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Duchenne muscular dystrophy

Benedict J.A. Lankestera, Michael R. Whitehouseb, Martin F. Garganc,!

aSpecialist Registrar in Trauma and Orthopaedics, Avon Orthopaedic Centre, Southmead Hospital,Westbury-on-Trym, Bristol BS10 5NB, UKbSHO in Trauma and Orthopaedics, Bristol Royal Infirmary, Bristol BS2 8HW, UKcConsultant in Trauma and Orthopaedics, Bristol Royal Infirmary and Bristol Hospital for Sick Children, Bristol BS2 8HW, UK

Introduction

In 1868, Guillaume Duchenne (18061875), working in Paris,described a pseudohypertrophic paralysis y which de-ceives and deludes by giving the limbs the appearance ofgreat muscularity.1 Duchenne muscular dystrophy (DMD) isthe most common childhood neuromuscular disorder, wasthe first muscular dystrophy described, is incurable atpresent and is invariably fatal. The disease involves aprogressive degeneration of skeletal muscle without asso-ciated abnormality in the central or peripheral nervoussystem.2

Epidemiology and genetics

DMD has an incidence of 23 per 100,000, or 1 in 3500 boys.It is an X-linked recessive disorder, and can thereforepresent in XO females (Turners syndrome). The incidence isreducing due to genetic counselling, but 30% of cases involvespontaneous mutations. The gene involved was first mappedin 1987 and is located on the short arm of the X chromosome(Xp21). It codes for dystrophin, a 400 kDa membrane proteininvolved in membrane stability. Many different mutationsand deletions have been described, causing varying pheno-typic severity.

Clinical presentation and diagnosis

Affected boys are normal at birth and early motor mile-stones may be appropriate (head control, sitting, etc.).Independent ambulation is usually delayed, with tiptoewalking and delayed speech. Steady progression results in awaddling gait with frequent stumbling and tripping, diffi-culty standing up and problems with stair climbing.

Proximal muscle weakness precedes distal. Early involve-ment of the gluteal musculature results in Gowers sign(when rising from the floor, the child walks his hands uphis thighs due to weakness of hip extension, although widelydescribed as pathognomonic for DMD, this sign can also bepresent in the early stages of discitis).3 Relative sparing oftibialis posterior function causes tiptoe walking and equi-novarus deformity (Fig. 1). Another classic feature is calfpseudohypertrophy due to fibro-fatty infiltration, giving afirm rubbery feel on palpation.

By the age of 7, walking becomes increasingly difficult.The knee is hyperextended and the torso tilted back in anattempt to lock out the hip and knee joints. The ability towalk is lost on average at 9 years of age (range 612), afterwhich the patient becomes wheelchair bound and maydevelop severe flexion contractures. Scoliosis affects 90%,with progressive collapse into a C shape, and severe pelvicobliquity leading to loss of sitting balance. Painful hipdislocation may occur. Most die in their early 20s fromcardio-respiratory failure.

The lack of dystrophin in the cell membrane leads to therelease of creatine kinase (CK) from myocytes, allowing thediagnosis to be made by markedly increased serum CK levels(100!normal) before symptoms and signs develop. Carrier

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!Corresponding author. Tel.: +44 0117 923 2121;fax: +44 0117 928 2659.

E-mail addresses: jblankester@aol.com (B.J.A. Lankester),mike_whitehouse@yahoo.com (M.R. Whitehouse),martin.gargan@ubht.swest.nhs.uk (M.F. Gargan).

Current Orthopaedics (2007) 21, 298300

females, although asymptomatic, will also have CK levels75% greater than normal. Electromyography will demon-strate myopathic signs (short duration action potentials andpolyphasic units) and muscle biopsy shows absence of

dystrophin on staining. Genetic testing is available forconfirmation in the affected boy, carrier mother or foetus.

The pattern of physical findings should allow a clinicaldiagnosis to be made from the age of 3 years onwards, but itis often missed at first presentation, leading to the potentialfor further affected pregnancies in uninformed families.A serum CK estimation should be carried out on any boy witha clumsy or abnormal gait or with an unexplained equinusdeformity.4 The only way reliably to reduce the age ofdiagnosis would be to introduce a newborn screeningprogramme,5 but there are no plans for this in the UK.

The less common but milder Becker muscular dystrophy,which involves a different type of mutation in the same gene,causes structurally abnormal dystrophin to be produced.There is a later age of onset and slower progression.

Treatment

General

Currently, no curative treatment is available for DMD.Affected boys should be kept ambulatory or standing for as

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Figure 1 Equino-varus foot deformity.

Figure 2 Scoliosis pre and post operatively.

Duchenne muscular dystrophy 299

long as possible. Regular stretching and strengtheningexercises, night-time splinting, ground-reaction AFOs and astanding frame may all be useful. Corticosteroids (predni-solone and deflazacort) have been shown to delay the loss ofmuscle strength and function by up to 3 years2 and delay orprevent the onset of scoliosis,6 but have serious potentialside effects including weight gain and Cushings syndrome.

