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NeoQuest May 2023: Two-Month-Old Infant With Respiratory Distress and Hypotonia

May 2, 2023

A term infant with a benign history presents to the emergency department with respiratory distress and feeding difficulties at two months of age. The physical exam reveals tachycardia, increased work of breathing, hepatomegaly, and generalized hypotonia. Laboratory evaluation is reassuring, with no concerns for sepsis and no metabolic derangements. An electrocardiogram shows a short PR interval, broad QRS complexes, and deep Q waves in the left precordial leads. An echocardiogram reveals biventricular hypertrophy. The infant’s chest radiograph is shown in Figure 1.


Figure 1. Chest radiograph of infant in the vignette showing enlarged cardiac silhouette. From: Dwivedi M, Naranje KM, Mandal K, Singh A. A neonate with hypotonia and respiratory distress. Neoreviews. 2023;24(5);e314–e3171

Which enzyme deficiency is associated with this infant’s underlying diagnosis?

  1. Carnitine palmitoyl transferase
  2. Co-enzyme Q
  3. Debrancher enzyme
  4. Lysosomal acid alpha-glucosidase
  5. Ornithine transcarbamylase 

Explanation:

Answer: D. Lysosomal acid alpha-glucosidase

The presentation of hypotonia, cardiomyopathy, and hepatomegaly in the neonatal period should prompt concern for classic infantile-onset Pompe disease (CIOPD), or glycogen storage disease type II, a rare autosomal recessive disorder caused by a deficiency in lysosomal acid alpha-glucosidase (GAA) (Option D).1 GAA enzyme hydrolyzes both alpha-1,4- and alpha-1,6-glycosidic linkages in lysosomes, and when deficient, results in an accumulation of lysosomal glycogen (Figure 2A).2 The accumulation of glycogen may begin in utero with clinical manifestations of CIOPD, presenting at a median of 2 months of age postnatally.1,2 Excess glycogen storage can lead to conduction disorders and hypertrophic cardiomyopathy, as revealed by the electrocardiogram findings (Figure 3) and cardiomegaly on a chest radiograph (Figure 1), respectively.1-4 Neuromuscular manifestations of CIOPD include early-onset generalized hypotonia, hyporeflexia, and myopathic facies such as ptosis and sunken cheeks.1,2 Respiratory insufficiency due to respiratory muscle weakness is a major cause of morbidity in CIOPD (Figure 2B). Laboratory findings include elevated creatinine kinase and liver transaminase levels due to muscle damage.2 Diagnosis is made by the measurement of enzyme activity by fluorometric assay, colorimetric assay, or tandem mass spectrometry. State-mandated newborn screens include analysis of GAA activity on dried blood spots. Molecular testing for the GAA gene provides a definitive diagnosis, though there are more than 100 mutations and numerous variants identified in this disease (Figure 2C).2


Figure 2. (A) Abnormal metabolic pathway, (B) clinical manifestations, (C) and diagnostic evaluation and management options for classic infantile-onset Pompe disease. Based on data from Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genetics in Medicine. 2006;8(5):267–2882


Figure 3. Electrocardiogram demonstrates (A) short PR intervals due to glycogen deposition in the conducting tissue, causing shortened atrio-ventricular intervals as well as high-voltage QRS complexes, and (B) deep Q waves in the left precordial lead due to ventricular hypertrophy. From: Dwivedi M, Naranje KM, Mandal K, Singh A. A neonate with hypotonia and respiratory distress. Neoreviews. 2023;24(5);e314–e3171

Fatty acid oxidation disorders, such as carnitine palmitoyl transferase (CPT) II deficiency, can present in the neonatal period with hypotonia, hypertrophic cardiomyopathy, and cardiac conduction defects due to deficient beta-oxidation of fatty acids and accumulation of unoxidized fatty acyl-coenzyme A (CoA) molecules (Option A).5,6 The neonatal form of CPT II deficiency is characterized by biochemical derangements, including hypoketotic hypoglycemia, metabolic acidosis, hyperammonemia, low free and total carnitine levels, increased long-chain acylcarnitine fractions, and elevated serum creatine kinase, findings that were not present in the infant in this vignette.5,6

Primary coenzyme Q10 deficiency, a primary mitochondrial disorder, can present with neonatal hypotonia, cardiomyopathy, severe encephalopathy, and neonatal seizures (Option B).7 However, primary mitochondrial disorders are typically associated with severe lactic acidosis, which was not noted in the infant in this vignette.7

The presence of hepatomegaly, failure to thrive, and hypertrophic cardiomyopathy should raise suspicion for Cori disease, or glycogen storage disorder type III, which is caused by a deficiency in glycogen debrancher enzyme (Option C).8 Affected infants, in contrast to the infant in the vignette, can present with ketotic hypoglycemia, elevated creatinine kinase, abnormal liver enzymes, and hypertriglyceridemia due to impaired degradation and increased glycogen accumulation.8

Infants presenting with generalized hypotonia, hyperammonemia, and primary respiratory alkalosis should raise suspicion for urea cycle disorders, such as ornithine transcarbamylase (OTC) deficiency (Option E).9 Cardiac manifestations, such as cardiomegaly and conduction defects, as seen in the infant in this vignette, are not typically found in infants with OTC deficiency.

Did you know?

  • Enzyme replacement therapy with intravenous infusions of recombinant human GAA is an approved therapeutic strategy for patients with Pompe disease and has been reported to reduce cardiomegaly, improve cardiac function, and improve overall survival in patients with CIOPD.2,10

What infectious diseases are associated with neonatal cardiomyopathy? For a step-by-step approach to the evaluation of neonatal cardiomyopathy, refer to Table 1 in: Wallis G, Fricker FJ. Neonatal cardiomyopathy. Neoreviews. 2012;13(12):e711–e7233

Which inborn errors of metabolism are most commonly associated with myocardial disorders in the neonate? For an overview of neonatal myocardial disorders, refer to the Table in: Bansal M. Myocardial disorders in the neonate. Neoreviews. 2018;19(7):e403–e4094

May NeoQuest Authors
Srirupa Hari Gopal, MBBS, Baylor College of Medicine
Lila S. Nolan, MD, Washington University School of Medicine

References:

  1. Dwivedi M, Naranje KM, Mandal K, Singh A. Neonate with Hypotonia and Respiratory Distress. Neoreviews. 2023;24(5);e314-e317
  2. Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genetics in Medicine. 2006;8(5):267–288
  3. Wallis G, Fricker FJ. Neonatal cardiomyopathy. Neoreviews. 2012;13(12):e711–e723
  4. Bansal M. Myocardial disorders in the neonate. Neoreviews. 2018;19(7):e403–e409
  5. Tiwari P, Dwyer K, Siegfried B, Schrier Vergano SA. Rare cause of arrhythmia and seizures in a late-preterm newborn. Neoreviews. 2022;23(10):e696–e698
  6. Thangavelu S. Fatty acid oxidation disorders. Indian Journal of Practical Pediatrics. 2010;12(2):181–183
  7. Starosta RT, Shinawi M. Primary mitochondrial disorders in the neonate. Neoreviews. 2022;23(12):e796-e812
  8. Schreuder AB, Rossi A, Grünert SC, Derks TGJ. Glycogen storage disease type III. In: GeneReviews®. University of Washington, Seattle, Seattle (WA); 1993. PMID: 20301788.
  9. Niemi AK. Neonatal presentations of metabolic disorders. Neoreviews. 2020;21(10):e649–62
  10. Breilyn MS, Wasserstein MP. Established and emerging treatments for patients with inborn errors of metabolism. Neoreviews. 2020;21(10):e699–e707
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