Investigating Late-Onset Pompe Prevalence in Neuromuscular Medicine Academic Practices: The IPaNeMA Study

Marie Wencel, Aziz Shaibani, Namita A Goyal, Mazen M Dimachkie, Jaya Trivedi, Nicholas E Johnson, Laurie Gutmann, Matthew P Wicklund, Sankar Bandyopadhay, Angela L Genge, Miriam L Freimer, Neelam Goyal, Alan Pestronk, Julaine Florence, Chafic Karam, Jeffrey W Ralph, Zinah Rasheed, Melissa Hays, Steve Hopkins, Tahseen Mozaffar, Marie Wencel, Aziz Shaibani, Namita A Goyal, Mazen M Dimachkie, Jaya Trivedi, Nicholas E Johnson, Laurie Gutmann, Matthew P Wicklund, Sankar Bandyopadhay, Angela L Genge, Miriam L Freimer, Neelam Goyal, Alan Pestronk, Julaine Florence, Chafic Karam, Jeffrey W Ralph, Zinah Rasheed, Melissa Hays, Steve Hopkins, Tahseen Mozaffar

Abstract

Background and objectives: We investigated the prevalence of late-onset Pompe disease (LOPD) in patients presenting to 13 academic, tertiary neuromuscular practices in the United States and Canada.

Methods: All successive patients presenting with proximal muscle weakness or isolated hyperCKemia and/or neck muscle weakness to these 13 centers were invited to participate in the study. Whole blood was tested for acid alpha-glucosidase (GAA) assay through the fluorometric method, and all cases with enzyme levels of ≤10 pmoL/punch/h were reflexed to molecular testing for mutations in the GAA gene. Clinical and demographic information was abstracted from their clinical visit and, along with study data, entered into a purpose-built REDCap database, and analyzed at the University of California, Irvine.

Results: GAA enzyme assay results were available on 906 of the 921 participants who consented for the study. LOPD was confirmed in 9 participants (1% prevalence). Another 9 (1%) were determined to have pseudodeficiency of GAA, whereas 19 (1.9%) were found to be heterozygous for a pathogenic GAA mutation (carriers). Of the definite LOPD participants, 8 (89%) were Caucasian and were heterozygous for the common leaky (IVS1) splice site mutation in the GAA gene (c -32-13T>G), with a second mutation that was previously confirmed to be pathogenic.

Discussion: The prevalence of LOPD in undiagnosed patients meeting the criteria of proximal muscle weakness, high creatine kinase, and/or neck weakness in academic, tertiary neuromuscular practices in the United States and Canada is estimated to be 1%, with an equal prevalence rate of pseudodeficiency alleles.

Trial registration information: Clinical trial registration number: NCT02838368.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. CONSORT Diagram for the Study
Figure 1. CONSORT Diagram for the Study
Figure 2. CK Values
Figure 2. CK Values
There is no correlation between serum creatine kinase (CK) and acid alpha-glucosidase (GAA) levels. On Pearson correlation testing, there was no correlation between the CK levels and the GAA levels (r = 0.06; p = 0.09) in the overall population. Inset: Serum CK distribution in all 766 subjects (340 women and 424 men, 2 sex unspecified). Mean CK for all subjects was 1,472 (3,649) IU/L. Mean CK value for male subjects was 1332.3 (3,328) IU/L, whereas in women, the mean CK value was 801.9 (2,437) IU/L. The difference between CK values in men and women was significant (p = 0.01).

