Clinical  aspects  of  Duchenne  muscular  

dystrophy

M2M  2015  Muscular  Dystrophies  Theme    

Lecture  3  

COMMONWEALTH OF AUSTRALIA

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DMD  is  caused  by  loss  of  dystrophin

normal

DMD/ mdx

Muscle  immunohistochemical  

staining  for  dystrophin

Author’s own

Dystrophinopathies  

 Duchenne  muscular  dystrophy  

 Becker  muscular  dystrophy  

 Familial  cramps  +  myalgia  syndrome  

 Other  

– X-­‐linked  dilated  cardiomyopathy  

– Isolated  elevated  CK  

– ManifesIng  carrier  females    

–   Isolated  quadriceps  myopathy  

Guillaume-Benjamin Duchenne de Boulogne US National Library of Medicine

Onset  

  DMD:  onset  <5  years  –   Incidence  1/5000  boys    –   Clinical  diagnosis  typically  2-­‐4  yrs  

   Wheelchair  dependency  <13  yrs  

   BMD:  onset  >  5yrs  –   Incidence  1/35  000  male  births  – Clinical  onset  variable    

 Wheelchair  dependency  >16  yrs  

Clinical  presentaIons  of  DMD  

  Delayed  motor  milestones    – Mean  age  walking  18m  (normal  <18  months)      

   Gait  difficulIes    

– Broad-­‐based,  waddling  gait,  proximal  weakness  – Trouble  climbing  steps,  Gowers’  manoeuvre  

– Persistent  toe-­‐walking,  flat  feet     FaIgability,  frequent  falls  

–  Inability  to  run  or  to  keep  up  with  peers     Calf  /  thigh  cramps,  muscle  enlargement  

   Speech  delay,  learning  problems  

Physical  examinaIon

 Waddling  gait     Proximal  weakness   Enlarged,  rubbery  muscles    

– calves  +/-­‐  quads,  gluteal,  deltoid,  even  tongue    – early  hypertrophy,  late  pseudohypertrophy  

   Facial  muscles  spared       Extra-­‐ocular  muscles  always  spared  

   Weak  neck  flexors     Lumbar  lordosis  

Muscle  hypertrophy  

Muscles  look  larger  but  in  fact  this  apparent  enlargement  is  due  to  increased  fat  and  fibrosis  rather  than  an  increase  in  true  muscle  Issue  i.e.  ‘pseudohypertrophy  ‘

Muscle  hypertrophy  

http://neuromuscular.wustl.edu/musdist/dmd.html

Gowers’  sign  (1)  

Gowers’  sign  (2)  

Gowers’  sign  (3)  

Gowers’  sign  (4)  

Gowers’  sign  (5)  

Gowers’  sign  (6)  

Gowers’  sign  

  ‘Climbing  up’  legs  on  arising  from  ground    IndicaIve  of  proximal  weakness  in  older  children  (>4  yrs)    

 Normal  in  younger  children  <3  yrs  

 Non-­‐specific  i.e.  seen  in  any  muscle  disorder  causing  proximal  weakness  – DMD,  BMD  

– Myotonic  dystrophy  – Congenital  myopathies  

– Muscle  disorders  of  adulthood  including  steroid  myopathy

Muscle  atrophy  

Author’s own

Diagnosis  of  DMD

   Serum  creaIne  kinase  level    – Enzyme  released  by  damaged  muscle  cells  into  blood    

– Normal  <200  IU/L,  DMD  >10  000  

  Thyroid  funcIon  tests  (  blood)    – Hypothyroidism  can  look  very  much  like  DMD    

  GeneIc  tesIng  (by  MLPA)  for  DMD  – PosiIve  in  65-­‐70%  cases  – DeleIons  65%,  duplicaIons  5%,  point  mutaIons  10-­‐15%  

 Muscle  biopsy    

– High  suspicion  of  DMD,  geneIc  tests  are  negaIve      – Necessary  in  about  1/3  of  cases    

Serum  CK  (creaIne  kinase)  levels Normal  (<  200  U/L)  

 Elevated    

(200-­‐  800  U/L)  Markedly  elevated  

(>1000  U/L)  

