Mark Tarnopolsky, MD, PhD. Dept of Pediatrics (Neuromuscular and Neurometabolic Diseases), McMaster University, Hamilton, ON.

Transcription

1 Late Onset Pompe Disease - General Overview. Mark Tarnopolsky, MD, PhD. Dept of Pediatrics (Neuromuscular and Neurometabolic Diseases), McMaster University, Hamilton, ON.

2 Learning Objectives. To review the general clinical approach to myopathy. To review pathophysiology and diagnosis of Pompe disease. To review the therapeutic options for myopathy and specific therapies for Pompe disease.

3 Disclosure Genzyme speaker honorarium Amicus Therapeutics, Biomarin - consultant, 2011, Wyeth research funding GSK - speaker honoraria Genzyme - research funding, Founder of Exerkine Corporation.

4 Thanks Giant Tiger Stores Warren Lammert and Family Children s Celebration CIHR NSERC Canada Genzyme/Sanofi

5 HISTORY/EXAMINATION -? myopathy Weakness Pattern: Proximal vs distal (DM1, sibm, FSH, nemaline rod, distal myopathy (TCAP (telethonin), hibm (GNE)). Exercise related (MG, metabolic, pseudometabolic, Pompe). Examination: Ptosis - MG, mitochondrial, DM1, OPMD, Pompe. Ophthalmoplegia - mitochondrial, MYH2, MG, RYR1, SEPN1, centronuclear. Bulbar - MG, DM1, nemaline rod, OPMD, sibm. Facial - DM1, FSHD, nemaline rod, infantile Pompe. Contractures - COL6A, RSS, RYR1, EDMD, DMD, Pompe.

6 Physical Exam Complete Neurological Exam. MSK exam FSHD may get rotator cuff issues. Contractures. Check the back (spinal stenosis with radiculopathy can mimic myopathy, lead to fatigue with activity, and elevate CK).

7 Physical Exam - often yields Dx!

8 Routine Bloodwork CK not aldolase. Remember that AST and ALT are in skeletal muscle. Cramps cramps at rest are rarely significant (usually neurogenic) BUT they can increase the CK. Make sure TSH is sent (commonly the CK will be elevated). Patients with motor neuropathy and motor radiculopathy can have elevated CK (< 1,000 U/L).

9 Needle EMG Fibs./PSW Myotonia Myopathic Potentials

10 When to send for further testing. No cause for the high CK. Neurological exam is abnormal (beyond radiculopathy or diabetic neuropathy). Any CK consistently over 1,000 iu/l. EMG shows active or chronic myopathic changes. Positive family history of high CK or NMD (incl. MH) or arrhythmia/pacer or non-hypertensive cardiomyopathy (lamin A/C, BMD). SOBOE + weakness (Pompe, MG, LGMD, mito.). Sitting/supine FVC - > 20 % drop = diaphragm weak.

11 Muscle Biopsy Bourgeois and Tarnopolsky, Mitochondrion, 4:441-52, Tarnopolsky, et al, Muscle Nerve, 2011.

12 Biopsy Patterns Central Core Ragged Red Dystrophic Inflammation Dennervation Pompe

13 EM Changes

14 Genetic Testing in Ontario. DM1, DM2, FSHD, OPMD - CHEO. Duchenne/Becker - HSC. Congenital MD (incl. FKRP) - HSC. RYR1/CACNA1S (MH) - UHN. SMA (smn deletion) - CHEO. MOH - out of province - Medical Neurogenetics (184 genes including mtdna).

