Nonfatal Isolated Cardiac Nonlysosomal Glycogenosis: A Rare Cause of Infantile Hypertrophic Cardiomyopathy

Metabolic diseases are common causes of infantile hypertrophic cardiomyopathy. Glycogen storage diseases with predominant cardiac involvement can be characterized as either lysosomal or nonlysosomal. Isolated cardiac nonlysosomal glycogenosis has been described as the result of PRKAG2 or PHK gene mutations. Despite aggressive therapy, such diagnosis generally causes rapid demise. In this report, we outline the pathophysiology of infantile hypertrophic cardiomyopathy and describe a rare case of non-fatal isolated cardiac nonlysosomal glycogenosis of undetermined genetic cause. Metabolic diseases are common causes of infantile hypertrophic cardiomyopathy. Glycogen storage diseases with predominant cardiac involvement can be characterized as either lysosomal or nonlysosomal. Isolated cardiac nonlysosomal glycogenosis has been described as the result of PRKAG2 or PHK gene mutations. Despite aggressive therapy, such diagnosis generally causes rapid demise. In this report, we outline the pathophysiology of infantile hypertrophic cardiomyopathy and describe a rare case of non-fatal isolated cardiac nonlysosomal glycogenosis of undetermined genetic cause. A three-day-old baby girl was readmitted with poor feeding, lethargy, and syncope. Twelve hours after discharge, the patient started taking shorter and less frequent feeds. She was ultimately found unresponsive, pale, hypotonic and barely breathing in her crib. Her parents immediately called emergency medical services and delivered rescue breaths, which triggered a cry. Upon arrival of the paramedics, the neonate appeared alert and active, displayed normal vital signs and was in sinus rhythm. In the emergency department, physical examination revealed a non-dysmorphic neonate with a hyperdynamic precordium and harsh holosystolic murmur over the left upper sternal border. There was no blood pressure difference between extremities, cyanosis or hepatomegaly. Laboratory investigations, including a serum glucose level, were unremarkable. A chest radiograph demonstrated moderate cardiomegaly with normal pulmonary vascular markings. Serial electrocardiograms displayed significant heart rate variations, high voltages, and a short PR interval with preexcitation (Supplemental Figure S1) A transthoracic echocardiography demonstrated severe hypertrophy of the interventricular septum (IVS) with reverse curve morphology (IVS thickness: 1.1cm z-score: +7.4), moderate hypertrophy of ventricular free walls (left ventricular posterior wall LVPW thickness: 0.5cm z-score: +2.3) and dynamic mid-cavitary left ventricular outflow tract (LVOT) obstruction (peak gradient: 64mmHg) with normal biventricular function (Supplemental Videos 1-3). This baby girl was born at term from a healthy mother. She was delivered by caesarian section after labor arrest and failed forceps extraction. Besides a brief episode of noninvasive positive pressure ventilation, she had an uneventful fetal-to-neonatal transition. She was of South Asian descent. A detailed three-generation pedigree ruled out the presence of consanguinity, intellectual disability, genetic syndromes, neuromuscular diseases, metabolic disorders, cardiomyopathies, arrhythmias, and premature or sudden cardiac deaths within the family. Differential diagnosis of infantile hypertrophic cardiomyopathy (HCM) is presented in Table 1. In children A/ p.R278H). The mother shared the same variant but did not display phenotype of cardiomyopathy on EKG or transthoracic echocardiography. After her episode of syncope likely caused by an arrhythmia, the baby was admitted and started on propranolol, which was titrated up to the maximum tolerable dose, targeting a heart rate of 100-120bpm. On this regimen, she remained free of arrhythmia and her peak LVOT gradient dropped below 50mmHg. On discharge, parents were provided with an automated external defibrillator and trained in basic life support. The patient was then followed every four to six weeks with echocardiography (Figure 1A). During the first four months, her peak LVOT gradient increased progressively for which disopyramide was added. She responded initially well to dual therapy. However, around 16 months of age, she developed again worsening fatigue and LVOT obstruction. A decision was then made to proceed with myectomy. Leading to surgery, no other malformations or systemic illnesses were detected. Her comprehensive neurodevelopmental assessment was normal. At 20 months of age, the patient underwent extensive transaortic septal myectomy and placement of an implantable loop recorder (ILR). Coming off cardiopulmonary bypass, her peak LVOT gradient was only 10mmHg. Postoperatively, the patient experienced pulmonary edema secondary to diastolic dysfunction requiring reintubation. Nevertheless, she recovered quickly and was discharged on postoperative day nine. Surprisingly, the histologic examination of myocardial fragments resected at the time of surgery revealed extensive monoparticulate glycogen deposits within the cytosol of myocytes (Figure 1B). In view of these findings pointing at a diagnosis of isolated cardiac nonlysosomal glycogenosis, genetic sequences were re-examined, but no pathologic mutation of the AMP-activated protein kinase or phosphorylase kinase genes was identified. Five months after surgery, the patient was more energetic and appeared to keep up better with her peers. Her peak LVOT gradient was <30mmHg on low-dose propranolol. She did not have documented arrhythmia on ILR tracings. On last assessment, at the age of five, more than three years post myectomy, she remains asymptomatic on 2mg/kg/day of propranolol. To date, the patient has not expressed any extracardiac manifestations of glycogen storage diseases (GSD). There are many enzymes and receptors involved in glucose metabolism within the myocyte (Figure 1C). Although there are 15 distinct types of GSD, only 5 can trigger symptomatic HCM: type II (Pompe), type IIb (Danon), type III (Cori), GSD due to γ2-subunit of AMP-activated protein kinase deficiency (PRKAG2) and GSD due to phosphorylase kinase deficiency (PHK). At a cellular level, Pompe and Danon diseases cause lysosomal glycogen deposits while Cori disease and GSD due to kinase deficiencies lead to the accumulation of cytosolic, or nonlysosomal, deposits (3Arad M. Maron B.J. Gorham J.M. et al.Glycogen storage diseases presenting as hypertrophic cardiomyopathy.N Engl J Med. 2005; 352: 362-372Crossref PubMed Scopus (526) Google Scholar,4Chen M.A. Weinstein D.A. Glycogen storage diseases: Diagnosis, treatment and outcome.Transl Sci Rare Dis. 2016; 1: 45-72Google Scholar). In newborns with predominant cardiac involvement, the most common GSD is Pompe disease. A handful of cases of PRKAG2 and PHK gene mutations were also described in the literature (5Burwinkel B. Scott J.W. Bührer C. et al.Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency.Am J Hum Genet. 2005; 76: 1034-1049Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). In contrast, Cori and Danon diseases are usually diagnosed based on extracardiac manifestations and cardiomyopathy does not emerge before the second or third decade of life (6Arbustini E. Di Toro A. Giuliani L. Favalli V. Narula N. Grasso M. Cardiac phenotypes in hereditary muscle disorders: JACC state-of-the-art review.J Am Coll Cardiol. 2018; 72: 2485-2506Crossref PubMed Scopus (65) Google Scholar). Early-onset Pompe disease is associated with hepatomegaly, macroglossia and severe myopathy. Infants with the disease live a few years before dying from respiratory failure. Cardiomyopathy may be treated with enzyme replacement. However, as penetration of the recombinant enzyme into skeletal muscle is poor, targeted treatment does not generally impact survival (7Tarnopolsky M. Katzberg H. Petrof B.J. et al.Pompe disease: diagnosis and management. Evidence-based guidelines from a Canadian expert panel.Can J Neurol Sci. 2016; 43: 472-485Crossref PubMed Scopus (55) Google Scholar). Kinase deficiencies causing GSD are cardiospecific. Babies diagnosed with such conditions usually experience a fulminant course of illness with rapid demise within the first few days of life. Consequently, many diagnoses of PRKAG2 and PHK gene mutations in infants are made post-mortem (5Burwinkel B. Scott J.W. Bührer C. et al.Fatal congenital heart glycogenosis caused by a recurrent activating R531Q mutation in the gamma 2-subunit of AMP-activated protein kinase (PRKAG2), not by phosphorylase kinase deficiency.Am J Hum Genet. 2005; 76: 1034-1049Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). To this date, there is still no specific therapy targeting GSD due to kinase deficiencies. There are many unusual characteristics about the presented case. First, nonlysosomal cardiac glycogenosis in the absence of any other organ involvement is very rare. Second, such presentation is usually lethal with poor survival beyond the first year of life. In contrast, our patient was medically stabilized for months before undergoing myectomy and she has been thriving since. Lastly, our patient remains genetically elusive with no evidence of PRKAG2 or PHK gene mutations, the two causes of nonlysosomal cardiac glycogenosis so far reported in the literature. •Genetic syndromes and metabolic diseases are the commonest causes of infantile HCM.•Isolated nonlysosomal cardiac glycogenosis is a very rare presentation of infantile HCM•Isolated nonlysosomal cardiac glycogenosis is usually caused by PRKAG2 or PHK gene mutations and is rapidly fatal.•However, a genetically elusive case of isolated nonlysosomal cardiac glycogenesis may result in a less malignant course treatable with standard medical and surgical therapies . We described a unique presentation of isolated cardiac nonlysosomal glycogenolysis diagnosed as infantile HCM without any known causative genetic mutation. Our report emphasizes an instance when such a pathology does not necessarily result in a malignant course and can be successfully treated with a combination of medical therapy and timely surgical myectomy in the face of refractory ventricular obstructive symptoms.