McArdle Disease And Related Glycogen Storage Disorders Highly specialized National Service. Ros Quinlivan Taunton 2018

Transcription

1 McArdle Disease And Related Glycogen Storage Disorders Highly specialized National Service Ros Quinlivan Taunton 2018

2 Muscle glycogen metabolism disorders Fixed: muscle weakness GSDII Pompe Disease GSDIII GSDXV Dynamic: exercise intolerance GSDV (MGP) McArdle disease GSDVII (PFK) GSDIX (B kinase) GSDXIII (beta enolase) GSDIV (PGM1) PGAM2 PGK LDH Average 20 year delay between diagnosis and patient first seeking a medical opinion

3 Skeletal muscle energy metabolism -Creatine phosphate 8-10 seconds =100m -Anaerobic glycolysis seconds = m -Aerobic 800m-marathon Greg Glassman 2003

4 McArdle Disease Autosomal Recessive Prevalence 1:100,000 USA 1:170,000 Spain 1:350,000 Netherlands Absence of MGP Severely limited access to Glycogen stores Inability to produce lactate during exercise Godfrey Nature: Neurol Rev 2016 Haller RG. Arch Neurol. 2000; 57: Lucia A et alj Neurol Neurosurg Psychiatr. 2012; 83: van Alfen N et al, Neuromuscul Disord. 2002; 12:

5 Symptoms Exercise intolerance (99%) Within 1-2 minutes of initiating aerobic activity Immediate with isometric muscle activity Can t squat or run Second wind (86%) Hyperuricaemia/ gout Contracture Acute rhabdomyolysis Myoglobinuria (60%) Compartment syndrome Acute renal failure (10%) Quinlivan JNNP 2010 Lucia JNNP 2012

6 Children Difficulty crawling, arms collapsing Complain of leg pains as soon as they can walk, want to be carried everywhere Unable to run more than a few metres, get left behind by other children in playground Don t understand second wind until 9-10 years (on average) Socially isolated and may have problems integrating in school May have some additional learning needs 6

7 Examination Often normal Muscle hypertrophy 40% Muscle wasting Muscle weakness 20% shoulder girdle axial/ paraspinal Quinlivan et al JNNP

8 Late onset axial wasting and weakness

9 Upper limb weakness/ scapular winging

10 Maximal exercise/ Isometric muscle contraction Sprinting/ running Lifting and carrying Opening jars Squatting/crouching Muscle tension Pain Excitement Fighting Sex Seizures All activities of daily living are affected Brady et al BMJ 2014

11 Contracture and compartment syndrome

12 Ocular involvement Ptosis Retinal detachment Pattern Retinal dystrophy 10 patients all male and over 50yrs Ophthalmology 11 Oct 2018 Mahroo OA, Khan KN et al 12

13 Atypical patients Isolated progressive biceps weakness Progressive proximal rimmed vacuolar myopathy Moderate-severe axial/shoulder weakness LGMD phenotype Late onset myopathy, camptocormia and ptosis Splice site mutation mild phenotype 3% functioning enzyme 1.Scarpelli M. et al McArdle disease and sporadic inclusion body myositis. Neuropath & Applied Neurobiol. 35(4):442-5, 2009) 2.Witting N. Duno M. Piraud M. Vissing J. JAMA Neurology. 71(1):88-90, 2014) Vissing J. et al Brain. 132(Pt 6): , 2009) 3.Cheraud et al Novel variant in the PYGM gene causing late-onset limb-girdle myopathy, ptosis and camptocormia. Muscle Nerve 2017 e pub ahead of print

14 Co-morbidities in McArdle disease Sedentary lifestyle leading to chronic fatigue and chronic pain Psychological issues Obesity/ morbid obesity High incidence of thyroid disease: 11% hypothyroid Thyroid medullary cancer: 3 patients (prevalence 1-9/100,000) N=118 McArdle Disease Adult male population Diabetes 8 6.7% 4.8% Angina % 4.8% MI 13 11% 4% CVA 3 1.5% 2.4% Gout % 5%

15 Coronary artery disease approx. 100 asymptomatic patients screened 18 asymptomatic coronary artery disease 13 CAD requiring medical treatment 5 required urgent intervention 1x double bypass surgery 3x stents 1x Pacemaker McArdle symptoms mask angina

