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Long-term enzyme-replacement therapy (ERT) with alglucosidase alfa: Evolution of two siblings with juvenile late-onset Pompe disease
JNS-13956; No of Pages 2 Journal of the Neurological Sciences xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Long-term enzyme-replacement therapy (ERT) with alglucosidase alfa: Evolution of two siblings with juvenile late-onset Pompe disease Keywords: Pompe disease Late-onset Pompe disease Enzyme-replacement therapy Juvenile late-onset Pompe disease
589 IU/L and ALT 51 IU/L). In December 2013, functionality was moderately affected (Table 1). Muscle strength was decreased, however, spirometry tests (March 2014), showed normal values in both siblings (Table 1). Muscle MRI of the lower limbs showed intramuscular adipose substitution in affected muscles. No cardiac abnormalities have been observed. Both patients continued treatment and no serious adverse events have been observed up to date (after 10 and 6 years, for the boy and girl, respectively). 1. Discussion
Dear Editor, Enzyme-replacement therapy (ERT) with recombinant human alglucosidase alfa for Pompe disease was approved in 2006, and thus, it is just now that long-term experience can be reported. Furthermore, although there are multiple reports of adult late-onset Pompe disease (LOPD), reports of the infantile and juvenile LOPD form are scarce [1]. We report clinical, laboratory and functional data of two siblings with LOPD after ERT for over 9 years in the boy and almost 5 years in the girl. The hospital ethics committee and health authorities approved the treatment protocol for the boy in 2005. The children's parents provided informed consent for all the procedures. Patient 1 is a boy who showed the first symptoms at age 3 (year 2002), consisting in difficulties in climbing stairs, getting up, running and jumping. CK, ALT and AST levels were increased. Biopsy of the quadriceps revealed PAS positive vacuolar myopathy, and lysosomal and free glycogen. The enzymatic activity was severely reduced in muscle, at 13 nkat/kg wet tissue at pH 4.5 and in cultured skin fibroblasts, at 39.1 nmol/h/mg Prot. The patient started ERT treatment at age 5 (January 2005) and motor symptoms radically improved. Antialglucosidase alfa antibodies were positive after 12 months of therapy (titer 1:200), rose during the second year (1:800) but subsequently disappeared. Patient 2, the sister, noted decreased muscle strength in lower extremities at age 11 (year 2009), presenting Gowers' positive sign. CK, ALT and AST levels were increased. She suffered from muscle pain and chronic headache. The disease was confirmed by mutation analysis of the GAA gene, which revealed, for both siblings, the following two mutations: c.32-13 T N G, and c.2255_2257del (p.Ile752del). She started ERT and the muscle pain and headaches disappeared. After 2 years, she developed fever after therapy administration, which was solved by premedication with acetaminophen and dexchlorpheniramine. Anti-alglucosidase alfa antibodies were positive 5 months after starting therapy with a titer of 1:400, which rose to 1:3200 up and has been sustained. After long-term ERT, mean CK and ALT decreased in the boy (from 2005: CK 722 and ALT 153 IU/L to 2013: CK 550 IU/L and ALT 76 IU/L) and in the girl (from 2009: CK 779 and ALT 85 IU/L to 2013: CK
Pompe disease is inherited with an autosomal recessive pattern. Both children were compound heterozygotes for the c.32-13 T N G mutation, coding for an enzyme with residual activity and mild phenotypic effect [2]. The other mutation, c.2255_2257del, with unknown phenotypical effect, was described in a 3 year-old boy with the same mutations and residual GAA activity (11.4%) than our boy [2]. Although bearing the same mutations, the siblings manifested initial symptoms at different ages, in agreement with a previous study in three Argentinean siblings with PD [3], suggesting that secondary factors may influence the clinical course. While correlations between some mutant allele and severity of the disease exist, the power of this information