SHOULD PATIENTS WITH ASYMPTOMATIC POMPE DISEASE BE TREATED? A NATIONWIDE STUDY IN FRANCE ANDONI ECHANIZ-LAGUNA, MD, PhD,1 ROBERT-YVES CARLIER, MD,2 KENZA LALOUI, MD,3 PIERRE CARLIER, MD, PhD,3 EMMANUELLE SALORT-CAMPANA, MD,4 JEAN POUGET, MD, PhD,4 and PASCAL LAFORET, MD, PhD3 1
Centre de Reference des Maladies Neuromusculaires, D epartement de Neurologie, H^ opital de Hautepierre 1, Avenue Molie`re, 67098, Strasbourg, France 2 Assistance Publique-H^ opitaux de Paris (APHP), Service d’imagerie m edicale, CIC-IT handicap, H^ opital Poincar e, Garches, France 3 Centre de Reference Neuromusculaire Paris-Est, H^ opital Piti e-Salp^ etrie`re, and U974, Universit e Pierre et Marie Curie, Paris, France 4 Centre de Reference des Maladies Neuromusculaires, Aix-Marseille Universit e, APHP, Marseille, France Accepted 10 March 2015 ABSTRACT: Introduction: Acid a-glucosidase deficiency, that is, Pompe disease, is a glycogenosis for which enzyme replacement therapy (ERT) is available. It is not known whether patients diagnosed at an asymptomatic stage should be treated to prevent progression of the disease. Methods: We investigated 7 patients with asymptomatic Pompe disease identified from the French Pompe registry. Results: The patients had a mean age of 45 (range 24–75) years, a median follow-up duration of 2 (range 1–22) years, and normal clinical examination, pulmonary function tests (PFTs), and echocardiography. All presented with at least 1 subclinical abnormality, including hyperCKemia, vacuolar myopathy, and muscle MRI abnormalities, suggesting that subclinical myopathy was present in all cases. Conclusions: Asymptomatic Pompe disease may remain clinically silent for decades, and affected patients should be monitored closely for overt myopathy using clinical examination, PFTs, and muscle MRI to determine when to start ERT. Muscle Nerve 51: 884–889, 2015
Pompe
disease is a rare inborn error of metabolism caused by deficiency of the lysosomal enzyme acid a-glucosidase encoded by the GAA gene and responsible for the degradation of lysosomal glycogen.1 Based on age of onset, 2 main patient groups may be distinguished: (1) infantile-onset Pompe disease, which appears in the first years of life and usually presents with severe myopathy, cardiomyopathy, and respiratory failure; and (2) late-onset Pompe disease, which develops mainly in adult patients and is usually limited to skeletal muscle involvement, including respiratory muscles.1 Enzyme replacement therapy (ERT) with recombinant human acid a-glucosidase has been available since 2006 for patients with Pompe disease.1 ERT is associated with improved survival, Abbreviations: 6MWT, 6-minute walk test; CK, creatine kinase; ECG, electrocardiogram; EMG, electromyogram; ERT, enzyme replacement therapy; MFM, motor function measure scale; MMT, manual muscle testing; PAS, periodic–acid Schiff; PFT, pulmonary function test; WBMRI, whole-body magnetic resonance imaging Key words: asymptomatic; enzyme replacement therapy; Pompe disease; whole-body muscle MRI; late-onset; myopathy Disclosures: A.E.-L. and E.S.-C. received honoraria from Genzyme Co., and P.L. has received grants and honoraria from Genzyme Co. and grants from BioMarin and Amicus Therapeutics. Correspondence to: A. Echaniz-Laguna; e-mail: andoni.echaniz-laguna@ chru-strasbourg.fr C 2015 Wiley Periodicals, Inc. V
Published online 18 March 2015 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24653
884
Asymptomatic Pompe Disease
walking distance, and respiratory function in patients with infantile-onset Pompe disease, and with improved walking distance and stabilization of pulmonary function in patients with late-onset Pompe disease.2–4 Because of the availability of ERT and the improvement of enzymatic assessment techniques, an increasing number of patients with Pompe disease are now diagnosed at an early stage of the disease.5–7 As only a few patients with asymptomatic Pompe disease have been described until now, very few data are available about the natural history of these “patients-in-waiting.”8 There is controversy about whether these patients should be treated with ERT in order to prevent progression of the disease.8 We investigated 7 adult patients in France with asymptomatic Pompe disease, with a median follow-up of 2 years. The size of our cohort and the prolonged follow-up allowed us to: (1) provide an accurate estimate of the frequency of asymptomatic Pompe disease in comparison with symptomatic late-onset Pompe disease; (2) provide useful information on the natural history of asymptomatic Pompe disease; and (3) propose a strategy for monitoring patients with asymptomatic Pompe disease. METHODS Standard Protocol Approvals, Registration, and Patient Consent. All procedures were performed in accordance with the ethics standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for study inclusion. Additional informed consent was obtained from all patients for whom identifying information is included in this study. Cohort of Patients with Disease. We searched the
