, it is kn o w n
t h at t h e earlier t h e o n set , t h e fast er is t h e p ro g res-sio n .Th e in h erit an ce w as au t o so m ic recessive: t h eir p aren t s w ere first d eg ree co u sin s an d t h ey d id n ’t have the d isease. Recently it has b een d escrib ed that MM is d u e t o t h e ab sen ce o r d ecrease o f a p ro t ein in t h e m u scles m em b ran e called d ysferlin . Th e fu n c-t io n o f c-t h is p ro c-t ein o f 273k DA, m ad e o f 2080 am i-noacid s is unknow n, b ut it m ig ht function in calcium m ed iat ed m em b ran e fu sio n o r t raffickin g5,7,9,10. Th e
co d in g fo r d ysferlin h as 55 exo n s an d it s m u t at io n w o u ld p ro b ab ly d u e t o a ch an g e in o n e n u cleo t id e9.
Th e lim b g ird le m u scu lar d yst ro p h y 2B (LGMD 2B) h as t h e sam e d ysferlin lo cu s t h an MM9. Meu g fat t
and col d escrib ed a new m ethod to d ifferenciate MM fro m LGMD 2B. In t h e MM t h ere is a lack in b lo o d d ysferlin , as it exist s in m o n o cyt es. Th e t ech n iq u e w o u ld p erm it s a less in vasive, fast er an d ch eap er diagnosis and allows to quantify dysferlin levels when n ew t reat m en t s w o u ld b e t est ed9. Th e h ig h levels o f
CK in MM is d u e t o g reat m u scu lar lesio n . Miyo sh i an d co l an d Baro h n8,11 rep o rt ed h ig h level o f t h is
enzym e in asym p tom atic p atients’ relatives. Prob ab ly they were p re-clinical ind ivid uals or were heterozigot ics. Besid es en zym aheterozigot ic in crease, heterozigot h e EMG also co n -firm s m yo p at ic p at t ern w it h b rief last in g p o t en t ial, w it h sm a ll a m p lit u d e a n d p o lip h a sic p o t e n t ia ls. Alth o u g h fib rilatio n d isch arg es h ave b een d escrib ed in t h is illn ess, t h a t ’s n o t t h e p a t t ern t h a t u su a lly h ap p en s. Th e im u n o cit o ch em ist ry o n m u scle b io p sy p erfo rm ed in o n e o f o u r p at ien t s sh o w ed ab sen ce o f d ysferlin in m u scle m em b ran e. Th ere w ere also n e cro sis a n d p h a g o cyt o se s in fe w fib e rs. Th e se d yst ro p h ic ch a ra ct erist ics w it h fib er n ecro sis a n d reg en erat io n w it h o u t t h e p resen ce o f vacu o les h ave b een revealed in o t h er cases o f MM12,13. Th ere are
o t h er d ist al m yo p at h ies t h at lo o k like MM. Th ey can h ave d o m in an t o r recessive au t o so m ic p at t ern s. Th e Nonaka‘s m yop athy is a recessive autosom ic d isord er with the onset in young ad ults. This m yop athy shows w eakn ess in feet d o rsiflexo rs m u scles an d t o e ex-t en so rs (fallen feeex-t ). Th e CK is h ig h an d o n m u scle b io p sy t h ere are rim m ed vacu o les, fo cal m yo fib rilar d estruction and autop hag ocytoses14. The lysossom al
system is activated w ith m yofib rilar d estruction that cleans the d estroyed m aterial13. The vacuoles are
sur-ro u n d ed b y a g ran u lar b aso filic m at erial13.Am o n g
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co m m o n h ered itary d istal m u scle d iso rd er. It is a d o -m inant autoso-m ic d isease w ith the onset in the later ad u lt ag e w it h w eakn ess an d at ro p h y o f feet an d t o e s e xt e n so rs. Th e a n t e rio r t ib ia l is t h e m o st affect ed15. Th e CK is alm o st n o rm al an d t h ere is n o
g enetic know n location. Muscular b iop sy show s d ys-t ro p h ic p ays-t ys-t ern , o fys-t en w iys-t h rim m ed vacu o les an d n o in fla m m a t o ry in filt ra t io n15. As w ell a s Wela n d er’s
m yo p a t h y, t h e Ma rke sb e rg -Grig g ’s m yo p a t h y o r t ib ial m u scu lar d yst ro p h y13 b eg in s in t h e lat er ad u lt
ag e, w it h w eakn ess in t h e an t erio r leg m u scles. Th e CK is n o rm al o r slig h t ly elevat ed . In t h is d isease t h e frozen m uscle b iop sy show s uniq ue or m ultip le fib er m u scles vacu o les .An o t h er d ist al au t o so m ic d o m i-n ai-n t m yo p at h y is t h e fo rm d escrib ed b y Lai-n g ai-n d co l. In t h is d iso rd er t h ere are w eakn ess in t h e an t eri-o r leg m u scles an d in n eck flexeri-o rs w it h t h e eri-o n set in ch ild h o o d . Ge n e t ic lo ca t io n is in ch ro m o so m e 14q 1117. Th e CK is slig h t ly h ig h an d t h ere are n o
vacu o les in t h e m u scu lar b io p sy.
Ot h er d ist al m yo p at h ies are t h e in clu sio n b o d y m yo sit is, m yo t o n ic d yst ro p h y an d so m e m et ab o lic m yo p at h ies. Ho w ever t h ey h ave d ist in ct clin ical an d h ist o lo g ical feat u res.
In o u r ca ses a ll sist ers w ere a ffect ed a n d t h e p aren t s w ere first d eg ree co u sin s. Th e ab sen ce o f d ysferlin in m u scle co n firm t h e d iag n o sis o f MM. In Brazil2 an d Lat in Am erica t h ere are o n ly five cases
d escrib ed o f MM. We t h in k t h at in p at ien t s w it h h e-red it ary d ist al m u scle w eakn ess it is m an d at o ry t o p e rfo rm g e n e t ic t e st s a n d m u scle b io p sy w it h im m u n o h ist o ch em ical t ech n iq u es.
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