Late-onset Pompe disease: what is the prevalence of limb-girdle muscular weakness presentation?

ABSTRACT

Pompe disease is an inherited disease caused by acid alpha-glucosidase (GAA) deficiency. A single center observational study aimed at assessing the prevalence of late-onset Pompe disease in a high-risk Brazilian population, using the dried blood spot test to detect GAA deficiency as a main screening tool. Dried blood spots were collected for GAA activity assay from 24 patients with “unexplained” limb-girdle muscular weakness without vacuolar myopathy in their muscle biopsy. Samples with reduced enzyme activity were also investigated for GAA gene mutations. Of the 24 patients with dried blood spots, one patient (4.2%) showed low GAA enzyme activity (NaG/AaGIA: 40.42; %INH: 87.22%). In this patient, genetic analysis confirmed two heterozygous mutations in the GAA gene (c.-32-13T>G/p.Arg854Ter). Our data confirm that clinicians should look for late-onset Pompe disease in patients whose clinical manifestation is an “unexplained” limb-girdle weakness even without vacuolar myopathy in muscle biopsy.

RESUMO

A doença de Pompe é uma doença hereditária causada pela deficiência da enzima alfa-glicosidase ácida (GAA). Estudo observacional foi realizado, em um único centro, para determinar a prevalência da doença de Pompe de início tardio (LOPD) em uma população brasileira de alto risco, usando teste em gota seca (DBS) como ferramenta principal de triagem para detectar a deficiência da GAA. DBS foi coletado para avaliar a atividade da GAA em 24 pacientes com fraqueza muscular de cinturas “não explicada” sem miopatia vacuolar na biópsia muscular. As amostras com atividade enzimática reduzida foram também submetidas a análise de mutações no gene GAA. Dos 24 pacientes com DBS, baixa atividade da enzima GAA (NaG/AaGIA: 40.42; %INH: 87.22%) foi encontrada em um paciente (4.2%). Nessa paciente, a análise genética confirmou duas mutações em heterozigose composta no gene GAA (c.-32-13T > G/p.Arg854Ter). Nossos resultados confirmam que LOPD deve ser investigada quando a manifestação clínica é uma fraqueza muscular de cinturas “não explicada”, mesmo na ausência de miopatia vacuolar na biópsia muscular.

Keywords:

glycogen storage disease type II - muscular weakness - muscle diseases

Palavras-chave:

doença de depósito de glicogênio tipo II - debilidade muscular - doenças musculares

Support

This study was supported by UFPR, Fundação Araucária, CAPES and CNPq. Genetic analysis (GAA gene) was supported by Sanofi Genzyme.