Congenital  myopathies   Congenital  myopathies  +  muscular  dystrophies    

Congenital  muscular  dystrophies  

Endocrine  myopathies   Endocrine  myopathies   FSH  MD    

Myotonic  dystrophy   Myotonic  dystrophy   Duchenne  +  Becker  MD  

DermatomyosiIs   DermatomyosiIs   Limb  girdle  MD  

Metabolic  myopathies   Metabolic  myopathies  

Myasthenic  syndromes   Idiopathic    

SMA   SMA  

Pompe  disease  

Neuropathies   Motor  neuropathies  

Natural  history  of  DMD  

 3-­‐6  yrs:  ‘honeymoon’  phase  – Mild  weakness  but  overall  strength  and  funcIon  may  increase  

–  Increasing  disparity  between  affected  child  and  his  peers   8  yrs:  difficulty  climbing  stairs,  walking  

–   Increasing  faIgability,  inability  to  run  and  jump    

–  Increasingly  prominent  lumbar  lordosis  

– Progressive  contractures  Achilles,  ITBs,  hips   ~  10-­‐13yrs:  transiIon  to  wheelchair  use       Respiratory  or  cardiac  failure  late  teens-­‐early  20s      

Duchenne  muscular  dystrophy  Course  

 Some  variability  in  course  

 AmbulaIon  lost  anywhere  between  8-­‐14  years  

 Gradual  decline  in  upper  limb  funcIon  

– Difficulty  bringing  hands  to  mouth  by  16-­‐18years  

 Death  average  approx.  25  years    

 Death  is  usually  from  respiratory  failure  

 Cardiac  death  in  about  10%  

–  Cardiomyopathy  or  arrhythmias  

Natural  history  of  Becker  MD  

   Onset  amer  age  5  yrs  – Commonly  5-­‐15  yrs  – Occasionally  as  late  as  3rd  or  4th  decade    

   Progressive  limb-­‐girdle  weakness     Calf  pain  and  myalgias  common  

   Able  to  walk  amer  15  yrs     Respiratory  failure  amer  4th  decade     Cardiomyopathy  is  MORE  common  than  in  DMD  

– Greater  strain  on  heart  caused  by  greater  exercise  and  acIvity  

Duchenne  muscular  dystrophy    Respiratory  deficit  

 Weakness  of  intercostal  muscles  >  diaphragm  

  In  the  early  years,  vital  capacity  increases  with  age  and  growth  

  In  the  early  teens,  vital  capacity  plateaus  and  then  declines  steadily  (5-­‐10%/  year)  

 Respiratory  failure  typically  occurs  in  the  late  teens  or  early  20s  

Sleep-­‐disordered  breathing

 Muscle  weakness  causes  restricIve  lung  disease    In  all  neuromuscular  disorders,  respiratory  muscle  funcIon  is  worst  in  sleep  

– Decreased  respiratory  muscle  tone  and  central  drive    This  sleep-­‐disordered  breathing  (SDB)  is  worst  in  REM  sleep  

 May  manifest  with  sleepiness,  headache  etc    

– FaIgability,  poor  exercise  tolerance,  poor  school  performance  – Symptoms  relate  to  CO2  retenIon,  not  to  hypoxia      

– Does  not  cause  shortness  of  breath  or  cough      Progresses  to  nocturnal  and  then  also  dayIme  hypovenIlaIon  

  Early  recogniIon  enables  appropriate  treatment

Typical  forms  of  lung  disease    

  Obstruc(ve  lung  disease    –  Increased  resistance  to  airflow  due  to  parIal  or  complete  obstrucIon  at  any  

level  (trachea,  bronchi,  terminal  or  respiratory  bronchioles)  

–  Lung  funcIon  tests  show  decreased  maximal  airflow  rates  during  forced  expiraIon,  usually  measured  by  forced  expiratory  volume  in  1  sec  (FEV1)      

  Restric(ve  lung  disease    

–  Reduced  expansion  of  lung  parenchyma  and  decreased  total  lung  capacity.  

–  Lung  funcIon  tests  show  a  reduced  total  lung  capacity  (TLC),  and  an  expiratory  flow  rate  that  is  normal  or  reduced  proporIonately  to  TLC.    