16 Investigations: Baseline Serum CK almost always raised 16

17 Non-ischaemic forearm exercise test 17

18 Muscle Biopsy Healthy individual Mc Ardle patient

19 PYGM 11q exons 147 mutations 91% exonic, 50% missense, 18% deletions,13% nonsense, 11% splicing (Nogales-Gadea et al Human mutation , ) 19

20 [p.r50*; c.148c>t]. Stop codon mutation in exon 1 Useful and inexpensive screening test Screening for R50X and G205S in UK patients prevents muscle biopsy Nogales-Gadea, 2015 Hum Mutat

21 Minutes Heart rate and perceived muscle pain responses to a functional walking test in McArdle disease. Buckley JP; Quinlivan RM; Sim J; Eston RG; Short DS. Journal of Sports Sciences. 32(16):1561-9, Heart Rate Walking speed km/hr RPP Borg RPP

22 Walking distance for n=75 patients tested (Richard Godfrey and Sherryl Chatfield)

23 Mean SF36v2 scores grouped by distance achieved on 12MWT at baseline (Jatin Pattni unpublished data)

24 Aerobic Training Average increase in walking distance (from assessment to follow-up) = 117.3m (39 follow-up patients)(sherryl Chatfield)

25 SF 36 Change in Mental Component Score and Physical Component Scores across 4 visits (Jatin Pattni) Visit 1 n 26 Visit 2 n 42 Visit 3 n 24 Visit 4 n 16 PCS MCS Munguía-Izquierdo D, Santalla A, Lucia A Cardiorespiratory fitness, physical activity, and quality of life in patients with McArdle disease. Med Sci Sports Exerc Apr;47(4):

26 Caution with isometric activity

27 Skeletal muscle energy metabolism -Creatine phosphate 8-10 seconds =100m -Anaerobic glycolysis seconds = m -Aerobic 800m-marathon Greg Glassman 2003

28 Resistance training in McArdle Disease Resistance (weight lifting) training in an adolescent with McArdle disease. Garcia-Benitez S; Fleck SJ; Naclerio F; Martin MA; Lucia A. Journal of Child Neurology. 28(6):805-8, 2013 Feasibility of resistance training in adult McArdle patients: clinical outcomes and muscle strength and mass benefits. Santalla A; Munguia-Izquierdo D; Brea-Alejo L; Pagola- Aldazabal I; Diez-Bermejo J; Fleck SJ; Ara I; Lucia A. Frontiers in aging neuroscience. 6:334, Aerobic warm up and Glucose loading essential for resistance training Report on the EUROMAC McArdle Exercise Testing Workshop, Madrid, Spain, July Quinlivan R; Lucia A; Scalco RS; Santalla A; Pattni J; Godfrey R; Marti R; Workshop Participants. Neuromuscular Disorders. 25(9):739-45, 2015 Sep.

29 Phosphofructokinase deficiency GSDVII (PFKM) Severe exercise intolerance (nausea and vomiting) Out of wind phenomenon Exercise is easier when fasted Improved with aerobic exercise Haemolytic anaemia Gout Cardiac involvement Polyglucosan bodies seen on muscle biopsy

30 Sex CK 12 MWT Myoglobinuria Age of onset other F no child LV trabecular thickening Post partum haemorrhage Vomits with exercise M no child Haem anaemia LVH, vomits with exercise F 98 -unable no child SLE, crohns Depression Hypertrophic LV F no child Vomits with exercise F 891 -unable yes child Haem anaemia, Mitral Valve replacement M yes child Gout, haemolytic anaemia Vomits with exercise

31 PFKM mutations: no genotype phenotype correlation Patient Allelle 1 Allele 2 1. Ashkenazi c.450+1g>a c.2216del, p.pro738fs 2. Ashkenazi c.450+1g>a c.450+1g>a 3. UK Caucasian p.val407* p.val407* 4. Ashkenazi c.450+1g>a c.450+1g>a 5. Pakistani c g>a c g>a 6. UK Caucasian c.1087c>t c.1087c>t

32 Management Prevention of rhabdomyolysis Gout prevention/treatment Diet/ nutrition Avoid glucose pre-exercise Low carb Fasting Ketogenic diet Strategies for exercise Encourage aerobic exercise Greg Glassman