is limited in its ability to fully predict patient prognosis; it is likely that genetic and environmental factors also contribute to the overall disease presentation and progression [3]. After 9 and 5 years of ERT treatment, in the boy and girl, respectively, WS was mildly impaired (1) although muscle strength remained clearly below (25–51%) that of healthy peers (Table 1) [4]. The 6MWT showed half the average speed (5.5 and 5.2 km/h for the boy and girl, respectively) than that reported in a study with healthy children during a 6 minute-endurance run (11.8 km/h) [5]. Rising from supine to standing position took about 6.3 times longer for the boy and 3.3 times longer for the girl, as compared to healthy 11-year old children (0.99 s in boys and 1.13 in girls) [6]. Spirometry data were within normal limits in both siblings but worse in the boy, probably due the longer disease evolution in this patient; however, still after 10 years of treatment, the boy does not need ventilator support. Unfortunately, there were no data of muscle or respiratory functions at treatment start to compare with but our patients seem to have evolved with improvement or stabilization without clinical decline. The reduction of CK levels observed in our patients is considered a useful indicator of response to treatment [1]. In LOPD, there is overall no clinically identifiable heart disease, as it is the case of our patients who showed normal echocardiographic examinations. The muscle MRI images showed the distribution pattern of intramuscular adipose substitution in affected muscles, as described previously [7]. ERT experience in childhood and juvenile late-onset disease is still limited; [1,8,9]. The present two cases add evidence to previous reports showing ERT to stabilize (or improve) pulmonary and motor functions in treatment periods above 3 years [8,9].
http://dx.doi.org/10.1016/j.jns.2015.08.007 0022-510X/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: J. Rafael Bretón Martínez, A.C. Martínez, Long-term enzyme-replacement therapy (ERT) with alglucosidase alfa: Evolution of two siblings with juvenile late-onset Pompe disea, J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.08.007
2
Letter to the Editor
Table 1 Functional results, muscular strength and respiratory function of patients after long-term treatment. Boy (2005)⁎ Functional tests — December 2013 WS, score points 1 10-meter run test, sec 4.1 Both feet off ground Rise from supine position, sec 6.3 Without using hands Four step climbing, sec 2.7 Four step descending, sec 2.3 Alternating feet No need handrail 6MWT, meters 550
Girl (2009)⁎ 1 3.3 Both feet off ground 3.7 Both hands on floor 2.4 2.2 Alternating feet No need handrail 520
(institutional and national) and with the Helsinki Declaration. The ethics committee of the hospital and health authorities issued an investigational drug authorization for the boy to start ERT in 2005. Informed consent was obtained from the patients' parents to report these cases.
Contributions of authors JRB collected the data and wrote the first draft of the paper. ACM was the person responsible for the clinical management of the patients, and critically revised the final paper. Both, JRB and ACM, planned the manuscript and determined its content and they both are the guarantors of the article.
§
Myometry, newtons — December 2013 Knee extensors 131 [296] Knee flexors 102 [273] Hip flexors 73 [289] Shoulder abduction 74 [159] Elbow flexion 97 [195] Elbow extension 65 [128]
134 [325] 97 [282] 78 [288] 82 [173] 86 [198] 67 [141]
Spirometry — March 2014 FVC, L FEV1, L/1 s (%) FEV1/FVC MEF25–75%, L/s (%) PEF, %
3.80 (119%) 3.38 (106%) 89 4.09 (112%) 96%
Acknowledgments Almudena Pardo provided editorial assistance.
References 3.05 (84%) 2.86 (84%) 94 3.96 (104%) 72%
WS: Walton scale for disability; 6MWT: 6-meter walk test; FVC: Forced expiratory vital capacity; Forced expiratory volume in 1 s; MEF: Mean forced expiratory flow; and PEF: Peak expiratory flow. ⁎ Year of ERT treatment initiation. § In square brackets: Reference value of healthy controls of the same age and sex [4].