Lower limbs

Serial hip radiographs are used to screen for subluxation.7

Flexion and abduction contractures of the hip may re-quire percutaneous release. Equinovarus foot deformity istreated with tendo achillis lengthening and tibialis post-erior transfer which prolongs the ability to walk.8 Surgicalrelease of soft tissue knee contractures is less effective.Aggressive post-operative rehabilitation is needed to pre-serve overall function, with an avoidance of prolongedimmobilisation.

Spine

The spinal deformity is not amenable to non-surgicalcontrol.2 Early fusion with segmental instrumentationimproves the Cobb angle, delays the deterioration in lungfunction and improves survival (Fig. 2).9,10 Timing is crucial,with a narrow window of opportunity after the curve startsto develop, but before respiratory and cardiac function arecompromised to the point that the risk of surgery is toogreat.2 An FVC less than 30% of the predicted value does notnecessarily preclude surgery.11

A long thoraco-lumbar fusion is performed. In boys withsignificant shoulder weakness, any kyphosis should be onlypartially corrected to avoid the loss of ability to raise thehand to the mouth. Blood loss12 and overall complications13

are higher than for idiopathic scoliosis correction. The vitalcapacity at the age of 10 is a good predictor of the speed ofprogression14 and is useful in identifying those that requireearly surgical intervention.

Gene therapy

Although the gene defect responsible for DMD was identifiednearly 20 years ago, the development of effective therapyhas been slow. The large size of the dystrophin gene makestransfer difficult by the standard vector systems, necessi-tating the development of novel approaches. A minigene hasbeen successfully transferred in a mouse model of DMD, withrestoration of normal muscle function.15 Other attempts arebeing made to target the downstream effects of DMD, suchas the implantation of myoblasts into dystrophic muscle torepair a proportion of damaged myofibrils.16 Together theseadvances in molecular biology suggest a cure for DMD maybe available in the near future.

Acknowledgements

The authors would like to thank Simon Gatehouse and MikeGibson, Newcastle General Hospital, for providing thefigures.

References

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3. Miroysky A, Copeliovich L, Halperin N. Gowers sign in childrenwith discitis of the lumbar spine. J Paediatr Orthop B 2005;14:6870.

4. Read L, Galasko CSB. Delay in diagnosing Duchenne musculardystrophy in orthopaedic clinics. JBJS [B] 1986;68B:4812.

5. Parsons EP, Clarke AJ, Bradley DM. Developmental progress inDuchenne muscular dystrophy: lessons for earlier detection. EurJ Paediatr Neurol 2004;8:14553.

6. Alman BA, Raza SN, Biggar WD. Steroid treatment and thedevelopment of scoliosis in males with Duchenne musculardystrophy. JBJS [A] 2004;86A:51924.

7. Chan KG, Galasko CSB, Delaney C. Hip subluxation anddislocation in Duchenne muscular dystrophy. J Paediatr OrthopB 2001;10:21925.

8. Scher DM, Mubarak SJ. Surgical prevention of foot deformity inpatients with Duchenne muscular dystrophy. J Paediatr Orthop2002;22:38491.

9. Galasko CSB, Delaney C, Morris P. Spinal stabilization inDuchenne muscular dystrophy. JBJS [B] 1992;74B:2104.

10. Bentley G, Haddad FS, Bull TM, Seingry D. The treatment ofscoliosis in muscular dystrophy using modified Luque andHarringtonLuque instrumentation. J Bone Joint Surg Br 2001;83:228.

11. Marsh A, Edge G, Lehovsky J. Spinal fusion in patients withDuchennes muscular dystrophy and a low forced vital capacity.Eur Spine J 2003;12:50712.

12. Fox HJ, Thomas CH, Thompson AG. Spinal instrumentation forDuchennes muscular dystrophy: experience of hypotensiveanaesthesia to minimise blood loss. J Paediatr Orthop 1997;17:7503.

13. Ramirez N, Richards BS, Warren PD, Williams GR. Complicationsafter posterior spinal fusion in Duchennes muscular dystrophy.J Paediatr Orthop 1997;17:10914.

14. Yamashita T, Kanaya K, Kawaguchi S, Murakami T, Yokogushi K.Prediction of the progression of spinal deformity in Duchennemuscular dystrophy: a preliminary report. Spine 2001;26:2236.

15. Biggar WD, Klamut HJ, Demacio PC, Stevens DJ, Ray PN.Duchenne muscular dystrophy: current knowledge, treatment,and future prospects. Clin Orthop 2002;401:88106.

16. Sohn RL, Gussoni E. Stem cell therapy for muscular dystrophy.Expert Opin Biol Ther 2004;4:19.

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Duchenne muscular dystrophyIntroductionEpidemiology and geneticsClinical presentation and diagnosisTreatmentGeneralLower limbsSpineGene therapy

AcknowledgementsReferences