Muscle disease for physios May 2014

Categories of muscle disease Congenital muscular dystrophy, congenital myopathy Mitochondrial Metabolic Channelopathy Inflammatory polymyositis Degenerative eg inclusion body myopathy Iatrogenic eg drugs, statins

Function – watch how they walk into clinic/get out of their seat etc before actual assessment Limb girdle type of pattern? (waddling gait; lordosis) Facial weakness? Droopy eyelid? Foot drop? Odd shoulders? Scoliosis/other spinal deformity? Small stature? Dysmorphic? Hearing aids? Walking aids, Wheelchair?

Alteration in function Difficulty getting up and out of chairs/sofas/cars Difficulty rising from a squat Climbing stairs/holding onto bannisters Reaching out for shelves; raising arms; hairdrying; shaving Difficulty opening jars; picking objects; doing buttons Slapping feet

Muscle pain Myalgia (flu-like) – myositis, Vitamin D def, fibromyalgia/PMR Cramp Contracture (cramp but muscle goes rock hard) Myotonia (muscle stiffness) look for grip and percussion myotonia Muscle pain with focal swelling (myositis/metabolic)

Contractures Progressive fibrosis of muscle + weakness of antagonistic muscles = muscle shortening and inability to passively stretch to normal length Sometimes pathognomic of certain disease

Contractures are typical especially in Lamin A/C mutations (LGMD) and Bethlem myopathy (congenital myopathy with collagen 6 mutations)

Skeleton – look for rigid spine Emery-Dreifuss Selenoprotein

Scapular winging in FSH muscular dystrophy But other LGMDs can give you scapular winging

Muscle weakness Distribution Axial (do they have a dropped head? Do they have a bent spine – camptocormia?) Limbs Face Eyes Bulbar

Anaesthetic complications Patient should wear Medic-Alert bracelet Anaesthetist should be informed of condition and long-acting neuromuscular blocking agents should be avoided

Dystrophinopathies Duchenne (DMD): Commonest childhood muscular dystrophy 1:3500 male births Becker (BMD): 1:18,000 male births X-linked recessive Females not generally affected, but some may have abnormalities on clinical exam, or nonprogressive myopathy, or manifesting carriers (skewed inactivation of X chromosome and higher proportion of defective gene producing mutant protein)

Origin of DMD 1/3 previous family history 2/3 no family history In the latter, mother is an undiagnosed carrier (33%) Or mutation occurred in ovum producing the son with DMD (germ line mutation) (66%) Once the diagnosis is made, genetic counselling should be offered to the family especially maternal female relatives who are likely to be carriers

Molecular genetics Dystrophin is a large protein Gives structural integrity to the sarcolemma and prevents contraction-induced damage Links intracellular cytoskeleton to the extracellular matrix Gene lies on X chromosome, at Xp21 Large gene – 2500 kb long, >70 exons

Clinical manifestations Progressive weakness and wasting of mainly proximal muscles first, distal muscles later Girdle muscles affected first Calf pseudohypertrophy (fat replacement) Abnormal gait in the child, frequent falls Waddling gait because of involvement of hip abductors and more lordotic because of weakness of hip extensors

Calf pseudohypertrophy Increasing lordosis

Course of disease Progressive weakness and wasting Worse after period of inactivity/bedrest Kyphoscoliosis (spinal surgery and bracing) Wheelchair bound Frequent respiratory infections Respiratory muscle weakness (non-invasive ventilation) Contractures (may need releasing)

Cardiac manifestations Conduction defects Congestive heart failure often in terminal stages when respiratory failure develops Beta-blockers and ACEI Important to monitor female carriers (even in absence of limb muscle involvement)

Intellectual impairment Not progressive IQ at least one SD below normal Minor cerebral atrophy

Becker MD Milder version of DMD Phenotype more variable Onset between 5 and 15 years but may present in their 30s or 40s Similar distribution of muscle weakness Contractures and spinal deformity almost never Dilated cardiomyopathy even when weakness is mild Intellectual impairment less common

Diagnosis Clinical features + High CK Muscle biopsy – frequently not required/done Genetic analysis (detects deletions/duplications in 70% of DMD and 80% of BMD)

Treatment options and trials Corticosteroids: improvement in muscle strength in 11% and improved functional activity (climb stairs faster) Viral vector delivery of dystrophin cDNA (AAV safer) Exon skipping

Females Females not generally affected, but some may have abnormalities on clinical exam, or nonprogressive myopathy Can be manifesting carriers (skewed inactivation of X chromosome and higher proportion of defective gene producing mutant protein) Large calves May have proximal muscle weakness May have cardiomyopathy

Facioscapulohumeral MD Age of onset of symptoms: 7 to 30 years Can present much later Autosomal dominant inheritance Signs can be subtle and asymmetric Facial weakness often detected first Unable to close eyes tightly/bury eyelashes Transverse smile Unable to whistle

Progression Facial weakness first Foot dorsiflexors Abdominal muscles Shoulder girdle and humeral muscles Pelvic girdle and proximal lower limb muscles later 20% are wheelchair dependent by age 40

Odd shoulder contour High-riding scapulae Scapular winging Weakness of shoulder girdle develops first. Weakness of triceps/biceps and supraspinatus develops later

Cardiac muscle not affected But respiratory muscle involvement is common and respiratory muscle function needs to be regularly monitored

Sensorineural hearing loss (75%) Patients need to be asked specifically about this Commoner in those who present earlier in life Retinal vasculopathy (50%) (Coat’s disease)

Pain Beyond the deformity from their periscapular and pelvic muscle weakness Often difficult to control

Limb-girdle MD Marked genetic heterogeneity Clinically diverse with wide range of phenotypes Different ages of presentation, different muscle group involvement, different grades of severity with different rate of progression LGMD 1 = autosomal dominant LGMD 2 = autosomal recessive Diagnosis mostly made by protein immunoblotting from muscle biopsies

LGMD Autosomal dominant Autosomal recessive LGMD 2A:Calpain 3 LGMD1A: Myotilin LGMD1B: Lamin A/C (+cardiac involvement) LGMD1C: Caveolin 3 LGMD1D: ? Gene product (+cardiac involvement) LGMD1E: ? Gene product Autosomal recessive LGMD 2A:Calpain 3 LGMD 2B: Dysferlin LGMD 2C: Gamma-sarcoglycan LGMD 2D: Alpha-sarcoglycan LGMD 2E: Beta-sarcoglycan LGMD 2F: Delta-sarcoglycan LGMD 2G: Telethonin LGMD 2H: TRIM32 LGMD 2I: FKRP LGMD 2J: Titin LGMD 2K: POMT1 LGMD 2L: ANO5

LGMD 1B Contractures Rigid spine Some patients have lipodystrophy Cardiac involvement requiring pacemakers/ICDs Proximal and distal muscle weakness

Emery-dreifuss: typical contractures at the elbows Rigid spine

LGMD 2A Contractures esp around calf, elbows, fingers Waddling gait Toe-walking as a child Leg>arms Periscapular and quadriceps Respiratory failure

LGMD 2L FKRP Proximal>distal Legs and arms Legs affecting thigh adductors, psoas and quads Arms – periscapular, deltoid, biceps and triceps Type 2 respiratory failure even when ambulant Can have calf, thigh and tongue hypertrophy

LGMD 2L ANO5 Progressive proximal muscle weakness Previously can be very strong individuals including marathon runners etc Can have focal atrophy of biceps and focal hypertrophy of lateral gastrocnemius Can have mild distal lower limb weakness

Oculopharyngeal muscular dystrophy Men>women Autosomal dominant Ptosis Bulbar problems – may require gastrostomy for feeding Progressive myopathy May develop respiratory muscle involvement

Metabolic myopathies Lipid storage myopathies CPT2 deficiency Glycogen storage disorders McArdle’s Mitochondrial myopathies Syndromes Defects in fatty acid oxidation pathways Complex

Cramps Exercise intolerance Rhabdomyolysis Progressive myopathy

Mitochondrial disorders Multi-system disorders Myopathy Complex eye problems Endocrinological problems Hearing loss Gastrointestinal problems CNS problems including migraine and seizures Learning disabilities Short stature etc

Pompe’s disease Infantile onset – severe and fatal In infants with cardiac involvement and hepatosplenomegaly Adult-onset Progressive myopathy Respiratory involvement Enzyme replacement therapy

Inclusion body myopathy An acquired degenerative muscle condition Slow, insiduous and progressive Usually affects >4th decade Fine motor tasks (eg opening bottle jars, buttons) Early falls in IBM due to involvement of quadriceps (with wasting often by time of presentation) Also wasting of flexor muscle compartment of forearm with finger flexion weakness in IBM Patients with IBM do not respond to immunomodulatory treatments eg steroids

Quadriceps wasting in IBM

Wasting of forearm flexor compartment in IBM

Prognosis Poor Develop facial weakness and problems swallowing Can have neck weakness Often end up in wheelchair No cardiac complications but may require NIV and PEG feeding