Infusion-associated mild reactions occurred in the girl. No consistent association has been found between anti-alglucosidase alfa antibody titer and the incidence of adverse events, including infusionassociated reactions [10]. The majority of Pompe patients on ERT develop antibodies against alglucosidase alfa, with a trend toward decreasing levels with continued treatment, as it occurred in the boy. The influence of these antibodies on the clinical effect of ERT has not been consistent [10]. In conclusion, long-term ERT was well tolerated and safe in our patients. ERT reduced CK and ALT and it is probably stabilizing motor deterioration and lessening respiratory impairment. It is worth noting the significant reduction in muscle pain and headaches in the girl after beginning ERT. The ERT effect is difficult to assess since Pompe disease may have a long natural history without treatment. The boy has currently (2015) a history of 13 years of illness, and his evolution would have been probably worse without treatment. Conflict of interest J. Rafael Bretón Martínez has received financial support from Genzyme Corporation to attend a meeting on lysosomal storage diseases. Andrés Cánovas Martínez has received financial support from Genzyme Corporation to attend a meeting on lysosomal storage diseases.
[1] A. Toscano, B. Schoser, Enzyme replacement therapy in late-onset Pompe disease: a systematic literature review, J. Neurol. 260 (2013) 951–959. [2] L. Gort, M.J. Coll, A. Chabas, Glycogen storage disease type II in Spanish patients: high frequency of c.1076-1G N C mutation, Mol. Genet. Metab. 92 (2007) 183–187. [3] R.E. Palmer, H.M. Amartino, G. Niizawa, M. Blanco, R.J. Pomponio, N.A. Chamoles, Pompe disease (glycogen storage disease type II) in Argentineans: clinical manifestations and identification of 9 novel mutations, Neuromuscul. Disord. 17 (2007) 16–22. [4] E.A. Beenakker, J.H. van der Hoeven, J.M. Fock, N.M. Maurits, Reference values of maximum isometric muscle force obtained in 270 children aged 4–16 years by hand-held dynamometry, Neuromuscul. Disord. 11 (2001) 441–446. [5] W. van Mechelen, H. Hlobil, H.C. Kemper, Validation of two running tests as estimates of maximal aerobic power in children, Eur. J. Appl. Physiol. Occup. Physiol. 55 (1986) 503–506. [6] E.A. Beenakker, N.M. Maurits, J.M. Fock, O.F. Brouwer, J.H. van der Hoeven, Functional ability and muscle force in healthy children and ambulant Duchenne muscular dystrophy patients, Eur. J. Paediatr. Neurol. 9 (2005) 387–393. [7] A. Pichiecchio, G.U. Poloni, S. Ravaglia, M. Ponzio, G. Germani, D. Maranzana, et al., Enzyme replacement therapy in adult-onset glycogenosis II: is quantitative muscle MRI helpful? Muscle Nerve 40 (2009) 122–125. [8] C.I. van Capelle, L.P. Winkel, M.L. Hagemans, S.K. Shapira, W.F. Arts, P.A. van Doorn, et al., Eight years experience with enzyme replacement therapy in two children and one adult with Pompe disease, Neuromuscul. Disord. 18 (2008) 447–452. [9] L. Deroma, M. Guerra, A. Sechi, G. Ciana, G. Cisilino, A. Dardis, et al., Enzyme replacement therapy in juvenile glycogenosis type II: a longitudinal study, Eur. J. Pediatr. 173 (2014) 805–813. [10] A.T. van der Ploeg, P.R. Clemens, D. Corzo, D.M. Escolar, J. Florence, G.J. Groeneveld, et al., A randomized study of alglucosidase alfa in late-onset Pompe's disease, N. Engl. J. Med. 362 (2010) 1396–1406.