15 So should we all just do exome Seq? Does not cover intronic mutations. Depth of coverage can lead to regions not well covered. Difficult to detect large deletions (small indels are OK) - oligonucleotide acgh first > may need MLPA of select genes after for single exon deletions. Does not capture repeat sequences well (do not map well to Ref. Seq.). Requires a major amount of

16 Pompe Disease First described in 1932 by Dutch pathologist J.C. Pompe Also known as acid maltase deficiency (AMD) or GSD-II. Characterised by the deficiency of a lysosomal enzyme, acid alphaglucosidase (GAA) Results in progressive intracellular accumulation of glycogen, primarily in muscle cells Signs and symptoms begin anywhere from early infancy through adulthood

17 Pompe Disease: Natural Evolution and Clinical Manifestations Mutation of GAA gene GAA enzyme deficiency Cellular accumulation of glycogen Pathological changes in muscle fibres Early mortality Loss of ambulation and cardio-respiratory distress Continuous progressive decline to organ failure Clinical manifestations and events

18 Pompe Disease Continuum Ranges from a rapidly progressive course (fatal by 1 year of age) to a variable and relentlessly progressive course with significant morbidity and/or premature mortality

19 Onset of Pompe Disease in Adults Age-specific distribution of events in a Dutch cohort of mean age 48.6 years Black line = mean age for event First complaints n=54 Running problems n=31 Diagnosis Problems going up and down staircase Problems rising from armchair Problems rising from lying position Walking problems n=54 n=46 n=45 n=37 n=41 Problems with dressing Problems going to toilet Start of walking aid use Start of wheelchair use n=32 n=18 n=23 n=26 Start use of artificial ventilation (n=54) yrs n=20 Figure from Hagemans ML, Winkel LP, Van Doorn PA, et al. Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients. Brain 2005; 128:671-7, by permission of Oxford University Press.

20 Pompe - Adult clinical Often delay in diagnosis of 7-10 y. Late onset disease (> 18y, confirmed diagnosis): Leg weakness > arm weakness. First symptoms = difficulty running (pre-diagnosis). SOBOE is an early sign due to diaphragm involvement. Mean onset in mid 20s. Mid 40s = W/C use and ventilator support. Cardiac involvement is rare (5-10 % cardiomyopathy; 10 % WPW/short P>R).

21 Pompe diagnosis. Adult form (AR) shortness of breath, proximal weakness, exercise intolerance. CK usually up. EMG fibs, PSW, myotonia paraspinals. EM membrane bound glycogen, autophagic vacuoles. LM PAS increase (blebs), acid phosphatase +ve, vacuolar myopathy.

22 Genetics Chromosome 17q25. > 400 pathogenic mutations ( Most common mutation is IVS1-13T>G. Arg854X - African Americans. c.525delt, c.1935c>a and exon 18 deletions - usually infantile. 90 % - mutation found in those with low GAA activity. Deletion of exon 18 in 5-7 % of alleles.

23 Biopsy Patterns ADULT INFANT

24 Pompe diagnosis - DBS. Fibroblasts/muscle/dry blood spot (DBS) reduction of α-glucosidase. DBS in Ontario - raj.kapur@genzyme.com DBS in BC - lorna.desveaux@genzyme.c om

25 Most common mimics of Pompe/ other diagnoses at time of Dx. Calpainopathy - LGMD2A. Mitochondrial myopathy. Fibromyalgia/CFS. Polymyositis (ALL Pompe will be 3/4 Bohan and Peter criteria +ve). Becker MD. FSHD1 and FSHD2. LGMD - NOS.

26 General Therapy for Myopathies. Supportive: ID. and Rx - low vitamin D (85 % insufficient; 13 % ricketic myopathy levels (< 25 nmol/l). Mol Ther Mar 21. pii: S (17) T2DM - increased risk. Hypothyroid - easy to id. and Rx. Exercise (3 sets of repetitions). Gait assistive devices. Sleep study. Adequate protein (1.2 g/kg/d). Creatine monohydrate (100 mg/kg/d).

