A 2 month old male infant born at 39 weeks gestation via SVD as a home birth presents to the ED for respiratory distress. Pt is tachypneic and tachycardic with global retractions, head bobbing, and grunting. Pt was placed on BiPAP, and a chest X-ray was then obtained, which showed marked cardiomegaly. Subsequent EKG showed left ventricular hypertrophy. On further examination, pt was also noted to have hepatomegaly, macroglossia, and hypotonia. What enzyme is likely deficient in this patient?

A. Glucose-6-Phosphatase 

B. Acid Alpha-Glucosidase

C. Glycogen Debranching Enzyme

D. Myophosphorylase

E. Phosphofructokinase

The correct answer is B, Acid Alpha-Glucosidase.

 

Answer Choice A: Glucose-6-Phosphatase 

Glycogen Storage Disease Type IA (Von Gierke Disease) is caused by a deficiency of Glucose-6-Phosphatase activity, whereas Type IB is caused by a defect in the transport of Glucose-6-Phosphate. This causes glycogen and fat to build up in the liver, kidneys, and intestines, leading to dysfunction in those organs.

Type 1A presents with hypoglycemia, hepatomegaly, lactic acidemia, hyperuricemia, nephromegaly, hyperlipidemia (both total lipids and triglycerides), and growth retardation/short stature. Hypoglycemia tends to be the major presenting symptom in infancy, especially when feeds start being spaced to every 3-4 hours, and this may present as seizures due to severe hypoglycemia (<40mg/dL after 3-4 hours since the last feed). If they do not present for hypoglycemia, they are often diagnosed within the first few months of life when they develop a Cushingoid face (doll-like facies with fat cheeks) and protuberant abdomen (due to hepatomegaly and nephromegaly).

Type 1B additionally presents with neutropenia, impaired neutrophil function, and inflammatory bowel disease. These defects lead to frequent bacterial infections and oral and intestinal mucosal ulcers.

For more information on management of GSD I, the American College of Medical Genetics and Genomics (ACMG) has great, thorough guidelines posted in 2014, linked in the references.

 

Answer Choice C: Glycogen Debranching Enzyme

Deficiency in this enzyme causes Glycogen Storage Disease Type III (Cori Disease or Forbes Disease). This disease is inherited as an autosomal recessive trait. This disease presents similarly to GSD IA, but less severe, with hypoglycemia, hyperlipidemia, hepatomegaly, hypotonia, immunodeficiency, and mild intellectual disability. Patients also present with myopathy that begins mildly in childhood and worsens throughout early-adulthood. These patients are treated with a high-protein diet and cornstarch to maintain a consistent, normal blood glucose.

 

Answer Choice B: Acid Alpha-Glucosidase

This enzyme deficiency, also known as Acid Maltase, causes Glycogen Storage Disease Type II (Pompe Disease), which is the correct answer. This disease has an autosomal recessive inheritance pattern.

The “Classic Infantile” form of Pompe Disease causes more severe disease, where infants present within the first 3 months of life with feeding difficulties, poor weight gain, cardiomyopathy, hepatomegaly, macroglossia, and progressively worsening proximal muscle weakness leading to hypotonia and respiratory insufficiency. The cardiomyopathy is due to deposition of glycogen in the cardiac muscle, often causing a hypertrophic cardiomyopathy. Median age at symptom onset is 1.6 months, with median age at diagnosis of about 5 months of age. These patients often need positive pressure support or mechanical ventilation by 4-5 months of age, and they typically die of cardiorespiratory failure by 2 years of age.

The “Late-onset” form of Pompe Disease can develop at any age, and this is due to a deficiency of the acid alpha-glucosidase enzyme, as opposed to the absence of this enzyme in the infantile form. Because of this, these patients often live past 2 years of life. Typically if you present with symptoms earlier in life, it tends to be more aggressive with a faster progression and higher severity. These patients also have progressive muscle weakness and eventually become wheelchair and/or ventilator dependent before dying of respiratory failure due to diaphragmatic weakness.

In Ohio, every child is screened for Pompe Disease at birth as part of their newborn screen. This patient was born at home, so they did not likely have newborn screening done and therefore went undiagnosed. On the Ohio Department Health website, they make this disclaimer,

“The test for Lysosomal Storage Diseases has not been cleared or approved by the FDA but the performance characteristics have been validated by the Ohio Department of Health Laboratory.”

On a positive note, Pompe Disease can be treated by enzyme replacement therapy with Alglucosidase alfa! Myozyme was the first brand name drug approved by the United States FDA for use in 2006 for infantile Pompe, and Lumizyme was approved for use in 2010 for patients aged 8 years or older with non-infantile Pompe. These drugs have been shown to decrease heart size, maintain normal heart function, improve muscle function, tone, and strength, and reduce glycogen build-up in organs. Patients receive this medication as a 4-hour infusion every 2 weeks. On the downside, these medications are incredibly expensive.