Asymptomatic
Pompe
French Pompe registry for adult patients diagnosed in the 1991–2013 interval with asymptomatic Pompe disease; that is, Pompe disease without obvious clinical signs of myopathy.9 The registry includes all French MUSCLE & NERVE
June 2015
patients with Pompe disease aged >18 years who had been diagnosed using enzymatic or genetic analysis.9 The diagnosis of Pompe disease was established in all patients by GAA enzyme activity levels and GAA gene analysis in accordance with published diagnostic criteria for late-onset Pompe disease.10 All patients underwent standardized clinical examination, including manual muscle testing (MMT), timed tests (time to climb 4 steps, to rise from a chair, and to walk 10 m), motor function measurement (MFM scale), and the 6-minute walk test (6MWT).9 Paraclinical Investigations. All patients underwent pulmonary function testing (PFT), electrocardiography (ECG), echocardiography, and serum creatine kinase (CK) testing. Muscle biopsy was processed with standard methods for histology and histochemistry, and whole-body magnetic resonance imaging (WBMRI) was performed, as described elsewhere.11 Electrodiagnostic studies included nerve conduction studies in the upper and lower limbs and electromyography (EMG) using a concentric needle electrode in at least 3 muscles, including an upper limb muscle, a lower limb muscle, and paraspinal muscles. GAA Enzyme Activity Level. Acid a-glucosidase activity level was investigated in all patients in at least 1 tissue (blood lymphocytes, cultured skin fibroblasts, or skeletal muscle), as reported elsewhere.1 GAA Gene Analysis. GAA (Gene ID 2548, MIM #606800) coding region and intron/exon boundaries were amplified and sequenced from genomic DNA from all patients, as reported elsewhere.1 RESULTS Clinical Characteristics of Patients with Asymptomatic Pompe Disease. Seven adult patients with asymptomatic Pompe disease were identified in the French Pompe registry, representing 5% of all French patients with adult Pompe disease.9 One patient has previously been described elsewhere.5 Pompe disease was investigated due to a positive family history for late-onset Pompe disease in 4 patients and due to hyperCKemia in 3. There were 5 women and 3 men. Three women from our series (patients 1, 5, and 7) had 5 younger brothers with symptomatic late-onset Pompe disease, including 2 wheelchair-bound patients and 2 patients with noninvasive ventilation. One woman (patient 4) had a mother with symptomatic lateonset Pompe disease; genetic analysis showed that she inherited 1 mutation from her mother and another mutation from her father, who was a heterozygous carrier. Mean age at diagnosis was in the 40s (range 2–68); mean age at the time of the study was 45 (range 24–75) years; and the median Asymptomatic Pompe Disease
Table 1. Clinical characteristics of 7 patients with asymptomatic Pompe disease. Age at diagnosis (years)
Gender
Follow-up (years)
1 2 3*
48 51 2
W M M
2 1 22
4 5 6 7
25 44 68 43
W W W W
4 1 7 1
Patient
Miscellaneous NA NA Bilateral calf hypertrophy NA NA Scoliosis NA
W, woman; M, man; NA, not applicable. *Patient 3 was described by Laloui et al.5
duration of follow-up was 2 (range 1–22) years (Table 1). Clinical examinations, including MMT, timed tests, MFM scale, and the 6MWT, were normal in all cases. Bilateral calf hypertrophy was observed in 1 patient, and 1 patient presented with scoliosis. Muscle pathology, EMG, WBMRI, and cardiorespiratory characteristics of patients are shown in Table 2. PFT, ECG, and echocardiography findings were normal in all 7 patients. EMG was performed in the deltoid, tibialis anterior, and paraspinal muscles of 3 patients, and was normal. Muscle biopsy was performed in the left deltoid muscle in 6 patients and demonstrated a vacuolar myopathy with increased periodic acid–Schiff (PAS) staining in 3. In the other 3 patients, muscle histology was normal. CK levels were mildly elevated (1.5–5 times normal) in 6 patients, and normal in 1. WBMRI was performed in 5 patients, demonstrating tongue and subscapularis muscle abnormalities in 1, and shoulder girdle, lumbar extensor, and hamstring muscle abnormalities in another (Figs. 1 and 2), and no abnormal findings in the other 3. Thus, at least 1 subclinical abnormality was observed in all patients, including significant hyperCKemia (6 of 7; 86%), vacuolar myopathy with increased PAS staining (3 of 6; 50%), and muscle MRI abnormalities (2 of 5; 40%). GAA Enzyme Activity Level and GAA Mutations. All patients had GAA deficiency in at least 1 tissue, and all had 2 GAA mutations (Table 3). All patients harbored the common mutation c.-3213T>G in combination with different causal mutations on the second allele, with the exception of patient 6 who harbored the c.-32-13T>G mutation in a homozygous state. All GAA mutations have already been reported, with the exception of the p.Val350Met mutation, which has been predicted to be pathogenic by various bioinformatics tools.12–14 MUSCLE & NERVE
