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How to Diagnose Pompe Disease

Late-onset Pompe Disease (LOPD)

is a progressive, genetic neuromuscular disease that can affect patients of all ages2

The progressive signs and symptoms of Pompe disease overlap with several other diseases you may see in your practice2

Patients face potentially irreversible and life-threatening muscle damage that can result in respiratory failure, loss of motor function, and premature death1,2

  • Approximately 1 in 40,000 people worldwide has Pompe disease4
  • Symptoms of motor function impairment are often most pronounced while early respiratory manifestations of diaphragmatic muscle weakness may present with more subtle signs1,5
  • In some patients, respiratory manifestations present before motor symptoms5
  • Early detection and treatment are key to avoid ongoing and irreversible decline2,7

Patients with Pompe disease most often present with signs of motor and respiratory impairment1,2

  • 77% of patients with LOPD present with both exercise intolerance and limb-girdle muscle weakness1
  • 55% of patients with LOPD present with both respiratory insufficiency and limb-girdle muscle weakness1
    • Adapted from Schuller et al, Seminars in Medical Genetics, 2012. A Study of 44 patients with LOPD at the Friedrich-Baur-Institute from 1985-2011. The Munich Cohort comprised of 27 females and 17 males.

Each year, patients with LOPD are at an increased risk of major disease burdens8,9

In Pompe disease, deficient acid α-glucosidase (GAA) enzyme activity leads to progressive and debilitating muscle damage2,6,7

Uncontrolled glycogen accumulation causes lysosomes to swell and rupture,11 resulting in:

  • Irreversible cellular damage10,11
  • Progressive destruction of skeletal muscle (including respiratory musculature) and smooth muscle5,11
  • Debilitating respiratory, motor, musculoskeletal, cardiac, bulbar,and gastrointestinal (GI) manifestations1,2,5,14

LOPD can manifest in many different parts of the body

Test early for Pompe disease if you spot these common signs or symptoms in your practice7

Should you wish to test for Late-Onset Pompe Disease, kindly use the contact details below for any DBS kit requests, sample collections or diagnostics related queries:

Email: Ansie.Mienie@nwu.ac.za / pliem@nwu.ac.za

Contact Numbers: 018 299 2312 / 018 285 2544

WhatsApp Number: 082 393 8505

References

  1. Schüller A, et al. Toward deconstructing the phenotype of late-onset Pompe disease. InAmerican Journal of Medical Genetics Part C: Seminars in Medical Genetics 2012 Feb 15 (Vol. 160, No. 1, pp. 80-88). Hoboken: Wiley Subscription Services, Inc., A Wiley Company.
  2. Kishnani PS, et al. Pompe disease diagnosis and management guideline. Genetics in Medicine. 2006 May 1;8(5):267- 88.
  3. Van Capelle CI, et al. Childhood Pompe disease: clinical spectrum and genotype in 31 patients. Orphanet journal of rare diseases. 2016 Dec;11(1):1-1.
  4. Ausems MG, et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. European Journal of Human Genetics. 1999 Sep;7(6):713-6.
  5. Cupler EJ, et al. AANEM CONSENSUS COMMITTEE ON LATE-ONSET POMPE DISEASE. Consensus treatment recommendations for late-onset Pompe disease. Muscle & nerve. 2012 Mar;45(3):319-33.
  6. Kishnani PS, Howell RR. Pompe disease in infants and children. The Journal of pediatrics. 2004 May 1;144(5):S35-43.
  7. American Association of Neuromuscular & Electrodiagnostic Medicine. Diagnostic criteria for late-onset (childhood and adult) Pompe disease. Muscle & nerve. 2009 Jul;40(1):149-60.
  8. Rigter T, et al. Severely impaired health status at diagnosis of Pompe disease: A cross-sectional analysis to explore the potential utility of neonatal screening. Molecular Genetics and Metabolism. 2012 Nov 1;107(3):448-55.
  9. Hagemans ML, et al. Disease severity in children and adults with Pompe disease related to age and disease duration. Neurology. 2005 Jun 28;64(12):2139-41.
  10. Chien YH, et al. Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. The Journal of pediatrics. 2011 Jun 1;158(6):1023-7.
  11. Al Jasmi F, et al. Diagnosis and treatment of late-onset Pompe disease in the Middle East and North Africa region: consensus recommendations from an expert group. BMC neurology. 2015 Dec;15(1):1-7.
  12. Thurberg BL, et al. Characterization of pre-and posttreatment pathology after enzyme replacement therapy for Pompe disease. Laboratory investigation. 2006 Dec;86(12):1208-20.
  13. Raben N, et al. Differences in the predominance of lysosomal and autophagic pathologies between infants and adults with Pompe disease: implications for therapy. Molecular genetics and metabolism. 2010 Dec 1;101(4):324-31.
  14. Chan J, et al. The emerging phenotype of late-onset Pompe disease: A systematic literature review. Molecular genetics and metabolism. 2017 Mar 1;120(3):163-72.
  15. Karabul N, et al. Urge incontinence and gastrointestinal symptoms in adult patients with Pompe disease: a cross-sectional survey. JIMD Reports, Volume 17. 2014:53- 61.
  16. Bernstein DL, et al. Pompe disease: dramatic improvement in gastrointestinal function following enzyme replacement therapy. A report of three later-onset patients. Molecular Genetics and Metabolism. 2010 Oct 1;101(2-3):130-3.
  17. Toscano A, Montagnese F, Musumeci O. Early is better? A new algorithm for early diagnosis in late onset Pompe disease (LOPD). Acta Myologica. 2013 Oct;32(2):78.
  18. Preisler N, et al. Late-onset Pompe disease is prevalent in unclassified limb-girdle muscular dystrophies. Molecular genetics and metabolism. 2013 Nov 1;110(3):287-9.
  19. Manganelli F, et al. Clinical features of Pompe disease. Acta Myologica. 2013 Oct;32(2):82.
  20. Moghadam-Kia S, et al. Approach to asymptomatic creatine kinase elevation. Cleveland Clinic journal of medicine. 2016 Jan;83(1):37.
  21. Mellies U, et al. Pompe disease: a neuromuscular disease with respiratory muscle involvement. Respiratory medicine. 2009 Apr 1;103(4):477-84.
  22. Boentert M, et al. Practical recommendations for diagnosis and management of respiratory muscle weakness in late-onset Pompe disease. International journal of molecular sciences. 2016 Oct 17;17(10):1735.
  23. Fuller DD, et al. The respiratory neuromuscular system in Pompe disease. Respiratory physiology & neurobiology. 2013 Nov 1;189(2):241-9.
  24. Jaradeh S. Muscle disorders affecting oral and pharyngeal swallowing. GI Motility online. 16 May 2006.
  25. Chaudhuri A, et al. Fatigue in neurological disorders. The Lancet. 2004 Mar 20;363(9413):978-88.
  26. Pfeffer G, Chinnery PF. Hereditary myopathy with early respiratory failure. GeneReviews® [Internet]. 2020 Mar 19.
  27. Barohn RJ, et al. A pattern recognition approach to the patient with a suspected myopathy. Neurologic clinics. 2014 Aug;32(3):569.
  28. Feasson L, et al. Fatigue and neuromuscular diseases. InAnnales de réadaptation et de médecine physique. 2006 Jul 1 (Vol. 49, No. 6, pp. 375-384.
  29. Gilchrist JM. Overview of neuromuscular disorders affecting respiratory function. InSeminars in respiratory and critical care medicine. 2002 (Vol. 23, No. 03, pp. 191-200).
  30. Ozawa E, et al. Creatine kinase, cell membrane and Duchenne muscular dystrophy. Molecular and cellular biochemistry. 1999 Jan;190(1):143-51.
  31. Mah JK, et al. A systematic review and meta-analysis on the epidemiology of Duchenne and Becker muscular dystrophy. Neuromuscular Disorders. 2014 Jun 1;24(6):482-91.
  32. Barnabei MS, et al. Exercise and muscular dystrophy: implications and analysis of effects on musculoskeletal and cardiovascular systems. Comprehensive Physiology. 2011 Jan;1(3):1353-63.
  33. Limb-girdle muscular dystrophy. Genetics Home Reference website. https://ghr.nlm.nih.gov/condition/limb-girdle-muscular-dystrophy. Reviewed September 2019. Accessed July 28, 2020.
  34. Pegoraro E, Hoffman EP. Limb-girdle muscular dystrophy overview. GeneReviews®[Internet]. 30 Aug 2012.
  35. Siciliano G, et al. Muscle exercise in limb girdle muscular dystrophies: pitfall and advantages. Acta Myologica. 2015 May;34(1):3.
  36. Myasthenia gravis. Genetics Home Reference website. https://ghr.nlm.nih.gov/condition/myastheniagravis. Reviewed June 2016. Accessed July 29, 2020.
  37. Myasthenia gravis: what is it? Harvard Health Publishing website. https://www.health.harvard.edu/a_to_z/myasthenia-gravis-a-to-z. Published December 2018. Accessed July 29, 2020.
  38. Smoyer-Tomic KE, et al Incidence and prevalence of idiopathic inflammatory myopathies among commercially insured, Medicare supplemental insured, and Medicaid enrolled populations: an administrative claims analysis. BMC musculoskeletal disorders. 2012 Dec;13:1-3.
  39. Inflammatory myopathies information page. National Institute of Neurological Disorders and Stroke website. https://www.ninds.nih.gov/Disorders/All-Disorders/Inflammatory-Myopathies-Information-Page. Published February 27, 2017. Accessed July 29, 2020.
  40. Gazeley DJ, Cronin ME. Diagnosis and treatment of the idiopathic inflammatory myopathies. Therapeutic advances in musculoskeletal disease. 2011 Dec;3(6):315-24.
  41. Polymyositis. Johns Hopkins Medicine website. https://www.hopkinsmedicine.org/health/conditions-and-diseases/polymyositis. Published February 27, 2017. Accessed July 29, 2020.
  42. Mastaglia FL, et al. Idiopathic inflammatory myopathies: epidemiology, classification, and diagnostic criteria. Rheumatic Disease Clinics. 2002 Nov 1;28(4):723-41.

Children With Late-onset Pompe Disease (LOPD)

Pompe disease should be considered in the differential diagnosis of children with less familiar signs such as disproportional weakness of the neck flexors, unexplained fatigue and persistent diarrhoea.1

Children With Late-onset Pompe Disease (LOPD)

Patients with paediatric LOPD (ages 1 to 18) typically present with delayed motor development and/or limb-girdle muscle weakness.1 Lung function may be widely compromised and neck flexor muscles may also be severely affected (a particular distinction from symptoms of adult LOPD).1 In addition, paediatric LOPD may be characterised by low or absent reflexes, facial myopathy and scoliosis.1

Pompe Disease is an autosomal recessive disorder caused by a deficiency of the lysosomal enzyme acid-α-glucosidase (GAA).2

In Pompe disease, lysosomal glycogen accumulates in many tissues with skeletal, cardiac, and smooth muscle most prominently involved.2

  • LOPD can affect children older than 1 year of age to adults in their 60’s.2
  • The combined birth incidence of all forms of Pompe disease - including infantileonset Pompe disease, which can be fatal within the first year of life - is estimated to be 1:40,000.2

Common Paediatric Lopd Symptoms May Include:1

50% - 80% of patients

20% - 50% of patients

<20% of patients 

  • Neck flexor weakness was observed in 75% of patients.1
  • Other frequently affected muscles included the gluteus maximus, ileopsoas, biceps and deltoids.1

Adapted from Van Capelle CI, Van der Meijden JC, Van Den Hout JM, et al. Orphanet journal of rare diseases. 2016.

Diagnostic Algorithm for Late Onset (>1 Year) Pompe Disease2

Should you wish to test for Late-Onset Pompe Disease, kindly use the contact details below for any DBS kit requests, sample collections or diagnostics related queries:

Email: Ansie.Mienie@nwu.ac.za / pliem@nwu.ac.za

Contact Numbers: 018 299 2312 / 018 285 2544

WhatsApp Number: 082 393 8505

References

  1. Van Capelle CI, Van der Meijden JC, Van Den Hout JM, et al. Childhood Pompe disease: clinical spectrum and genotype in 31 patients. Orphanet journal of rare diseases. 2016 Dec;11(1):1-1.
  2. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genetics in Medicine. 2006 May;8(5):267-88.

Infantile-onset Pompe Disease (IOPD)

Early diagnosis and management are critical to improving therapeutic outcomes in patients with Pompe disease2,4

Patients face potentially irreversible and life-threatening muscle damage that can result in respiratory failure, loss of motor function, and premature death1,3,4

Symptoms present in early infancy and progress rapidly, typically leading to death by 1 year of age. Manifestations most commonly include cardiomyopathy, hypotonia, muscle weakness, respiratory distress, feeding difficulties, and failure to thrive1,5,6

In Pompe disease, deficient acid α-glucosidase (GAA) enzyme activity leads to progressive and debilitating muscle damage1,2,6

Uncontrolled glycogen accumulation causes lysosomes to swell and rupture,10 resulting in:

  • Irreversible cellular damage9,10
  • Progressive destruction of skeletal muscle (including respiratory musculature) and smooth muscle8,10
  • Debilitating respiratory, motor, musculoskeletal, cardiac, bulbar, and gastrointestinal (GI) manifestations1,3,4,8,13

Should you wish to test for Infantile-Onset Pompe Disease, kindly use the contact details below for any DBS kit requests, sample collections or diagnostics related queries:

Email: Ansie.Mienie@nwu.ac.za / pliem@nwu.ac.za

Contact Numbers: 018 299 2312 / 018 285 2544

WhatsApp Number: 082 393 8505

References

  1. Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE, Crowley JF, Downs S, Howell RR, Kravitz RM, Mackey J. Pompe disease diagnosis and management guideline. Genetics in Medicine. 2006 May 1;8(5):267-88.
  2. American Association of Neuromuscular & Electrodiagnostic Medicine. Diagnostic criteria for late‐onset (childhood and adult) Pompe disease. Muscle & nerve. 2009 Jul;40(1):149-60.
  3. Schüller A, Wenninger S, Strigl‐Pill N, Schoser B. Toward deconstructing the phenotype of lateonset Pompe disease. In American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2012 Feb 15 (Vol. 160, No. 1, pp. 80-88). Hoboken: Wiley Subscription Services, Inc., A Wiley Company.
  4. Van Capelle CI, Van der Meijden JC, Van Den Hout JM, Jaeken J, Baethmann M, Voit T, Kroos MA, Derks TG, Rubio-Gozalbo ME, Willemsen MA, Lachmann RH. Childhood Pompe disease: clinical spectrum and genotype in 31 patients. Orphanet journal of rare diseases. 2016 Dec;11(1):1-1.
  5. Kishnani PS, Hwu WL, Mandel H, Nicolino M, Yong F, Corzo D, Infantile-Onset Pompe Disease Natural History Study Group. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. The Journal of pediatrics. 2006 May 1;148(5):671-6.
  6. Kishnani PS, Howell RR. Pompe disease in infants and children. The Journal of pediatrics. 2004 May 1;144(5):S35-43.
  7. 7. Scriver CR. The metabolic & molecular bases of inherited disease. McGraw-Hill; 2001.
  8. 8. Cupler EJ, et al; AANEM Consensus Committee on Late-Onset Pompe Disease. Muscle Nerve. 2012;45(3):319-333. doi:10.1002/mus.22329.
  9. Chien YH, Lee NC, Huang HJ, Thurberg BL, Tsai FJ, Hwu WL. Later-onset Pompe disease: early detection and early treatment initiation enabled by newborn screening. The Journal of pediatrics. 2011 Jun 1;158(6):1023-7.
  10. Al Jasmi F, Al Jumah M, Alqarni F, Al-Sanna’a N, Al-Sharif F, Bohlega S, Cupler EJ, Fathalla W, Hamdan MA, Makhseed N, Nafissi S. Diagnosis and treatment of late-onset Pompe disease in the Middle East and North Africa region: consensus recommendations from an expert group. BMC neurology. 2015 Dec;15(1):1-7.
  11. Thurberg BL, Lynch Maloney C, Vaccaro C, Afonso K, Tsai AC, Bossen E, Kishnani PS, O’Callaghan M. Characterization of pre-and post-treatment pathology after enzyme replacement therapy for Pompe disease. Laboratory investigation. 2006 Dec;86(12):1208-20.
  12. Raben N, Ralston E, Chien YH, Baum R, Schreiner C, Hwu WL, Zaal KJ, Plotz PH. Differences in the predominance of lysosomal and autophagic pathologies between infants and adults with Pompe disease: implications for therapy. Molecular genetics and metabolism. 2010 Dec 1;101(4):324-31.
  13. Chan J, Desai AK, Kazi ZB, Corey K, Austin S, Hobson-Webb LD, Case LE, Jones HN, Kishnani PS. The emerging phenotype of late-onset Pompe disease: A systematic literature review. Molecular genetics and metabolism. 2017 Mar 1;120(3):163-72