–  RestricIve  defects  occur  in  two  general  condiIons  

  (1)  chest  wall  disorders  e.g.  neuromuscular  diseases,  severe  obesity,  kyphoscoliosis    

  (2)  chronic  inters((al  and  infiltra(ve  diseases,  e.g.  pneumoconioses  and  intersIIal  fibrosis    

Advanced  Duchenne  muscular  dystrophy  Respiratory  deficit  

  Progresses  to  nocturnal  and  then  also  dayIme  hypovenIlaIon  

  Hypoxia  occurs  late  in  the  disease  course        

  Development  of  atelectasis,  pneumoniIs    

– Pump  failure-­‐  poor  inflaIon  and  emptying  of  lungs      

   Loss  of  respiratory  reserve  correlates  with  severity  of  kyphoscoliosis      

– Scoliosis  is  caused  by  weakness  of  paraspinal  muscles  

  Diaphragm  relaIvely  spared  Ill  late  in  disease  

Cardiac  involvement  in  DMD  and  BMD      

  Dilated  cardiomyopathy  >  hypertrophic  >  conducIon  defects    Cardiomyopathy  

–  Decreased  lem  ventricular  contracIlity  ,  occasional  cardiac  failure    –  Commonly  asymptomaIc/  subclinical    

–  1/3  teenage  yrs,  ½  by  18  yrs,  all  >18  yrs  –  Symptoms  omen  minimal  unIl  late  owing  to  musculoskeletal  limitaIons      

 Myocardial  fibrosis,  sinus  tachycardia,  ectopic  rhythms    –  90%  abnormal  ECG  

  Cardiac  death  in  10%  of  cases  

  Cardiomyopathy  more  common  in  Becker  MD

Dilated  cardiomyopathy  most  common  in  DMD  

(NB: Images differ slightly from those in presentation)

© 2011 UpToDate ®

Orthopaedic  involvement  in  DMD  

   Early  toe-­‐walking  common      Achilles  tendon  and  ilioIbial  band  (ITB)  contractures  

  Progressive  contractures:  hips,  knees,  elbows,  wrists  

– More  problemaIc  amer  wheelchair-­‐bound,  immobile        Scoliosis  

–  Increases  rapidly  amer  non-­‐ambulant  

Leitao et al. Sao Paulo Medical Journal 113: 995 – 999, 1995

Scoliosis  repair  stabilises  but  does  not  improve  respiratory  funcIon    

http://www.uofmhealth.org/News/884surgical+approach+to+treat+scoliosis+

CNS  involvement  

 Non-­‐progressive  (staIc)  cogniIve  impairment  –   Affects  verbal  >  performance  IQ  –   Mean  IQ  shimed  1SD,  approx.  80    (normal:  100)  –   No  good  correlaIon  with  locaIon  of  deleIons  

 Two  major  types  –   Reduced  verbal  IQ  –   Reduced  total  IQ  <  80  

 Occasional  auIsm    

3

810

11

32

20

12

9

3

0

3

6

9

12

15

18

21

24

27

30

33

36

<50 50-59 60-69 70-79 80-89 90-99 100-109 110-119 120+

TOTA

L N

o. O

F C

ASE

S

IQ RANGE

Normal  IQ  distribuIon  PMD Cases TOTAL -106

MEAN IQ = 86.1

DistribuIon  of  IQ  scores  in  boys  with  DMD

Cohen  et  al.  Dev  Med.Child  Neurol  1968;  10:754-­‐765.  

CogniIve  issues  in  DMD

   Degree  of  cogniIve  involvement  is  variable  – 1/3  significant  learning  difficulIes  

   SelecIve  impairment  of  verbal  working  memory  skills  leads  to  increased  risk  of  learning  difficulty    

   Greater  difficulty  remembering  stories,  difficulty  manipulaIng  verbal  informaIon  that  requires  immediate  memory  storage,  difficulty  with  comprehension    

   Profile  similar  in  subjects  with  DMD  regardless  of  whether  high  or  low  intelligence

CogniIve  problems  in  DMD  may  be  mulIfactorial

  Altered  dystrophin  expression  in  brain    – StaIc  intellectual  deficits  

  Effect  of  chronic  illness  

– School  absences      Psychosocial  effects  

– Anxiety  – Depression  – Behavioural  problems  (increased  by  steroids)    

  Effect  upon  family  

– Parental  expectaIons    – Parental  mood  problems

DMD:  Summary:  clinical  findings  

 Boys  appear  relaIvely  normal  for  first  few  years  of  life     Then:  rapid  loss  of  muscle  strength  and  funcIon   MulIple  systems  involved  

– Musculoskeletal      

– Respiratory  – Cardiac  – CNS    – Orthopaedic    

 Management  must  address  all  affected  systems