June 2015
885
Table 2. Paraclinical characteristics of 7 patients with asymptomatic Pompe disease. Serum CK (U/L) (normal G (intron 1) c.923A>C (p.His308Pro) (exon 5) c.232-13T>G (intron 1) c.1048G>A (p.Val350Met) (exon 6) c.232-13T>G (intron 1) c.655G>A (p.Gly219Arg) (exon 3) c.232-13T>G (intron 1) c.2104C>T (p.Arg702Cys) (exon 15) c.232-13T>G (intron 1) c.1396delG (p.Val466Phefs*11) (exon 9) c.232-13T>G (intron 1) c.232-13T>G (intron 1) c.232-13T>G (intron 1) c.188811G>A (intron 13)
Acid a-glucosidase activity Muscle: 10 (N: 138–320) Lymphocytes: 2 (N: 6–25)
Family history of Pompe disease 2 brothers with symptomatic Pompe disease
Muscle: 8 (N: 138–320) Lymphocytes: 0.2 (N: 6–25) Fibroblasts: 6.2 (N: 42.8) Lymphocytes: 1.5 (N: 6–25)
None
Lymphocytes: 5 (N: 15–45) Fibroblasts: 3.2 (N: 32)
Mother with symptomatic Pompe disease
Lymphocytes: 2.0 (N:6–25)
1 brother with symptomatic Pompe disease None
Muscle: 0 (N: 138–320) Lymphocytes: 9 (N: 15–45)
None
2 brothers with symptomatic Pompe disease
Acid a-glucosidase activity is expressed as mkat per kilogram protein (mkat/kg prot) in blood lymphocytes and cultured skin fibroblasts, and in nkat per kilogram muscle (nkat/kg muscle) in skeletal muscle. Control enzyme activities are given as a range. As enzyme activity values in lymphocytes were measured in 2 different laboratories, normal (N) values were different in patients 1, 2, 3, and 5 than in patients 4 and 7.
Asymptomatic Pompe Disease
MUSCLE & NERVE
June 2015
887
men, including less exercise intolerance and less frequent recurrent exertional myoglobinuria.17 The molecular basis of gender contribution to the phenotype of muscle glycogenoses remains largely unknown.17 By definition, all the patients described here presented with a normal clinical examination and no obvious signs and/or symptoms of myopathy. Bilateral calf hypertrophy and scoliosis were observed in 1 patient each: it is unclear whether these conditions were related to Pompe disease or were coincidental. All patients presented with at least 1 subclinical abnormality. This suggests that a myopathy was present in all 7 patients, although it was clinically silent. EMG examination was also normal in 3 of 3 patients, demonstrating that electrodiagnostic studies are not sufficiently sensitive to detect myopathic changes in asymptomatic Pompe disease. Until now, only a few adult patients with asymptomatic Pompe disease have been reported, and all have presented with hyperCKemia, normal cardiorespiratory function, and mild vacuolar myopathy.6,7 However, in contrast to our series, some of these patients also presented with mild clinical features, such as slight proximal limb weakness and recurrent myalgia.6,7 WBMRI deserves special mention, because recent studies have shown a specific pattern of muscle involvement in late-onset Pompe disease with tongue, spine extensors, subscapularis, and thigh muscles being mainly involved.11 Interestingly, in our series, this typical late-onset Pompe disease WBMRI pattern was observed in only 1 patient. The GAA c.-32-13T>G mutation is by far the most frequent GAA mutation observed among Caucasian children and adults with Pompe disease.18 It is located in the first intron of the GAA gene and leads to improper splicing in 80%–90% of the GAA pre-mRNA splicing events.18 It is generally thought that the correlation between genotype and phenotype in Pompe disease is strict, in that patients with the most severe phenotype have 2 deleterious mutations that prevent the formation of GAA or render it completely nonfunctional; patients with less severe phenotypes have at least 1 sequence variation that allows normal or low-level synthesis of GAA that leads to formation of measurable low-level GAA activity.18 However, it is also known that patients with functionally the same GAA genotype and the same c.-32-13C>T haplotype present with considerable clinical heterogeneity, suggesting that modifying factors may disturb the GAA genotype–phenotype correlation and have a substantial effect on the clinical course of the disease.18 For instance, polymorphisms on “exercise genes,” such as ACE and ACTN3, may 888
Asymptomatic Pompe Disease