 

Answer Choice D: Myophosphorylase

Glycogen Storage Disease Type V (McArdle’s Disease) is caused by a deficiency in this enzyme. Patients tend to develop symptoms within the first decade of life with primarily skeletal muscular involvement, such as exercise intolerance, myalgias, and rapid fatigue with exertion. Patients also may develop muscle stiffness and contractures during exercise, especially towards the beginning of exercise, which resolves or decreases upon cessation of activity. Labs typically reveal an elevated creatinine kinase (CK) and myoglobinuria. Symptoms tend to worsen with sustained, intense aerobic exercise, so management of these patients consists of leading a fairly sedentary lifestyle with mild, regular aerobic exercise.

 

Answer Choice E: Phosphofructokinase

Glycogen Storage Disease Type VII (Tarui’s Disease) is another glycogen storage disorder, passed in an autosomal recessive pattern as well, that primarily affects skeletal muscles. However, this disease has 4 forms, and depending on the form, the patient may have additional symptoms, such as nausea/vomiting, hyperuricemia, curvature of the joints (arthrogryposis), and jaundice due to hemolytic anemia. Diagnosis can be made by muscle biopsy, which would show an elevated ammonia and decreased lactate.

 

If asked about other GSD, remember:

  • GSD-IA is similar to GSD Types 0, 3, and 4
  • GSD 5 is similar to GSD Type 7 and primarily involves the skeletal muscles
  • And if the child has cardiomyopathy, it is likely GSD 2

 

Resources

  1. Leslie N, Bailey L. Pompe Disease. 2007 Aug 31 [Updated 2017 May 11]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1261/
  2. Pompe Disease Diagnostic Working Group; B Winchester, D Bali, O A Bodamer, C Caillaud, E Christensen, A Cooper, E Cupler, M Deschauer, K Fumić, M Jackson, P Kishnani, L Lacerda, J Ledvinová, A Lugowska, Z Lukacs, I Maire, H Mandel, E Mengel, W Müller-Felber, M Piraud, A Reuser, T Rupar, I Sinigerska, M Szlago, F Verheijen, O P van Diggelen, B Wuyts, E Zakharova, J Keutzer. Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting. Mol Genet Metab. 2008;93:275-281. PMID: 18078773 Epub 2007 Dec 19.
  3. Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE, Crowley JF, Downs S, Howell RR, Kravitz RM, Mackey J, Marsden D, Martins AM, Millington DS, Nicolino M, O’Grady G, Patterson MC, Rapoport DM, Slonim A, Spencer CT, Tifft CJ, Watson MS. Pompe disease diagnosis and management guideline. Genet Med. 2006;8:267-288. PMID: 16702877 PMC3110959
  4. Chou JY, Mansfield BC. Mutations in the glucose-6-phosphatase-alpha (G6PC) gene that cause type Ia glycogen storage disease. Hum Mutat. 2008;29:921-30.
  5. Rake JP Visser G, Labrune P, et al. Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European study on glycogen storage disease type I (EGGSD I). Eur J Pediat. 2002a;161:20-34.
  6. Visser G, Rake JP, Labrune P, et al. Consensus guidelines for management of glycogen storage disease type 1b. Results of the European study on glycogen storage disease type I. Eur J Pediatr. 2002;161:120-3.
  7. Chen Y, & Kishnani P.S., & Koeberl D Chen, Yuan-Tsong, et al. (2019). Glycogen storage diseases. Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. Valle D.L., & Antonarakis S, & Ballabio A, & Beaudet A.L., & Mitchell G.A.(Eds.),Eds. David L. Valle, et al. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill. https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225080698
  8. Kishnani, P., Austin, S., Abdenur, J. et al. Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med 16, e1 (2014). https://doi.org/10.1038/gim.2014.128 
  9. Kishnani PS, Steiner RD, Bali D, Berger K, Byrne BJ, Case LE, Crowley JF, Downs S, Howell RR, Kravitz RM, Mackey J, Marsden D, Martins AM, Millington DS, Nicolino M, O’Grady G, Patterson MC, Rapoport DM, Slonim A, Spencer CT, Tifft CJ, Watson MS. Pompe disease diagnosis and management guideline. Genet Med. 2006 May;8(5):267-88. doi: 10.1097/01.gim.0000218152.87434.f3. Erratum in: Genet Med. 2006 Jun;8(6):382. ACMG Work Group on Management of Pompe Disease [removed]; Case, Laura [corrected to Case, Laura E]. PMID: 16702877; PMCID: PMC3110959.
  10. Chen Y, & Kishnani P.S., & Koeberl D Chen, Yuan-Tsong, et al. (2019). Glycogen storage diseases. Valle DL, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA. Valle D.L., & Antonarakis S, & Ballabio A, & Beaudet A.L., & Mitchell G.A.(Eds.),Eds. David L. Valle, et al. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill. https://ommbid.mhmedical.com/content.aspx?bookid=2709&sectionid=225080698
  11. Newborn Screening Panel. Ohio Department of Health website. Updated 4 February 2020. Accessed 16 January 2021. https://odh.ohio.gov/wps/portal/gov/odh/know-our-programs/Newborn-Screening/Newborn-Screening-Panel

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