Muscular Dystrophies Pinki Munot Consultant Paediatric Neurologist Great Ormond Street Hospital Practical Neurology Study days April 2018
Definition and classification Clinical guide to recognize muscular dystrophies Diagnostic tests Therapy options and anticipatory care
What are Muscular dystrophies? Genetically heterogenous disorders Progressive muscle weakness Dystrophic muscle biopsy: areas of muscle necrosis and increased fat and connective tissue i.e degeneration and regeneration Types and prevalence: Dystrophinopathies-DMD and Becker most common Congenital and Limb girdle muscular dystrophies FSHD and myotonic dystrophy distinct phenotypes
Dystrophinopathies - DMD 1 in 3500 X-linked Very high CK Presents with motor/global delay Rapidly progressive Proximal weakness, calf hypertrophy, waddling gait and difficulty climbing Wheelchair dependent by 13 years Cardiomyopathy Respiratory complications Deletions of one or more exons (~65%), but also duplications (~7%), and point mutations (~25%)
Becker muscular dystrophy Onset in teens May present with cramps or myoglobinuria Progression/severity variable Ambulant beyond 17 years Behaviour or speech difficulties DCM - cause of morbidity Dystrophinopathies Manifesting carriers in females
Clinical spectrum of congenital and Limb girdle Muscular dystrophies CMD LGMD Walker Warburg Syndrome Muscle Eye Brain MDC1C.MDC1B LGMD with abnormal Brain MRI LGMD with normal Brain
Group of inherited disorders with early onset of muscle weakness and hypotonia with histological features suggesting a dystrophic process Abnormalities of eye, skin and brain are commonly present Differentials: congenital myopathies, myotonic dystrophy, SMA, metabolic, Myasthenia. Muscle pathology is the key
Proteins involved in Congenital & Limb girdle Muscular Dystrophies
CMD Types
CMD Types UK NSCT data LMNA related CMD Sframeli et al, unpublished data May 2015
Assessment of CMD Reduced fetal movement Poor suck Not kicking Hypotonia Marked head lag Sub-gravity shoulders & hips Contractures in hips, knees, ankles and fingers Mild spinal rigidity Recurrent Chest infections CK 2600
LGMD Presentation Weakness Weakness Weakness Difficulty with stairs or running Gower s sign Incidental CK Contractures toe walking Abnormal Brain MRI
Assessment of children Muscle Bulk: wasting, scapular winging or pseudohypertrophy Muscle strength: Observe reaching, rising from floor, walking, running. Observe trunk/head control for axials Joint contractures Distal laxity Spinal rigidity Scoliosis Family History Review of Systems
Assessment of children
Example -A child with LGMD Mimics DMD Calf hypertrophy Difficulty with stairs/running Positive Gower s CK 10 times normal DMD genetics negative Reduced Alpha Dystroglycan
Proteins involved in Congenital & Limb girdle Muscular Dystrophies
Differential diagnosis of Limb girdle weakness Acquired inflammatory myositis Metabolic e.g. Pompe /Mitochondrial, Congenital/structural myopathy Neurogenic diseases such as SMA 3 Limb girdle Myasthenia FSHD Myotonic dystrophy Serum CK and muscle biopsy is of great importance
Fascioscapulohumeral muscular dystrophy Often presents before 20 y Face and shoulder weakness with foot drop Highly variable severity Retinal vascular involvt Hearing loss Autosomal Dominant Deletion of D4Z4 in 95%
Myotonic muscular dystrophy Most common muscular dystrophy in adults Autosomal dominant Clinical myotonia Early cataracts Cardiac rhythm disorders Face, legs neck and arms Type 1 (DMPK)and type 2 (CNBP) Congenital myotonic dystrophy
Diagnostic workup Creatine kinase : Usually markedly elevated. Can be normal. If very high SG or dysferlin Muscle histology -Dystrophic changes include necrosis, degeneration, regeneration, fibrosis and fatty infiltration, sometimes mild inflammation. Muscle Immunohistochemistry for the missing protein. Western blot quantifies percent of normal protein Brain MRI Muscle MRI Genetic confirmation Individual gene or panels
Muscle Histology and Immunohistochemistry
Muscle biopsy Merosin deficient CMD H&E TRICHROME
Muscle MRI - Differential involvement and pattern recognition Mercuri et al: Muscle MRI in Rigid Spine in annals of Neurology 2009 Collagen 6 SEPN1
Brain MRI in CMD MDC1A Dystroglycanopathy POMGNT1 Walker Warburg to B3GALNT2
Molecular testing Array CGH Dystrophin testing Gene sequencing Gene panels HST services (London/Newcastle) Clinical exomes Whole genomes Interpretation of variants
Therapies Standards of care Anticipatory care New treatments Ataluren, Etiplirsen, New treatments in early stage trials: omigapil, tideglusib, resolaris Access to research and clinical trials Supportive care Physiotherapy, education, housing, SLT and dietetics, social care.
Standards of care - MDT approach Updated Care Consideration Guidelines for Duchenne Published in The Lancet Neurology Jan 2018: Part 1: http://www.thelancet.com/journ als/laneur/article/piis1474-4422(18)30024-3/fulltext Part 2: http://www.thelancet.com/journ als/laneur/article/piis1474-4422(18)30025-5/fulltext Part 3: http://www.thelancet.com/journ als/laneur/article/piis1474-4422(18)30026-7/fulltext
DMD Treatment Approaches Challenges Trial capacities Changing Natural history Implementation of new treatments Reliable Outcome measures
Patient information and resources Referral to specialist centres Prevention and treatment of contractures Optimise Function Monitoring and treatment for scoliosis Breathing Cardiac particularly for LMNA & dystroglycanopathies annually Swallowing, weight gain and gastrostomy Eyes ophthalmologist Genetic counselling Malignant hyperthermia and anaesthesia risk Seizures
Cardio-Respiratory care Acute Paediatric admission Examine Saturations X-ray Blood gas with other bloods Give oxygen if hypoxic Antibiotics and Chest Physiotherapy Inform Nm/respiratory leads BIPAP Invasive ventilation Swallowing and aspiration Regular FVC, sleep studies Nocturnal BIPAP Cough Assist devices
Cardiac DMD, BMD LGMD2I, desmin related dystrophy Myotonic dystrophy Laminopathy and EDMD Regular Echocardiograms, ECG and/or 24 Holter depending on the disorder Treatment with ACE inhibitors or beta blockers at first signs of cardiac involvement
Nutrition Safe Adequate Aid with supplements, texture, posture Nasogastric feeds/gastrostomy
Bone health, orthopedic issues and scoliosis Vitamin D and exercise Scoliosis detection and treatment Contractures and Pain Foot surgery
Summary Common things are common Initial thorough clinical assessment Final diagnosis requires a combination of clinical-pathological-radiological-genetic assessment Good anticipatory care is key to survival Major advances in the last decade with better understanding of genetics and pathophysiology and a Tsunami of new treatments