References

    1. Hagemans ML, Winkel LP, Doorn VPA, et al. . Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients. Brain. 2005;128(pt 3):671-677.
    1. Lim J-AA, Kakhlon O, Li L, Myerowitz R, Raben N. Pompe disease: shared and unshared features of lysosomal storage disorders. Rare Dis. 2015;3(1):e1068978.
    1. American Association of Neuromuscular and Electrodiagnostic Medicine. Diagnostic criteria for late-onset (childhood and adult) Pompe disease. Muscle Nerve. 2009;40(1):149-160.
    1. van der Ploeg AT, Clemens PR, Corzo D, et al. . A randomized study of alglucosidase alfa in late-onset Pompe's disease. N Engl J Med. 2010;362(15):1396-1406.
    1. Ausems MG, Verbiest J, Hermans MP, et al. . Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet. 1999;7(6):713-716.
    1. Semplicini C, Letard P, De Antonio M, et al. . Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study. J Inherit Metab Dis. 2018;41(6):937-946.
    1. Palmio J, Auranen M, Kiuru-Enari S, Löfberg M, Bodamer O, Udd B. Screening for late-onset Pompe disease in Finland. Neuromuscul Disord. 2014;24(11):982-985.
    1. Chien Y-HH, Hwu W-LL, Lee N-CC. Pompe disease: early diagnosis and early treatment make a difference. Pediatr Neonatol. 2013;54(4):219-227.
    1. Chien Y-HH, Lee N-CC, Chen C-AA, et al. . Long-term prognosis of patients with infantile-onset Pompe disease diagnosed by newborn screening and treated since birth. J Pediatr. 2015;166(4):985-991.
    1. Klug TL, Swartz LB, Washburn J, Brannen C, Kiesling JL. Lessons learned from Pompe disease newborn screening and follow-up. Int J Neonatal Screen. 2020;6(1):11.
    1. Millington DS, Bali DS. Current state of the art of newborn screening for lysosomal storage disorders. Int J Neonatal Screen. 2018;4(3):24.
    1. Lindberg C, Anderson B, Engvall M, Hult M, Oldfors A. Search for Pompe disease among patients with undetermined myopathies. Acta Neurol Scand. 2016;133(2):131-135.
    1. Golsari A, Nasimzadah A, Thomalla G, Keller S, Gerloff C, Magnus T. Prevalence of adult Pompe disease in patients with proximal myopathic syndrome and undiagnosed muscle biopsy. Neuromuscul Disord. 2018;28(3):257-261.
    1. Guimarães MJ, Winck JC, Conde B, et al. . Prevalence of late-onset Pompe disease in Portuguese patients with diaphragmatic paralysis - DIPPER study. Rev Port Pneumol. 2017;23(4):208-215.
    1. Hansen JS, Pedersen EG, Gaist D, et al. . Screening for late-onset Pompe disease in western Denmark. Acta Neurol Scand. 2018;137(1):85-90.
    1. Lee JH, Shin J-HH, Park HJ, et al. . Targeted population screening of late onset Pompe disease in unspecified myopathy patients for Korean population. Neuromuscul Disord. 2017;27(6):550-556.
    1. Löscher WN, Huemer M, Stulnig TM, et al. . Pompe disease in Austria: clinical, genetic and epidemiological aspects. J Neurol. 2018;265(1):159-164.
    1. Musumeci O, la Marca G, Spada M, et al. . LOPED study: looking for an early diagnosis in a late-onset Pompe disease high-risk population. J Neurol Neurosurg Psychiatry. 2016;87(1):5-11.
    1. Oba-Shinjo SM, da Silva R, Andrade FG, et al. . Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations. J Neurol. 2009;256(11):1881-1890.
    1. Pérez-López J, Selva-O'Callaghan A, Grau-Junyent JM, et al. . Delayed diagnosis of late-onset Pompe disease in patients with myopathies of unknown origin and/or hyperCKemia. Mol Genet Metab. 2015;114(4):580-583.
    1. Preisler N, Lukacs Z, Vinge L, et al. . Late-onset Pompe disease is prevalent in unclassified limb-girdle muscular dystrophies. Mol Genet Metab. 2013;110(3):287-289.
    1. Tehrani KHNHN, Sakhaeyan E, Sakhaeyan E. Evaluation prevalence of Pompe disease in Iranian patients with myopathies of unknown etiology. Electron Physician. 2017;9(7):4886-4889.
    1. Ünver O, Hacıfazlıoğlu NEE, Karatoprak E, et al. . The frequency of late-onset Pompe disease in pediatric patients with limb-girdle muscle weakness and nonspecific hyperCKemia: a multicenter study. Neuromuscul Disord. 2016;26(11):796-800.
    1. Lukacs Z, Nieves Cobos P, Wenninger S, et al. . Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness. Neurology. 2016;87(3):295-298.
    1. Goldstein JL, Young SP, Changela M, et al. . Screening for Pompe disease using a rapid dried blood spot method: experience of a clinical diagnostic laboratory. Muscle Nerve. 2009;40(1):32-36.
    1. Bali DS, Goldstein JL, Banugaria S, et al. . Predicting cross-reactive immunological material (CRIM) status in Pompe disease using GAA mutations: lessons learned from 10 years of clinical laboratory testing experience. Am J Med Genet C Semin Med Genet. 2012;160C(1):40-49.
    1. Nallamilli BRR, Chakravorty S, Kesari A, et al. . Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. Ann Clin Transl Neurol. 2018;5(12):1574-1587.
    1. Gutiérrez-Rivas E, Bautista J, Vílchez JJ, et al. . Targeted screening for the detection of Pompe disease in patients with unclassified limb-girdle muscular dystrophy or asymptomatic hyperCKemia using dried blood: a Spanish cohort. Neuromuscul Disord. 2015;27(7):548-553.
    1. Savarese M, Di Fruscio G, Torella A, et al. . The genetic basis of undiagnosed muscular dystrophies and myopathies: results from 504 patients. Neurology. 2016;87(1):71-76.
    1. Johnson K, Töpf A, Bertoli M, et al. . Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness. Orphanet J Rare Dis. 2017;12(1):173.
    1. Yang C-FF, Liu H-CC, Hsu T-RR, et al. . A large-scale nationwide newborn screening program for Pompe disease in Taiwan: towards effective diagnosis and treatment. Amer J Med Genet. 2014;164A(1):54-61.
    1. Liu X, Wang Z, Jin W, et al. . Clinical and GAA gene mutation analysis in mainland Chinese patients with late-onset Pompe disease: identifying c.2238G > C as the most common mutation. BMC Med Genet. 2014;15:141.
    1. Burton BK, Charrow J, Hoganson GE, et al. . Newborn screening for Pompe disease in Illinois: experience with 684,290 infants. Int J Neonatal Screen. 2020;6(1):4.
    1. Tang H, Feuchtbaum L, Sciortino S, et al. . The first year experience of newborn screening for Pompe disease in California. Int J Neonatal Screen. 2020;6(1):9.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa