Muscular Dystrophies

Dr Meriel McEntagart St George’s Medical Genetics Unit Learning Objectives

 Meaning of term “muscular dystrophy”  Pros and cons of clinical versus molecular classification of muscular dystrophies  Have an appreciation of why such a large number of genes share the common feature of dystrophic muscle  Treatment options for muscular dystrophies

MUSCULAR DYSTROPHIES

Overview of inherited muscle disease Common pathology and classification of muscular dystrophies Duchenne/Becker muscular dystrophy & genetic counselling Facioscapulohumeral MD Limb girdle MD Congenital MD Other rarer types Common pathology

 Skeletal muscle  Cardiac muscle  Respiratory muscle  Additional clinical features

 CNS involvement

 Musculoskeletal involvement

 Eye abnormalities

 Skin changes Common pathology

 Elevated serum creatine kinase  Myopathic electrophysiology  Muscle biopsy finding  Dystrophic process affecting muscle fibres  Rounding up of fibres  Splitting of fibres  Regenerative fibres  Accumulation of connective tissue  Fat infiltration  Signs of inflammation  Immunohistochemistry to distinguish subtypes

Classification Muscular Dystrophies

 Phenotype ie Clinical

 Distribution muscle involvement

 Proximal eg Limb girdle MD

 Distal eg Tibial MD

 Generalised eg Congenital MD

 Genotype ie Molecular

 According to gene involved

 Allelic disorders different phenotypes

Clinical Classification Muscular Dystrophies  Duchenne/Becker Muscular Dystrophy  Limb Girdle Muscular Dystrophy  LGMD1A,B,C… autosomal dominant  LGMD2A,B,C… autosomal recessive  Congenital Muscular Dystrophy  MDC1A,B,C…  Distal Muscular Dystrophy  Muscular Dystrophy with contractures  Emery-Dreifuss XLR, AD  Bethlem myopathy  Facio-scapulo-humeral MD  Myotonic MD  Other rare

Molecular classification MD

 Dystrophinopathies DMD/BMD cardiomyopathy  Laminopathies EDMD, LGMD, Cardiomyopathy,(Lipodystrophy, CMT)  Dystroglycanopathies CMD and LGMD  Sarcoglycanopathies LGMD2  Dysferlinopathies LGMD and distal MD  Collagenopathies LGMD and CMD

DMD pedigree

5y 3y 5 m Dystrophin

 DMD

 70% Duplications or deletions of whole exons

 Point mutations

 Out of frame mutations  BMD

 Duplications/deletions of whole exons

 Point mutations

 In frame mutations

 Produce some dystrophin with residual function Limb girdle muscular dystrophies

Examples • Sarcoglycanopathies • Dystroglycanopathies • Dysferlinopathy

Muscular Dystrophy Congenital

 Classical CMD (Merosin deficient/laminin alpha 2)  Hypotonia +/- contractures  White matter changes MRI brain  Intellect normal  Fukuyama CMD  Mental retardation  Structural brain abnormality  Muscle-eye-brain MD  Mental retardation  Hydrocephalus  Ocular abnormalities eg myopia, glaucoma, retinal or optic atrophy  Walker-Warburg MD  Mental retardation  Lissencephaly II “smooth brain”  Ocular malformations

Muscle-eye-brain and Walker-Warburg FKRP Distal myopathies

Adult onset • late • early

Examples • Myofibrillar myopathies • Welander • Nonaka

Nuclear envelope protein neuromuscular diseases

Emery–Dreifuss muscular dystrophy (XL & AD) Emery Dreifuss muscular dystrophy

Onset usually childhood • rare after 20 years Contractures Cardiac conduction defects/ cardiomyopathy Humeral/peroneal muscle wasting

Genes • Emerin (XL) • Lamin A/C (AD)

Collagen VI related muscle disorders

Bethlem myopathy (AD) and Ullrich congenital MD (AD & de novo dominant) Ullrich CMD

FSH MD

Autosomal dominant

FSHD gene?

 Contraction of macrosatellite repeat D4Z4 in subtelomeric region 4q35

 FSHD patients 1-10 units, controls 11-100

 10-30% FSHD de novo contraction of D4Z4 repeat

 Contractions on specific 4q haplotypes pathogenic thus contraction itself not sufficient to cause the disease

 Molecular mechanism underlying the myopathy unknown

 ?alteration in transcriptional characteristics of 4q subtelomere Myotonic Dystrophy Myotonic Dystrophy

 Multisystem disorder

 Muscle weakness distal +

 Myotonia

 Respiratory failure

 Cardiac arrhythmias

 Cataracts

 Diabetes mellitus

 Hypogonadism

 Anaesthetic risks

 Two types

 DM1 (most common) CTG expansion 3’UTR DMPK gene ch 19

 DM2 untranslated CCTG expansion intron 1 ZNF9 ch 3

Triplet repeat disorder DM1 Risk congenital myotonic dystrophy on maternal transmission in DM1 Mode of action mutations DM1&2?

 Hypothesis that RNA pathogenesis causes multisystem clinical features  RNA gain of function  Splicing alterations

 Cardiac troponin T (cTNT)

 Insulin Recepton (IR)

 Muscle specific Chloride Channel (Clc-1)

 Tau CNS

 Myotubularin MTMR1 in congenital DM1 muscle Treatment of muscular dystrophies

 Supportive with physiotherapy and occupational therapy  Steroids in DMD  Gene therapy with viral vectors  Antisense oligomers to convert out-of-frame to in-frame ie DMD to BMD phenotype “molecular patch”  PTC124 a small organic molecule can force the translation machinary to ignore premature termination codons

TREAT NMD

 http://www.treat-nmd.eu/  Disease information  Patient Registries  Research  Industry  Biobanks The End

Muscle-eye-brain POMGnT1

Muscle-eye-brain 1p32 Distal Myopathies

 Late adult onset  Type 1 AD Welander 2p13  Type 2 AD Markesbery-Griggs/Udd Titin

 Early adult onset  Type 1 AR Nonaka (Familial IBM) GNE  Type 2 AR Miyoshi (LGMD2B) Dysferlin  Type 3 AD Laing MYH7  Myofibrillar myopathies Myotilin ZASP Desmin αBcrystallin

Collagen VI related muscle disorders  Genes involved COL6A1, COL6A2, COL6A3  Bethlem myopathy AD  Mild proximal myopathy  Contractures long finger flexors, wrists, elbows, ankles  Skin features eg follicular hyperkeratosis, keloid formation, cigarette paper scars  Ullrich congential MD AR and de novo AD  Early onset muscle weakness  Proximal joint contractures later spine, achilles and finger flexors  Distal joint laxity  Normal intelligence  May never walk independently  Respiratory failure second decade  Skin changes as per Bethlem myopathy

Nuclear envelope protein neuromuscular diseases  XLR and AD Emery-Dreifuss MD  Early contractures Achilles,elbows,spine  Muscle wasting humeral and peroneal  Cardiac conduction defect/cardiomyopathy

 Usually present by 30y  Onset usually in childhood rare after 20y  CK usually elevated but may be normal  XL Emerin gene  AD Lamin A/C gene