Muscular Dystrophies Patarawan Woratanarat, MD, PhD Department of Orthopaedics Faculty of Medicine Ramathibodi Hospital

A 7-year-old boy presents with progressive weakness of both legs for 4 years.

Definition A group of noninflammation inherited distroders progressive degeneration and weakness of skeletal muscles without cause in peripheral / central nervous system

Classification Sex-linked: DMD, BMD, EDMD Autosomal recessive: LGMD, infantile FSHD Autosomal dominant: FSHD, distalMD, ocular MD, oculopharyngeal MD.

Duchenne Muscular dystrophy Guillaume Benjamin Amand Duchenne (French neurologist, 1860s)

Duchenne Muscular dystrophy Etiology single gene defect Xp21.2 region absent dystrophin

Duchenne Muscular dystrophy

Duchenne Muscular dystrophy

DMD: pathology

DMD: Epidemiology Most common male, Turner syndrome 1:3500 live male birth 1/3 new mutation 65% family history

DMD: Clinical manifestation Onset : age 3-6 years Progressive weakness Pseudohypertrophy of calf muscles Spinal deformity Cardiopulmonary involvement Mild - moderate MR

Pseudohypertrhophy of calf muscle, Tip toe gait forward tilt of pelvis, compensatory lordosis

Disappearance of lordosis while sitting

DMD: Diagnosis Gower’s sign

DMD: Diagnosis Increase CPK (200x) Gait Myopathic change in EMG Bx: m. degeneration Immunoblotting: Absence dystrophin DNA mutation analysis Gait absent DTR Ober test Thomas test Meyeron sign Macroglossia Myocardial deterioration IQ ~ 80

Western blot Normal dystrophin bands (230kD)

DMD: Natural history Progress slowly and continuously muscle weakness lower --> upper extremities unable to ambulate: 10 year (7-12) death from pulmonary/ cardiac failure: 2-3rd decade

DMD: Treatment Prednisolone Dystrophin replacement Maintain function PMR orthosis cardiopulmonary Rx Counselling

DMD: Treatment Surgery Foot & ankle: Achillis, Tibialis posterior release Knee: Yount, hamstring release Hip: Ober, modified Soutter procedure

DMD: Treatment An 8-yr-old boy Unable to stand Percut. Tenotomy Achillis tendon Ambulate with orthosis

DMD: Treatment Surgery Upper extremity: - Spinal deformity: posterior spinal fusion + pelvis

Becker muscular dystrophy Peter Emil Becker (German doctor, 1950s)

Becker muscular dystrophy Milder version of DMD Etiology single gene defect short arm X chromosome altered size & decreased amount of dystrophin

Becker muscular dystrophy

BMD: Epidemiology Less common Less severe Family history: atypical MD 1: 30000 live male birth Less severe Family history: atypical MD

BMD: Clinical manifestation Similar & less severe than DMD Onset: age > 7 years Pseudohypertrophy of calf Equinous and varus foot High rate of scoliosis Less frequent cardiac involvement

BMD: Diagnosis The same as DMD Increase CPK (<200x) Decrease dystrophin and/or altered size

BMD Natural history Treatment Slower progression ambulate until adolescence longer life expectancy Treatment the same as in DMD forefoot equinous: plantar release, midfoot dorsal-wedge osteotomy

Emery-Dreifuss muscular dystrophy Etiology X-linked recessive Xq28 Emerin protein (in neuclear membrane) Epidemiology Male: typical phenotype Female carrier: partial

EDMD: Clinical manifestation Muscle weakness Contracture Neck extension, elbow, achillis tendon

EDMD: Clinical manifestation Scoliosis: common, low incidence of progression Bradycardia, 1st degree AV block  sudden death

EDMD Natural history Diagnosis 1st 10 y: mild weakness Gower’s sign Later: contracture, cardiac abnormality 5th-6th decade: can ambulate Poor prognosis in obesity, untreated equinus contractures. Diagnosis Gower’s sign Mildly/moderately elevated CPK EMG: myopathic Normal dystrophin

EDMD: Treatment Physical therapy Soft tissue contracture Prevent contracture: neck, elbow, paravertebral muscles For slow progress elbow flexion contracture Soft tissue contracture Achillis lengthening, posterior ankle capsulotomy + anterior transfer of tibialis posterior Spinal stabilization For curve > 40 degrees Cardiologic intervention Cardiac pacemaker

Limb-girdle muscular dystrophy Eitology Autosomal recessive at chromosome 15q Autosomal dominant at 5q Epidemiology Common More benign

Limb-girdle muscular dystrophy an absence of functional sarcoglycans components of the dystrophin glycoprotein complex (DCG). Other LGMD result from the absence of functional caveolin-3

Limb-girdle muscular dystrophy Clinical manifestation Age of onset: 3rd decade Initial: pelvic/shoulder m. (proximal to distal) Similar distribution as DMD

LGMD Diagnosis Classification Same clinical as DMD/BMD carriers Pelvic girdle type common Scapulohumeral type rare Diagnosis Same clinical as DMD/BMD carriers Moderately elevated CPK Normal dystrophin

LGMD Natural history Treatment Slow progression Similar to DMD After onset > 20 y: contracture & disability Rarely significant scoliosis Treatment Similar to DMD Scoliosis: mild, no Rx.