J. Rafael Bretón Martínez Department of Paediatrics, University Hospital Doctor Peset, Valencia, Spain University of Valencia, Spain Corresponding author at: Department of Paediatrics, University Hospital Doctor Peset, Av. Gaspar Aguilar, 90, 46017 Valencia, Spain. E-mail address: [email protected] Andrés Cánovas Martínez Department of Paediatrics, University Hospital Doctor Peset, Valencia, Spain
Informed consent All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation
11 June 2015 Available online xxxx
Please cite this article as: J. Rafael Bretón Martínez, A.C. Martínez, Long-term enzyme-replacement therapy (ERT) with alglucosidase alfa: Evolution of two siblings with juvenile late-onset Pompe disea, J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.08.007
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Long-term enzyme-replacement therapy (ERT) with alglucosidase alfa: Evolution of two siblings with juvenile late-onset Pompe disease Keywords: Pompe disease Late-onset Pompe disease Enzyme-replacement therapy Juvenile late-onset Pompe disease
589 IU/L and ALT 51 IU/L). In December 2013, functionality was moderately affected (Table 1). Muscle strength was decreased, however, spirometry tests (March 2014), showed normal values in both siblings (Table 1). Muscle MRI of the lower limbs showed intramuscular adipose substitution in affected muscles. No cardiac abnormalities have been observed. Both patients continued treatment and no serious adverse events have been observed up to date (after 10 and 6 years, for the boy and girl, respectively). 1. Discussion
Dear Editor, Enzyme-replacement therapy (ERT) with recombinant human alglucosidase alfa for Pompe disease was approved in 2006, and thus, it is just now that long-term experience can be reported. Furthermore, although there are multiple reports of adult late-onset Pompe disease (LOPD), reports of the infantile and juvenile LOPD form are scarce [1]. We report clinical, laboratory and functional data of two siblings with LOPD after ERT for over 9 years in the boy and almost 5 years in the girl. The hospital ethics committee and health authorities approved the treatment protocol for the boy in 2005. The children's parents provided informed consent for all the procedures. Patient 1 is a boy who showed the first symptoms at age 3 (year 2002), consisting in difficulties in climbing stairs, getting up, running and jumping. CK, ALT and AST levels were increased. Biopsy of the quadriceps revealed PAS positive vacuolar myopathy, and lysosomal and free glycogen. The enzymatic activity was severely reduced in muscle, at 13 nkat/kg wet tissue at pH 4.5 and in cultured skin fibroblasts, at 39.1 nmol/h/mg Prot. The patient started ERT treatment at age 5 (January 2005) and motor symptoms radically improved. Antialglucosidase alfa antibodies were positive after 12 months of therapy (titer 1:200), rose during the second year (1:800) but subsequently disappeared. Patient 2, the sister, noted decreased muscle strength in lower extremities at age 11 (year 2009), presenting Gowers' positive sign. CK, ALT and AST levels were increased. She suffered from muscle pain and chronic headache. The disease was confirmed by mutation analysis of the GAA gene, which revealed, for both siblings, the following two mutations: c.32-13 T N G, and c.2255_2257del (p.Ile752del). She started ERT and the muscle pain and headaches disappeared. After 2 years, she developed fever after therapy administration, which was solved by premedication with acetaminophen and dexchlorpheniramine. Anti-alglucosidase alfa antibodies were positive 5 months after starting therapy with a titer of 1:400, which rose to 1:3200 up and has been sustained. After long-term ERT, mean CK and ALT decreased in the boy (from 2005: CK 722 and ALT 153 IU/L to 2013: CK 550 IU/L and ALT 76 IU/L) and in the girl (from 2009: CK 779 and ALT 85 IU/L to 2013: CK
Pompe disease is inherited with an autosomal recessive pattern. Both children were compound heterozygotes for the c.32-13 T N G mutation, coding for an enzyme with residual activity and mild phenotypic effect [2]. The other mutation, c.2255_2257del, with unknown phenotypical effect, was described in a 3 year-old boy with the same mutations and residual GAA activity (11.4%) than our boy [2]. Although bearing the same mutations, the siblings manifested initial symptoms at different ages, in agreement with a previous study in three Argentinean siblings with PD [3], suggesting that secondary factors may influence the clinical course. While correlations between some mutant allele and severity of the disease exist, the power of this information is limited in its ability to fully predict patient prognosis; it is likely that genetic and environmental factors also contribute to the overall disease presentation and progression [3]. After 9 and 5 years of ERT treatment, in the boy and girl, respectively, WS was mildly impaired (1) although muscle strength remained clearly below (25–51%) that of healthy peers (Table 1) [4]. The 6MWT showed half the average speed (5.5 and 5.2 km/h for the boy and girl, respectively) than that reported in a study with healthy children during a 6 minute-endurance run (11.8 km/h) [5]. Rising from supine to standing position took about 6.3 times longer for the boy and 3.3 times longer for the girl, as compared to healthy 11-year old children (0.99 s in boys and 1.13 in girls) [6]. Spirometry data were within normal limits in both siblings but worse in the boy, probably due the longer disease evolution in this patient; however, still after 10 years of treatment, the boy does not need ventilator support. Unfortunately, there were no data of muscle or respiratory functions at treatment start to compare with but our patients seem to have evolved with improvement or stabilization without clinical decline. The reduction of CK levels observed in our patients is considered a useful indicator of response to treatment [1]. In LOPD, there is overall no clinically identifiable heart disease, as it is the case of our patients who showed normal echocardiographic examinations. The muscle MRI images showed the distribution pattern of intramuscular adipose substitution in affected muscles, as described previously [7]. ERT experience in childhood and juvenile late-onset disease is still limited; [1,8,9]. The present two cases add evidence to previous reports showing ERT to stabilize (or improve) pulmonary and motor functions in treatment periods above 3 years [8,9].