influence muscle performance and outcome in patients with Pompe disease.19 Identifying these factors and exploring them as therapeutic targets remains a challenge. Our results demonstrate that patients with Pompe disease may remain asymptomatic until very late in life. For example, patient 3 was diagnosed with Pompe disease at age 2 years and remains asymptomatic at age 24. Some patients with asymptomatic Pompe disease may never become symptomatic. For example, patient 6 was diagnosed with Pompe disease at age 68 years and remains asymptomatic at age 75. Our results have major implications for newborn screening in Pompe disease, as they suggest that patients identified via newborn screening with likely late-onset Pompe disease may not need to be treated immediately. As all patients in our study presented without overt clinical myopathy, cardiomyopathy, or respiratory insufficiency, ERT was not considered. However, all patients also presented with mild paraclinical abnormalities indicative of a subclinical myopathy. In this context, should ERT be considered? Late-onset Pompe disease is generally restricted to skeletal and respiratory muscles with slow progression, but also with potential early death. In these patients, ERT slows disease progression, but the benefits appear to be less dramatic than those observed in infantile-onset Pompe disease.20 Considering the very high cost of treatment (>$300,000 per year per adult patient), and the observation that patients with asymptomatic Pompe disease may remain asymptomatic for decades, and in some cases never even develop symptoms, we recommend that patients with asymptomatic Pompe disease be monitored closely for overt myopathy using muscle strength assessment, WBMRI, and PFT before deciding to start ERT. In our practice, we perform muscle strength assessment, ECG, echocardiography, and PFT every 12 months and WBMRI every 24 months before deciding, on an individual basis, whether or not to treat. Our current experience with patients with asymptomatic Pompe disease suggests that ERT should probably not be initiated before the occurrence of abnormalities in muscle strength, PFT, or WBMRI. REFERENCES 1. van der Ploeg AT, Reuser AJ. Pompe’s disease. Lancet 2008;372: 1342–1353. 2. Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL, et al. Recombinant human acid alfa-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology 2007;68:99–109. 3. van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ, et al. A randomized study of alglucosidase alfa in late-onset Pompe’s disease. N Engl J Med 2010;362:1396–1406. 4. van der Ploeg AT, Barohn R, Carlson L, Charrow J, Clemens PR, Hopkin RJ, et al. Open-label extension study following the LateOnset Treatment Study (LOTS) of alglucosidase alfa. Mol Genet Metab 2012;107:456–461.
MUSCLE & NERVE
June 2015
5. Laloui K, Wary C, Carlier RY, Hogrel JY, Caillaud C, Lafor^ et P. Making diagnosis of Pompe disease at a presymptomatic stage: to treat or not to treat? Neurology 2011;77:594–595. 6. Wagner M, Chaouch A, M€ uller JS, Polvikoski T, Willis TA, Sarkozy A, et al. Presymptomatic late-onset Pompe disease identified by the dried blood spot test. Neuromuscul Disord 2013;23:89–92. 7. Spada M, Porta F, Vercelli L, Pagliardini V, Chiado-Piat L, Boffi P, et al. Screening for later-onset Pompe’s disease in patients with paucisymptomatic hyperCKemia. Mol Genet Metab 2013;109:171–173. 8. Kwon JM, Steiner RD. “I’m fine; I’m just waiting for my disease”: the new and growing class of presymptomatic patients. Neurology 2011; 77:522–523. 9. Lafor^et P, Laloui K, Granger B, Hamroun D, Taouagh N, Hogrel JY, et al. The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease. Rev Neurol (Paris) 2013; 169:595–602. 10. American Association of Neuromuscular & Electrodiagnostic Medicine. Diagnostic criteria for late-onset (childhood and adult) Pompe disease. Muscle Nerve 2009;40:149–160. 11. Carlier RY, Lafor^ et P, Wary C, Mompoint D, Laloui K, Pellegrini N, et al. Whole-body muscle MRI in 20 patients suffering from late onset Pompe disease: involvement patterns. Neuromuscul Disord 2011;21:791–799. 12. Pompe disease mutation database. Available at: www.pompecenter.nl. Accessed March 7, 2014.
Asymptomatic Pompe Disease
13. PolyPhen-2. Available at: http://genetics.bwh.harvard.edu/pph2/. Accessed February 20, 2013. 14. J. Craig Venter Institute. SIFT. Available at: http://sift.jcvi.org/. Accessed February 20, 2013. 15. van der Beek NA, van Capelle CI, van der Velden-van Etten KI, Hop WC, van den Berg B, Reuser AJ, et al. Rate of progression and predictive factors for pulmonary outcome in children and adults with Pompe disease. Mol Genet Metab 2011;104:129–136. 16. Wens SC, van Gelder CM, Kruijshaar ME, de Vries JM, van der Beek NA, Reuser AJ, et al. Phenotypical variation within 22 families with Pompe disease. Orphanet J Rare Dis 2013;8:182. 17. Lucia A, Ruiz JR, Santalla A, Nogales-Gadea G, Rubio JC, GarciaConsuegra I, et al. Genotypic and phenotypic features of McArdle disease: insights from the Spanish national registry. J Neurol Neurosurg Psychiatry 2012;83:322–328. 18. Kroos M, Hoogeveen-Westerveld M, van der Ploeg A, Reuser AJ. The genotype-phenotype correlation in Pompe disease. Am J Med Genet C Semin Med Genet 2012;160C:59–68. 19. Ravaglia S, De Filippi P, Pichiecchio A, Ponzio M, Saeidi Garaghani K, Poloni GU, et al. Can genes influencing muscle function affect the therapeutic response to enzyme replacement therapy (ERT) in late-onset type II glycogenosis? Mol Genet Metab 2012;107:104–110. 20. Toscano A, Schoser B. Enzyme replacement therapy in late-onset Pompe disease: a systematic literature review. J Neurol 2013;260:951– 959.
MUSCLE & NERVE
June 2015
889
Centre de Reference des Maladies Neuromusculaires, D epartement de Neurologie, H^ opital de Hautepierre 1, Avenue Molie`re, 67098, Strasbourg, France 2 Assistance Publique-H^ opitaux de Paris (APHP), Service d’imagerie m edicale, CIC-IT handicap, H^ opital Poincar e, Garches, France 3 Centre de Reference Neuromusculaire Paris-Est, H^ opital Piti e-Salp^ etrie`re, and U974, Universit e Pierre et Marie Curie, Paris, France 4 Centre de Reference des Maladies Neuromusculaires, Aix-Marseille Universit e, APHP, Marseille, France Accepted 10 March 2015 ABSTRACT: Introduction: Acid a-glucosidase deficiency, that is, Pompe disease, is a glycogenosis for which enzyme replacement therapy (ERT) is available. It is not known whether patients diagnosed at an asymptomatic stage should be treated to prevent progression of the disease. Methods: We investigated 7 patients with asymptomatic Pompe disease identified from the French Pompe registry. Results: The patients had a mean age of 45 (range 24–75) years, a median follow-up duration of 2 (range 1–22) years, and normal clinical examination, pulmonary function tests (PFTs), and echocardiography. All presented with at least 1 subclinical abnormality, including hyperCKemia, vacuolar myopathy, and muscle MRI abnormalities, suggesting that subclinical myopathy was present in all cases. Conclusions: Asymptomatic Pompe disease may remain clinically silent for decades, and affected patients should be monitored closely for overt myopathy using clinical examination, PFTs, and muscle MRI to determine when to start ERT. Muscle Nerve 51: 884–889, 2015
Pompe
disease is a rare inborn error of metabolism caused by deficiency of the lysosomal enzyme acid a-glucosidase encoded by the GAA gene and responsible for the degradation of lysosomal glycogen.1 Based on age of onset, 2 main patient groups may be distinguished: (1) infantile-onset Pompe disease, which appears in the first years of life and usually presents with severe myopathy, cardiomyopathy, and respiratory failure; and (2) late-onset Pompe disease, which develops mainly in adult patients and is usually limited to skeletal muscle involvement, including respiratory muscles.1 Enzyme replacement therapy (ERT) with recombinant human acid a-glucosidase has been available since 2006 for patients with Pompe disease.1 ERT is associated with improved survival, Abbreviations: 6MWT, 6-minute walk test; CK, creatine kinase; ECG, electrocardiogram; EMG, electromyogram; ERT, enzyme replacement therapy; MFM, motor function measure scale; MMT, manual muscle testing; PAS, periodic–acid Schiff; PFT, pulmonary function test; WBMRI, whole-body magnetic resonance imaging Key words: asymptomatic; enzyme replacement therapy; Pompe disease; whole-body muscle MRI; late-onset; myopathy Disclosures: A.E.-L. and E.S.-C. received honoraria from Genzyme Co., and P.L. has received grants and honoraria from Genzyme Co. and grants from BioMarin and Amicus Therapeutics. Correspondence to: A. Echaniz-Laguna; e-mail: andoni.echaniz-laguna@ chru-strasbourg.fr C 2015 Wiley Periodicals, Inc. V
Published online 18 March 2015 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24653
884
Asymptomatic Pompe Disease
walking distance, and respiratory function in patients with infantile-onset Pompe disease, and with improved walking distance and stabilization of pulmonary function in patients with late-onset Pompe disease.2–4 Because of the availability of ERT and the improvement of enzymatic assessment techniques, an increasing number of patients with Pompe disease are now diagnosed at an early stage of the disease.5–7 As only a few patients with asymptomatic Pompe disease have been described until now, very few data are available about the natural history of these “patients-in-waiting.”8 There is controversy about whether these patients should be treated with ERT in order to prevent progression of the disease.8 We investigated 7 adult patients in France with asymptomatic Pompe disease, with a median follow-up of 2 years. The size of our cohort and the prolonged follow-up allowed us to: (1) provide an accurate estimate of the frequency of asymptomatic Pompe disease in comparison with symptomatic late-onset Pompe disease; (2) provide useful information on the natural history of asymptomatic Pompe disease; and (3) propose a strategy for monitoring patients with asymptomatic Pompe disease. METHODS Standard Protocol Approvals, Registration, and Patient Consent. All procedures were performed in accordance with the ethics standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for study inclusion. Additional informed consent was obtained from all patients for whom identifying information is included in this study. Cohort of Patients with Disease. We searched the
Asymptomatic
Pompe
French Pompe registry for adult patients diagnosed in the 1991–2013 interval with asymptomatic Pompe disease; that is, Pompe disease without obvious clinical signs of myopathy.9 The registry includes all French MUSCLE & NERVE
June 2015