Publication History

Received: 29 June 2017

Accepted: 10 January 2018

Article published online:
28 August 2023

• References

• 1 Werneck LC, Lorenzoni PJ, Kay CS, Scola RH. Muscle biopsy in Pompe disease. Arq Neuropsiquiatr. 2013 May;71(5):284-9. https://doi.org/10.1590/0004-282X20130022
• 2 Lévesque S, Auray-Blais C, Gravel E, Boutin M, Dempsey-Nunez L, Jacques PE et al. Diagnosis of late-onset Pompe disease and other muscle disorders by next-generation sequencing. Orphanet J Rare Dis. 2016 Jan;11(1):8. https://doi.org/10.1186/s13023-016-0390-6
• 3 Preisler N, Lukacs Z, Vinge L, Madsen KL, Husu E, Hansen RS et al. Late-onset Pompe disease is prevalent in unclassified limb-girdle muscular dystrophies. Mol Genet Metab. 2013 Nov;110(3):287-9. https://doi.org/10.1016/j.ymgme.2013.08.005
• 4 Lindberg C, Anderson B, Engvall M, Hult M, Oldfors A. Search for Pompe disease among patients with undetermined myopathies. Acta Neurol Scand. 2015 Jul;133(2):131-5. https://doi.org/10.1111/ane.12460
• 5 Gutiérrez-Rivas E, Bautista J, Vílchez JJ, Muelas N, Díaz-Manera J, Illa I 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 Jul;25(7):548-53. https://doi.org/10.1016/j.nmd.2015.04.008
• 6 Lukacs Z, Nieves Cobos P, Wenninger S, Willis TA, Guglieri M, Roberts M et al. Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness. Neurology. 2016 Jul;87(3):295-8. https://doi.org/10.1212/WNL.20180018201800182758
• 7 Musumeci O, la Marca G, Spada M, Mondello S, Danesino C, Comi GP et al. LOPED study: looking for an early diagnosis in a late-onset Pompe disease high-risk population. J Neurol Neurosurg Psychiatry. 2016 Jan;87(1):5-11. https://doi.org/10.1136/jnnp-2014-310164
• 8 Spada M, Porta F, Vercelli L, Pagliardini V, Chiadò-Piat L, Boffi P et al. Screening for later-onset Pompe's disease in patients with paucisymptomatic hyperCKemia. Mol Genet Metab. 2013 Jun;109(2):171-3. https://doi.org/10.1016/j.ymgme.2013.03.002
• 9 Bembi B, Cerini E, Danesino C, Donati MA, Gasperini S, Morandi L et al. Diagnosis of glycogenosis type II. Neurology. 2008 Dec;71(23 Suppl 2):S4-11. https://doi.org/10.1212/WNL.0b013e31818da91e
• 10 Genge A, Campbell N. Reevaluating muscle biopsies in the diagnosis of Pompe disease: a corroborative report. Can J Neurol Sci. 2016 Jul;43(4):561-6. https://doi.org/10.1017/cjn.2016.29
• 11 Werneck LC. The value of muscle biopsy in neurology: a study of 290 biopsies. Rev Bras Clin Ter. 1981;10 Suppl:2-24.
• 12 Müller KB, Rodrigues MD, Pereira VG, Martins AM, D'Almeida V. Reference values for lysosomal enzymes activities using dried blood spots samples - a Brazilian experience. Diagn Pathol. 2010 Sep;5(1):65. https://doi.org/10.1186/1746-1596-5-65
• 13 Chamoles NA, Niizawa G, Blanco M, Gaggioli D, Casentini C. Glycogen storage disease type II: enzymatic screening in dried blood spots on filter paper. Clin Chim Acta. 2004 Sep;347(1-2):97-102. https://doi.org/10.1016/j.cccn.2004.04.009
• 14 Turaça LT, Faria DO, Kyosen SO, Teixeira VD, Motta FL, Pessoa JG et al. Novel GAA mutations in patients with Pompe disease. Gene. 2015 Apr;561(1):124-31. https://doi.org/10.1016/j.gene.2015.02.023
• 15 Pérez-López J, Selva-O'Callaghan A, Grau-Junyent JM, Gallego-Galindo L, Coll MJ, García-Morillo S et al. Delayed diagnosis of late-onset Pompe disease in patients with myopathies of unknown origin and/or hyperCKemia. Mol Genet Metab. 2015 Apr;114(4):580-3. https://doi.org/10.1016/j.ymgme.2015.02.004
• 16 Goldstein JL, Young SP, Changela M, Dickerson GH, Zhang H, Dai J et al. Screening for Pompe disease using a rapid dried blood spot method: experience of a clinical diagnostic laboratory. Muscle Nerve. 2009 Jul;40(1):32-6. https://doi.org/10.1002/mus.21376
• 17 Ünver O, Haclfazlioğlu NE, Karatoprak E, Güneş AS, Sağer G, Kutlubay B 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 Nov;26(11):796-800. https://doi.org/10.1016/j.nmd.2016.09.001
• 18 Almeida V, Conceição I, Fineza I, Coelho T, Silveira F, Santos M, et al. Screening for Pompe disease in a Portuguese high risk population. Neuromuscul Disord 2017;S0960-8966:31014-8. https://doi.org/10.1016/j.nmd.2017.03.010
• 19 Palmio J, Auranen M, Kiuru-Enari S, Löfberg M, Bodamer O, Udd B. Screening for late-onset Pompe disease in Finland. Neuromuscul Disord. 2014 Nov;24(11):982-5. https://doi.org/10.1016/j.nmd.2014.06.438
• 20 Oba-Shinjo SM, da Silva R, Andrade FG, Palmer RE, Pomponio RJ, Ciociola KM et al. Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations. J Neurol. 2009 Nov;256(11):1881-90. https://doi.org/10.1007/s00415-009-5219-y