http://dx.doi.org/10.1016/j.jns.2015.08.007 0022-510X/© 2015 Elsevier B.V. All rights reserved.
Please cite this article as: J. Rafael Bretón Martínez, A.C. Martínez, Long-term enzyme-replacement therapy (ERT) with alglucosidase alfa: Evolution of two siblings with juvenile late-onset Pompe disea, J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.08.007
2
Letter to the Editor
Table 1 Functional results, muscular strength and respiratory function of patients after long-term treatment. Boy (2005)⁎ Functional tests — December 2013 WS, score points 1 10-meter run test, sec 4.1 Both feet off ground Rise from supine position, sec 6.3 Without using hands Four step climbing, sec 2.7 Four step descending, sec 2.3 Alternating feet No need handrail 6MWT, meters 550
Girl (2009)⁎ 1 3.3 Both feet off ground 3.7 Both hands on floor 2.4 2.2 Alternating feet No need handrail 520
(institutional and national) and with the Helsinki Declaration. The ethics committee of the hospital and health authorities issued an investigational drug authorization for the boy to start ERT in 2005. Informed consent was obtained from the patients' parents to report these cases.
Contributions of authors JRB collected the data and wrote the first draft of the paper. ACM was the person responsible for the clinical management of the patients, and critically revised the final paper. Both, JRB and ACM, planned the manuscript and determined its content and they both are the guarantors of the article.
§
Myometry, newtons — December 2013 Knee extensors 131 [296] Knee flexors 102 [273] Hip flexors 73 [289] Shoulder abduction 74 [159] Elbow flexion 97 [195] Elbow extension 65 [128]
134 [325] 97 [282] 78 [288] 82 [173] 86 [198] 67 [141]
Spirometry — March 2014 FVC, L FEV1, L/1 s (%) FEV1/FVC MEF25–75%, L/s (%) PEF, %
3.80 (119%) 3.38 (106%) 89 4.09 (112%) 96%
Acknowledgments Almudena Pardo provided editorial assistance.
References 3.05 (84%) 2.86 (84%) 94 3.96 (104%) 72%
WS: Walton scale for disability; 6MWT: 6-meter walk test; FVC: Forced expiratory vital capacity; Forced expiratory volume in 1 s; MEF: Mean forced expiratory flow; and PEF: Peak expiratory flow. ⁎ Year of ERT treatment initiation. § In square brackets: Reference value of healthy controls of the same age and sex [4].