patients with Pompe disease aged >18 years who had been diagnosed using enzymatic or genetic analysis.9 The diagnosis of Pompe disease was established in all patients by GAA enzyme activity levels and GAA gene analysis in accordance with published diagnostic criteria for late-onset Pompe disease.10 All patients underwent standardized clinical examination, including manual muscle testing (MMT), timed tests (time to climb 4 steps, to rise from a chair, and to walk 10 m), motor function measurement (MFM scale), and the 6-minute walk test (6MWT).9 Paraclinical Investigations. All patients underwent pulmonary function testing (PFT), electrocardiography (ECG), echocardiography, and serum creatine kinase (CK) testing. Muscle biopsy was processed with standard methods for histology and histochemistry, and whole-body magnetic resonance imaging (WBMRI) was performed, as described elsewhere.11 Electrodiagnostic studies included nerve conduction studies in the upper and lower limbs and electromyography (EMG) using a concentric needle electrode in at least 3 muscles, including an upper limb muscle, a lower limb muscle, and paraspinal muscles. GAA Enzyme Activity Level. Acid a-glucosidase activity level was investigated in all patients in at least 1 tissue (blood lymphocytes, cultured skin fibroblasts, or skeletal muscle), as reported elsewhere.1 GAA Gene Analysis. GAA (Gene ID 2548, MIM #606800) coding region and intron/exon boundaries were amplified and sequenced from genomic DNA from all patients, as reported elsewhere.1 RESULTS Clinical Characteristics of Patients with Asymptomatic Pompe Disease. Seven adult patients with asymptomatic Pompe disease were identified in the French Pompe registry, representing 5% of all French patients with adult Pompe disease.9 One patient has previously been described elsewhere.5 Pompe disease was investigated due to a positive family history for late-onset Pompe disease in 4 patients and due to hyperCKemia in 3. There were 5 women and 3 men. Three women from our series (patients 1, 5, and 7) had 5 younger brothers with symptomatic late-onset Pompe disease, including 2 wheelchair-bound patients and 2 patients with noninvasive ventilation. One woman (patient 4) had a mother with symptomatic lateonset Pompe disease; genetic analysis showed that she inherited 1 mutation from her mother and another mutation from her father, who was a heterozygous carrier. Mean age at diagnosis was in the 40s (range 2–68); mean age at the time of the study was 45 (range 24–75) years; and the median Asymptomatic Pompe Disease
Table 1. Clinical characteristics of 7 patients with asymptomatic Pompe disease. Age at diagnosis (years)
Gender
Follow-up (years)
1 2 3*
48 51 2
W M M
2 1 22
4 5 6 7
25 44 68 43
W W W W
4 1 7 1
Patient
Miscellaneous NA NA Bilateral calf hypertrophy NA NA Scoliosis NA
W, woman; M, man; NA, not applicable. *Patient 3 was described by Laloui et al.5
duration of follow-up was 2 (range 1–22) years (Table 1). Clinical examinations, including MMT, timed tests, MFM scale, and the 6MWT, were normal in all cases. Bilateral calf hypertrophy was observed in 1 patient, and 1 patient presented with scoliosis. Muscle pathology, EMG, WBMRI, and cardiorespiratory characteristics of patients are shown in Table 2. PFT, ECG, and echocardiography findings were normal in all 7 patients. EMG was performed in the deltoid, tibialis anterior, and paraspinal muscles of 3 patients, and was normal. Muscle biopsy was performed in the left deltoid muscle in 6 patients and demonstrated a vacuolar myopathy with increased periodic acid–Schiff (PAS) staining in 3. In the other 3 patients, muscle histology was normal. CK levels were mildly elevated (1.5–5 times normal) in 6 patients, and normal in 1. WBMRI was performed in 5 patients, demonstrating tongue and subscapularis muscle abnormalities in 1, and shoulder girdle, lumbar extensor, and hamstring muscle abnormalities in another (Figs. 1 and 2), and no abnormal findings in the other 3. Thus, at least 1 subclinical abnormality was observed in all patients, including significant hyperCKemia (6 of 7; 86%), vacuolar myopathy with increased PAS staining (3 of 6; 50%), and muscle MRI abnormalities (2 of 5; 40%). GAA Enzyme Activity Level and GAA Mutations. All patients had GAA deficiency in at least 1 tissue, and all had 2 GAA mutations (Table 3). All patients harbored the common mutation c.-3213T>G in combination with different causal mutations on the second allele, with the exception of patient 6 who harbored the c.-32-13T>G mutation in a homozygous state. All GAA mutations have already been reported, with the exception of the p.Val350Met mutation, which has been predicted to be pathogenic by various bioinformatics tools.12–14 MUSCLE & NERVE
June 2015
885
Table 2. Paraclinical characteristics of 7 patients with asymptomatic Pompe disease. Serum CK (U/L) (normal G (intron 1) c.923A>C (p.His308Pro) (exon 5) c.232-13T>G (intron 1) c.1048G>A (p.Val350Met) (exon 6) c.232-13T>G (intron 1) c.655G>A (p.Gly219Arg) (exon 3) c.232-13T>G (intron 1) c.2104C>T (p.Arg702Cys) (exon 15) c.232-13T>G (intron 1) c.1396delG (p.Val466Phefs*11) (exon 9) c.232-13T>G (intron 1) c.232-13T>G (intron 1) c.232-13T>G (intron 1) c.188811G>A (intron 13)
Acid a-glucosidase activity Muscle: 10 (N: 138–320) Lymphocytes: 2 (N: 6–25)
Family history of Pompe disease 2 brothers with symptomatic Pompe disease
Muscle: 8 (N: 138–320) Lymphocytes: 0.2 (N: 6–25) Fibroblasts: 6.2 (N: 42.8) Lymphocytes: 1.5 (N: 6–25)
None
Lymphocytes: 5 (N: 15–45) Fibroblasts: 3.2 (N: 32)
Mother with symptomatic Pompe disease
Lymphocytes: 2.0 (N:6–25)
1 brother with symptomatic Pompe disease None
Muscle: 0 (N: 138–320) Lymphocytes: 9 (N: 15–45)
None
2 brothers with symptomatic Pompe disease
Acid a-glucosidase activity is expressed as mkat per kilogram protein (mkat/kg prot) in blood lymphocytes and cultured skin fibroblasts, and in nkat per kilogram muscle (nkat/kg muscle) in skeletal muscle. Control enzyme activities are given as a range. As enzyme activity values in lymphocytes were measured in 2 different laboratories, normal (N) values were different in patients 1, 2, 3, and 5 than in patients 4 and 7.