27 Therapy for Pompe Disease. GENERAL: Exercise. Nutrition. DISEASE SPECIFIC: Enzyme Replacement Therapy.

28 What is the evidence that exercising + ERT is of benefit in humans? N = 44 late onset Pompe patients. ERT for one year. 6 min walk. N = 5 patients: 1 h on cycle ergometry during infusion. N = 3, regular physiotherapy. Strothotte, S, et al., J. Neurology, 2010

29 Combined END and RES training. N = 5 late onset Pompe patients on ERT. 5 months of supervised, combined RES + END exercise: % increase in strength (P < 0.05). No change in total FFM; upper extremity FFM (P < 0.05). Follow-up after 6 more months of exercise during infusion: No further benefit Pre-training Post-training * P < min walk (m) Terzis, et al., Mol Genet Metab Nov;104(3): Terzis, et al., Mol Genet Metab Dec;107(4):

30 Nutritional Inadequacy in Patients with Muscular Dystrophy N = 51 MD patients (DM1, LGMD, FSHD). Prospective dietary analysis for 3 days separated by 5 months. Mean values reported. Compare to Canadian DRI. Motglah, et al, Muscle and Nerve, 2005

31 Most Myopathies Show Similar Trends. Motagleh, and Tarnopolsky, Muscle Nerve, 2005, Tarnopolsky, et al, Muscle Nerve, DM1 (29) MD (21) MITO (9) Energy (< RNI) 62 % 82 % 43 % PRO (< RDI) 10 % 5 % 14 % FAT (> 30 %) 55 % 86 % 57 % Vit. E (< ADMR) 90 % 86 % 44 % Vit C (< ADMR) 31 % 18 % 14 % Vit. B2 (< ADMR) 45 % 14 % N/A Vit. B12 (< ADMR) 17 % 5 % N/A Folate (< ADMR) 68 % 48 % N/A

32 Serum Vitamin Levels July 1, 1996 June 15, McMaster University Neuromuscular Clinic N = 1852 ( = 905; = 947) blood tests with at least one vitamin level sent: RBC folate B12 Vitamin A Vitamin D (25-OH) Vitamin E Tarnopolsky M., et al., MS in preparation, 2017

33 Serum Vitamin Levels Mito (62) Acq Neur (250) New N = recommendations 4 Pompe: 100 % = < > nmol/l: 85 and % deficient. 50 % < 30 nmol/l Tarnopolsky M., et al., MS in preparation, 2017

34 Myozyme Mechanism of Action Myozyme (alglucosidase alfa) docks on M6P receptors on cell surface Inside cell, Myozyme molecules disassociate from M6P receptors, which cycle back to cell surface Inside lysosome, Myozyme breaks down glycogen to glucose

35 LOTS trial (vanderploeg, et al, NEJM, 362:1396-, 2010) N = 90 adult onset patients. Primary endpoints: 6 min walk test and FVC (% predicted). Rx: Myozyme 20 mg/kg q 2 weeks X 18 months. FVC: 3.4 % difference between groups*. 6-min walk: + 28 m for Rx; - 3 m placebo*. In general, those less affected at baseline showed the greatest effect.

36 Change in Forced Vital Capacity (co-primary endpoint) 3 alglucosidase alfa Mean Change in % Predicted FVC Placebo +1.2%* -2.2%* 3.4%* Weeks from Baseline ANCOVA p-value = *ANCOVA estimate of mean

37 Mean Change in Distance Walked (meters) Change in 6-Minute Walk Test (co-primary endpoint) alglucosidase alfa Placebo Weeks from Baseline ANCOVA p-value = meters* 28 meters* -3 meters* *ANCOVA estimate of mean

38 Summary Points. Pompe can mimic other myopathies and vice versa. Think of Pompe when there is respiratory involvement (sitting/supine spirometry). Most but not all cases will have high CK. Consider a DBS on all cases of unexplained hyperckemia. Use a DBS early in the work-up of myopathy patients. Identification and early treatment will likely slow disease progression.

39 The clinic: Ms. L. Brandt Ms. Erin Hatcher Ms. L. Brady Ms. K. Frescura Thanks Dan Wright and Family Warren Lammert and Family The lab: Dr. M. Nilsson Collaborators: Dr. D. Dodig Dr. B. Lach Dr. J. Bourgeois Dr. T. Hawke