33 Enzyme Gene Inheritance Other features Phosphorylase B kinase IX PHKG1 AR? IX PHKA1 AR Exercise intol. myoglobinuria IX PHKA2 XL Liver and muscle disease IX PHKB XL Liver and muscle disease Phosphoglucomutase PGM1 AR Glycosylation disorder Abnormal transferrin glycoforms Beta enolase 3 ENO3 AR Ex intolerance Phosphoglycerate mutase PGAM2 AR Ex intol myoglobinuria Tubular aggregates Phosphoglycerate kinase PGK XL Ex intol, myoglobinuria Haemolytic anaemia, Learning difficulty Lactate dehydrogenase LDHA AR Exercise intolerance myoglobinuria, Skin rash

34 NGS panel ACADVL, AGL, ALDOA, CAV3, CPT1B, CPT2, ENO3, ETFA, EFTB, ETFDH, FBP2, GAA, GBE1, GYG1, HADHA, HADHB, ISCU, LDHA, LPIN1, PFKM, PGAM2, PGK1, PGM1, PYGM, RBCK1, SLC22A5, PHKA1, RYR1 Cost 1000 Result available in 4 months Benefits: large number of genes tested Disadvantages: false positive results, not all genes causing rhabdomyolysis covered

35 Recurrent Rhabdomyolysis 28 year old male Parents 1 st cousins Exercise induced pain and cramps since childhood. Unable to sprint Myalgia walking up hills From 17 years recurrent episodes of myoglobinuria Maximum CK 75,000 iu/l

36 Examination Normal apart from mild left sided scapular winging 12 MWT 1000m onset of pain at 12 mins Decrease in lactate from 2.2mmol/l pre-exercise to 1.0mmol/l post exercise

37 MRI: Fatty infiltration soleus Muscle biopsy: Acid phosphatase, glycogen Phosphorylase, PFK, B kinase PGAM2 and RCE all normal Dystrophin and sarcolemmal Proteins normal EM mild increase in Glycogen Skin fibroblasts: normal FAOD Genes sequenced: RYR1, LPIN1, PYGM, PGM1, PFKM

38 Investigations Resting CK 129mmol/l Carnitine/ acylcarnitines normal OA normal CoQ10 normal EMG/ NCS normal Ischaemic forearm exercise test Time (minutes) Lactate (mmol/l; ) Pyruvate (mmol/l; ) Ammonia (µmol/l; 11-32) Lactate:pyruvate ratio (10-20)

39 Diagnosis GSDXIII Homozygous mutations in Beta ENO3 p.(glu187lys), c.559g>a Skeletal muscle beta enolase concentration 0.07nmol/min/mg prot. Nr 0.66+/- 0.1 (Ralph Wigley, GOSH) 2 nd patient recently diagnosed

40 Highly Specialised Service for Mc Ardle Disease and Related Disorders Diagnosis and management clinic NHNN/ GOSH Dr Quinlivan Sherryl Chatfield Dr Richard Godfrey Dr Jatin Pattni Clinical Fellow Clinical Nurse Specialist Diagnosis DNA testing Dr Richard Kirk, Sheffield Dr Carol Hardy Birmingham Muscle biochemistry (GOSH) Professor Simon Heales Dr Ralph Wigley 40

41 Summary Disorders of muscle glycogenolysis and glycolysis present with exercise intolerance?multi-system disorders Symptoms occur within minutes of activity Second wind occurs with GSDV Out of wind occurs with GSDVII Avoid carbs Management includes preventing acute rhabdomyolysis Progressive muscle atrophy and weakness Ocular and cardiac involvement Exercise is not harmful and is beneficial 41

42 Acknowledgements NHNN/ ION Sherryl Chatfield Jatin Pattni Andrew Wakelin Suzanne Booth Richard Godfrey Charlotte Ellerton Rachael Curruthers Renata Scalco Janice Holton Sheffield Children s Hospital Richard Kirk Birmingham Children s Hospital Mary Anne Preece Great Ormond Street Hospital Ralph Wigley Simon Heales Ramon Marti, Toni Andreu, Tomas Pinos, Xavier Ortager, Alejandro Lucia, Antonio Toscano, John Vissing, Miguel Angel Martin,Pascal Laforet, Andrea Martinuzzi, Matthius Vorgerd, Ron Haller, Piraya Oflazer, Sabrina Sacconi