Fascioscapulohumeral muscular dystrophy Etilogy Autosomal dominant Gene defect (FRG1) Chromosome 4q35 Epidemiology Female > male Clinical manifestation Age of onset: late childhood/ early adult No cardiac, CNS involvement

FSMD: Clinical manifestation Muscle weakness face, shoulder, upper arm Sparing Deltoid Distal pectoralis major Erector spinae

“Popeye” appearance Lack of facial mobility Incomplete eye closure Pouting lips Transverse smile Absence of eye and forehead wrinkles

FSMD: Clinical manifestation Winging scapula Markedly decreased shoulder flexion & abduction Horizontal clavicles forward sloping Rare scoliosis

FSMD Treatment Diagnosis Natural history Posterior scpulocostal fusion/ stabilization (scapuloplexy) Diagnosis PE, muscle biopsy Normal serum CPK Natural history Slow progression Face, shoulder m.  pelvic girdle, tibialis ant Good life expectancy

Distal muscular dystrophy Autosomal dominant trait Rare Dysferlin (mb prot) defect Age of onset: after 45 y

Distal muscular dystrophy Initial involvement: intrinsic hands, claves, tibialis posterior Spread proximally Normal sensation

DD: Classification Welander distal myopathy Finnish/Markesbery distal myopathy Miyoshi distal myopathy Nonaka distal myopathy Gower: autosomal dominant, Chromosome 14 Hereditary inclusion-body myositis Hereditary inclusion-body myuositis Distal myopathy with vocal cord & pharyngeal weakness

Congenital muscular dystrophy Etiology Autosomal recessive Integrin, fugutin defect Laminin 2 chain merosin

CMD: Epidemiology Classification Rare Both male and female Merosin-negative Merosin-positive Neuronal migration Fukuyama Muscle eye-brain Wlaker-Warburg

CMD: Clinical manifestation Stiffness of joint Congenital hip dislocation, subluxation Achillis tendon contracture, talipes equinovarus Scoliosis

CMD Diagnosis Treatment Muscle Bx: Perimysial and endomysial fibrosis Physical therapy Orthosis Soft tissue release Osteotomy

Summary Clinical DMD LGMD FSMD DD CMD Incidence common less Not common Rare Age of onset 3-6 y 2nd decade 20-77 y At/ after birth Sex Male Either sex M = F Both Inheritance Sex-linked recessive AR, rare AD AD Unknown Muscle involve. Proximal to distal Face & shoulder to pelvic Distal Generalized Muscle spread until late Leg, hand, arm, face, larynx,eye Upper ex, calf Back ext, hip abd, quad Proximal -

Summary Clinical DMD LGMD FSMD DD CMD Pseudo hypertrophy 80% calf < 33% Rare no No Contracture Common Late Mild, late Severe Scoliosis Kyphoscoliosis Common, late - ? Heart Hypertrophytachycardia Very rare Not observed Intellectual decrease Normal Course Stead, rapid Slow Insidious benign Steady

Thank you

Infantile fascioscapulohumeral muscular dystrophy Clinical manifestation Facial diplegia Sensorinueral hearing loss Mobius type of facial weakness Walk with hands and forearms folded across upper buttocks **Marked & progressive lumbar lordosis (pathog) Less common equinous, scoliosis Etiology Autosomal recessive Unidentified gene

IFSMD Natural history Treatment Infancy: facial diplegia Childhood: sensorineural hearing loss 2nd decade of life: wheelchair bound, severely compromised pulmonary function Treatment Flexible equinous/equinovarus foot: AFO + TAL Hip flextion contracture: no Rx in ambulate pt. Spinal deformity in wheelchai ambulator: orthosis+ post spinal fusion with instrumentation Scapulothoracic stabilization: not necessary

Ocular muscular dystrophy Rare Age of onset: adolescence Extraocular muscle weakness  diplopia  limit ocular movement May involve proximal upper extremities Slowly progressive

Oculopharyngeal muscular dystrophy Autosomal dominant with complete penetrane Age of onset: 3rd decade Ptosis in middle life

OPMD Pharyngeal involvement Dysarthria Dysphasia Repetitive regurgitation Frequently choking