Asymptomatic Pompe Disease
MUSCLE & NERVE
June 2015
887
men, including less exercise intolerance and less frequent recurrent exertional myoglobinuria.17 The molecular basis of gender contribution to the phenotype of muscle glycogenoses remains largely unknown.17 By definition, all the patients described here presented with a normal clinical examination and no obvious signs and/or symptoms of myopathy. Bilateral calf hypertrophy and scoliosis were observed in 1 patient each: it is unclear whether these conditions were related to Pompe disease or were coincidental. All patients presented with at least 1 subclinical abnormality. This suggests that a myopathy was present in all 7 patients, although it was clinically silent. EMG examination was also normal in 3 of 3 patients, demonstrating that electrodiagnostic studies are not sufficiently sensitive to detect myopathic changes in asymptomatic Pompe disease. Until now, only a few adult patients with asymptomatic Pompe disease have been reported, and all have presented with hyperCKemia, normal cardiorespiratory function, and mild vacuolar myopathy.6,7 However, in contrast to our series, some of these patients also presented with mild clinical features, such as slight proximal limb weakness and recurrent myalgia.6,7 WBMRI deserves special mention, because recent studies have shown a specific pattern of muscle involvement in late-onset Pompe disease with tongue, spine extensors, subscapularis, and thigh muscles being mainly involved.11 Interestingly, in our series, this typical late-onset Pompe disease WBMRI pattern was observed in only 1 patient. The GAA c.-32-13T>G mutation is by far the most frequent GAA mutation observed among Caucasian children and adults with Pompe disease.18 It is located in the first intron of the GAA gene and leads to improper splicing in 80%–90% of the GAA pre-mRNA splicing events.18 It is generally thought that the correlation between genotype and phenotype in Pompe disease is strict, in that patients with the most severe phenotype have 2 deleterious mutations that prevent the formation of GAA or render it completely nonfunctional; patients with less severe phenotypes have at least 1 sequence variation that allows normal or low-level synthesis of GAA that leads to formation of measurable low-level GAA activity.18 However, it is also known that patients with functionally the same GAA genotype and the same c.-32-13C>T haplotype present with considerable clinical heterogeneity, suggesting that modifying factors may disturb the GAA genotype–phenotype correlation and have a substantial effect on the clinical course of the disease.18 For instance, polymorphisms on “exercise genes,” such as ACE and ACTN3, may 888
Asymptomatic Pompe Disease
influence muscle performance and outcome in patients with Pompe disease.19 Identifying these factors and exploring them as therapeutic targets remains a challenge. Our results demonstrate that patients with Pompe disease may remain asymptomatic until very late in life. For example, patient 3 was diagnosed with Pompe disease at age 2 years and remains asymptomatic at age 24. Some patients with asymptomatic Pompe disease may never become symptomatic. For example, patient 6 was diagnosed with Pompe disease at age 68 years and remains asymptomatic at age 75. Our results have major implications for newborn screening in Pompe disease, as they suggest that patients identified via newborn screening with likely late-onset Pompe disease may not need to be treated immediately. As all patients in our study presented without overt clinical myopathy, cardiomyopathy, or respiratory insufficiency, ERT was not considered. However, all patients also presented with mild paraclinical abnormalities indicative of a subclinical myopathy. In this context, should ERT be considered? Late-onset Pompe disease is generally restricted to skeletal and respiratory muscles with slow progression, but also with potential early death. In these patients, ERT slows disease progression, but the benefits appear to be less dramatic than those observed in infantile-onset Pompe disease.20 Considering the very high cost of treatment (>$300,000 per year per adult patient), and the observation that patients with asymptomatic Pompe disease may remain asymptomatic for decades, and in some cases never even develop symptoms, we recommend that patients with asymptomatic Pompe disease be monitored closely for overt myopathy using muscle strength assessment, WBMRI, and PFT before deciding to start ERT. In our practice, we perform muscle strength assessment, ECG, echocardiography, and PFT every 12 months and WBMRI every 24 months before deciding, on an individual basis, whether or not to treat. Our current experience with patients with asymptomatic Pompe disease suggests that ERT should probably not be initiated before the occurrence of abnormalities in muscle strength, PFT, or WBMRI. REFERENCES 1. van der Ploeg AT, Reuser AJ. Pompe’s disease. Lancet 2008;372: 1342–1353. 2. Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL, et al. Recombinant human acid alfa-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology 2007;68:99–109. 3. van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ, et al. A randomized study of alglucosidase alfa in late-onset Pompe’s disease. N Engl J Med 2010;362:1396–1406. 4. van der Ploeg AT, Barohn R, Carlson L, Charrow J, Clemens PR, Hopkin RJ, et al. Open-label extension study following the LateOnset Treatment Study (LOTS) of alglucosidase alfa. Mol Genet Metab 2012;107:456–461.