Infusion-associated mild reactions occurred in the girl. No consistent association has been found between anti-alglucosidase alfa antibody titer and the incidence of adverse events, including infusionassociated reactions [10]. The majority of Pompe patients on ERT develop antibodies against alglucosidase alfa, with a trend toward decreasing levels with continued treatment, as it occurred in the boy. The influence of these antibodies on the clinical effect of ERT has not been consistent [10]. In conclusion, long-term ERT was well tolerated and safe in our patients. ERT reduced CK and ALT and it is probably stabilizing motor deterioration and lessening respiratory impairment. It is worth noting the significant reduction in muscle pain and headaches in the girl after beginning ERT. The ERT effect is difficult to assess since Pompe disease may have a long natural history without treatment. The boy has currently (2015) a history of 13 years of illness, and his evolution would have been probably worse without treatment. Conflict of interest J. Rafael Bretón Martínez has received financial support from Genzyme Corporation to attend a meeting on lysosomal storage diseases. Andrés Cánovas Martínez has received financial support from Genzyme Corporation to attend a meeting on lysosomal storage diseases.
[1] A. Toscano, B. Schoser, Enzyme replacement therapy in late-onset Pompe disease: a systematic literature review, J. Neurol. 260 (2013) 951–959. [2] L. Gort, M.J. Coll, A. Chabas, Glycogen storage disease type II in Spanish patients: high frequency of c.1076-1G N C mutation, Mol. Genet. Metab. 92 (2007) 183–187. [3] R.E. Palmer, H.M. Amartino, G. Niizawa, M. Blanco, R.J. Pomponio, N.A. Chamoles, Pompe disease (glycogen storage disease type II) in Argentineans: clinical manifestations and identification of 9 novel mutations, Neuromuscul. Disord. 17 (2007) 16–22. [4] E.A. Beenakker, J.H. van der Hoeven, J.M. Fock, N.M. Maurits, Reference values of maximum isometric muscle force obtained in 270 children aged 4–16 years by hand-held dynamometry, Neuromuscul. Disord. 11 (2001) 441–446. [5] W. van Mechelen, H. Hlobil, H.C. Kemper, Validation of two running tests as estimates of maximal aerobic power in children, Eur. J. Appl. Physiol. Occup. Physiol. 55 (1986) 503–506. [6] E.A. Beenakker, N.M. Maurits, J.M. Fock, O.F. Brouwer, J.H. van der Hoeven, Functional ability and muscle force in healthy children and ambulant Duchenne muscular dystrophy patients, Eur. J. Paediatr. Neurol. 9 (2005) 387–393. [7] A. Pichiecchio, G.U. Poloni, S. Ravaglia, M. Ponzio, G. Germani, D. Maranzana, et al., Enzyme replacement therapy in adult-onset glycogenosis II: is quantitative muscle MRI helpful? Muscle Nerve 40 (2009) 122–125. [8] C.I. van Capelle, L.P. Winkel, M.L. Hagemans, S.K. Shapira, W.F. Arts, P.A. van Doorn, et al., Eight years experience with enzyme replacement therapy in two children and one adult with Pompe disease, Neuromuscul. Disord. 18 (2008) 447–452. [9] L. Deroma, M. Guerra, A. Sechi, G. Ciana, G. Cisilino, A. Dardis, et al., Enzyme replacement therapy in juvenile glycogenosis type II: a longitudinal study, Eur. J. Pediatr. 173 (2014) 805–813. [10] A.T. van der Ploeg, P.R. Clemens, D. Corzo, D.M. Escolar, J. Florence, G.J. Groeneveld, et al., A randomized study of alglucosidase alfa in late-onset Pompe's disease, N. Engl. J. Med. 362 (2010) 1396–1406.
J. Rafael Bretón Martínez Department of Paediatrics, University Hospital Doctor Peset, Valencia, Spain University of Valencia, Spain Corresponding author at: Department of Paediatrics, University Hospital Doctor Peset, Av. Gaspar Aguilar, 90, 46017 Valencia, Spain. E-mail address: [email protected] Andrés Cánovas Martínez Department of Paediatrics, University Hospital Doctor Peset, Valencia, Spain
Informed consent All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation
11 June 2015 Available online xxxx
Please cite this article as: J. Rafael Bretón Martínez, A.C. Martínez, Long-term enzyme-replacement therapy (ERT) with alglucosidase alfa: Evolution of two siblings with juvenile late-onset Pompe disea, J Neurol Sci (2015), http://dx.doi.org/10.1016/j.jns.2015.08.007