MUSCLE & NERVE
June 2015
5. Laloui K, Wary C, Carlier RY, Hogrel JY, Caillaud C, Lafor^ et P. Making diagnosis of Pompe disease at a presymptomatic stage: to treat or not to treat? Neurology 2011;77:594–595. 6. Wagner M, Chaouch A, M€ uller JS, Polvikoski T, Willis TA, Sarkozy A, et al. Presymptomatic late-onset Pompe disease identified by the dried blood spot test. Neuromuscul Disord 2013;23:89–92. 7. Spada M, Porta F, Vercelli L, Pagliardini V, Chiado-Piat L, Boffi P, et al. Screening for later-onset Pompe’s disease in patients with paucisymptomatic hyperCKemia. Mol Genet Metab 2013;109:171–173. 8. Kwon JM, Steiner RD. “I’m fine; I’m just waiting for my disease”: the new and growing class of presymptomatic patients. Neurology 2011; 77:522–523. 9. Lafor^et P, Laloui K, Granger B, Hamroun D, Taouagh N, Hogrel JY, et al. The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease. Rev Neurol (Paris) 2013; 169:595–602. 10. American Association of Neuromuscular & Electrodiagnostic Medicine. Diagnostic criteria for late-onset (childhood and adult) Pompe disease. Muscle Nerve 2009;40:149–160. 11. Carlier RY, Lafor^ et P, Wary C, Mompoint D, Laloui K, Pellegrini N, et al. Whole-body muscle MRI in 20 patients suffering from late onset Pompe disease: involvement patterns. Neuromuscul Disord 2011;21:791–799. 12. Pompe disease mutation database. Available at: www.pompecenter.nl. Accessed March 7, 2014.
Asymptomatic Pompe Disease
13. PolyPhen-2. Available at: http://genetics.bwh.harvard.edu/pph2/. Accessed February 20, 2013. 14. J. Craig Venter Institute. SIFT. Available at: http://sift.jcvi.org/. Accessed February 20, 2013. 15. van der Beek NA, van Capelle CI, van der Velden-van Etten KI, Hop WC, van den Berg B, Reuser AJ, et al. Rate of progression and predictive factors for pulmonary outcome in children and adults with Pompe disease. Mol Genet Metab 2011;104:129–136. 16. Wens SC, van Gelder CM, Kruijshaar ME, de Vries JM, van der Beek NA, Reuser AJ, et al. Phenotypical variation within 22 families with Pompe disease. Orphanet J Rare Dis 2013;8:182. 17. Lucia A, Ruiz JR, Santalla A, Nogales-Gadea G, Rubio JC, GarciaConsuegra I, et al. Genotypic and phenotypic features of McArdle disease: insights from the Spanish national registry. J Neurol Neurosurg Psychiatry 2012;83:322–328. 18. Kroos M, Hoogeveen-Westerveld M, van der Ploeg A, Reuser AJ. The genotype-phenotype correlation in Pompe disease. Am J Med Genet C Semin Med Genet 2012;160C:59–68. 19. Ravaglia S, De Filippi P, Pichiecchio A, Ponzio M, Saeidi Garaghani K, Poloni GU, et al. Can genes influencing muscle function affect the therapeutic response to enzyme replacement therapy (ERT) in late-onset type II glycogenosis? Mol Genet Metab 2012;107:104–110. 20. Toscano A, Schoser B. Enzyme replacement therapy in late-onset Pompe disease: a systematic literature review. J Neurol 2013;260:951– 959.
MUSCLE & NERVE
June 2015
889
