Noninfectious endocarditis as a novel cardiac manifestation of glycogen storage disease type IV: a case report

Introduction

Glycogen storage disease type IV (GSD IV), also known as Andersen disease, is a rare autosomal recessive disorder of glycogen metabolism caused by pathogenic variants in the glycogen branching enzyme one (GBE1) gene. This leads to deficiency of the glycogen branching enzyme and subsequent accumulation of abnormally structured glycogen in affected tissues (1). The estimated incidence of GSD IV is approximately 1 in 600,000 to 800,000 live births. The clinical manifestations of GSD IV vary by subtype but most commonly include hepatomegaly, cirrhosis, and progressive liver failure requiring transplantation (2). Less frequently, patients may present with myopathy, cardiomyopathy, or neuromuscular dysfunction (1,3). Cardiac involvement, when present, typically manifests as hypertrophic or dilated cardiomyopathy (1). Here, we describe a novel presentation of GSD IV involving rapidly progressive polyvalvular disease with preserved ventricular function. The echocardiographic appearance mimicked infective endocarditis (IE), complicating the diagnostic and management approach. To our knowledge, this is the first reported case of non-infectious or Libman-Sacks endocarditis directly associated with GSD IV. We present this case in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-393/rc).

Case presentation

A 16-year-old male with a known history of GSD IV, status post living donor liver transplant at 9 months of age, presented with fever, worsening cough, and fatigue. He had recently been diagnosed with a Mycoplasma pneumoniae infection and was taking azithromycin as an outpatient. His most recent echocardiogram, performed four years prior to this presentation, had shown moderate tricuspid regurgitation with right ventricular systolic pressure estimated at 27 mmHg above central venous pressure, and preserved left ventricular function with an ejection fraction of 66% (Figure 1). The clinical course is summarized in Figure 2. On the day of admission, a transthoracic echocardiogram revealed a thickened, echogenic, and irregular tricuspid valve with moderate to severe regurgitation, raising concern for vegetation. No other valvular abnormalities were identified (Figure 3A).

Figure 1 Baseline transthoracic echocardiogram images prior to admission. (A) Tricuspid valve in parasternal long axis prior to the illness described showed a mild degree of regurgitation and thin, mobile valve leaflets (Nyquist 90 cm/s). (B) Mitral valve in parasternal long axis. (C) Mitral valve in short axis. The valve had normal appearance, mobility, and no regurgitation. (D,E) Parasternal views of the aortic valve showed normal morphology and function.

Figure 2 Relative timeline of the clinical course, acute events, imaging, laboratory data, pathology findings, and medical therapies in a patient with GSD IV and progressive polyvalvular disease. The top arrow represents the clinical course including key symptoms and acute events. The second arrow from the top highlights key imaging findings. The third arrow from the top emphasizes crucial laboratory and pathology data as well as treatment milestones. Each admission is shaded on a relative timeline. CRP, C-reactive protein; CT, computed tomography; ECHO, echocardiogram; ECMO, extracorporeal membrane oxygenation; GSD IV, glycogen storage disease type IV; PAS, periodic acid-Schiff; WBC, white blood cell.

Figure 3 Initial admission transthoracic and transesophageal echocardiogram findings. (A) Transthoracic imaging of the tricuspid valve in parasternal long axis shows a larger gap in coaptation and severe tricuspid regurgitation (Nyquist 61 cm/s). (B) Transthoracic imaging of the mitral valve in parasternal long axis at end-diastole. The valve has a thickened appearance with nodularity on the atrial side. (C) Transthoracic imaging of the mitral valve in parasternal long axis. In systole there was appearance consistent with a valve perforation and severe regurgitation. (D) Transesophageal imaging of the mitral valve. 2-dimensional imaging in the four-chamber view centered on the mitral valve in systole shows multiple nodules; one with a highly mobile peduncle. (E) Severe mitral valve regurgitation was evident with a 7-mm vena contracta (Nyquist 119 cm/s). (F) 3-dimensional transesophageal imaging of the mitral valve also shows the perforation. (G) Transthoracic imaging showed the aortic valve did not appear to be involved, as seen in this parasternal long axis in diastole. Color images from the same timepoint showed trivial regurgitation.

Initial laboratory evaluation demonstrated a C-reactive protein (CRP) of 22.7 mg/L, procalcitonin of 0.18 µg/L, and white blood cell count of 14.2×10⁹/L. Physical examination was unremarkable for peripheral stigmata of endocarditis. The patient was empirically started on broad-spectrum antibiotics, including doxycycline, levofloxacin, cefepime, and vancomycin, and admitted for further evaluation. During his one-month hospitalization, a chest computed tomography (CT) scan was negative for septic emboli. A follow-up transesophageal echocardiogram (TEE) demonstrated progression of valvular disease, including persistent tricuspid abnormalities and new findings of mitral valve pathology. These included a potential abscess, a mobile vegetation, and a perforation of the anterior leaflet resulting in moderate mitral regurgitation, with preserved biventricular systolic function (Figure 3B-3G).

The infectious work-up included six sets of negative blood cultures and five negative Karius^© tests for circulating pathogen deoxyribonucleic acid (DNA). Inflammatory markers remained elevated, with a peak CRP of 27.9 mg/L, and all six repeated procalcitonin values remained below 1 µg/L. A comprehensive rheumatologic evaluation was also unrevealing. Despite a full month of empiric broad-spectrum antibiotic therapy for presumed culture-negative endocarditis, there was no significant clinical improvement, and valvular disease continued to progress. The patient was discharged on diuretics and an angiotensin-converting enzyme (ACE) inhibitor, with plans for close outpatient follow-up.

He was readmitted 1 week later with abdominal distension, diarrhea, and concern for worsening heart failure. At the time of readmission, he did not meet American Association for Thoracic Surgery (AATS) or American Heart Association (AHA) criteria for surgical intervention (4). Transthoracic echocardiography revealed progression of his valvular disease, including a thickened pulmonary valve with a mobile pedunculated lesion and new thickening of the left coronary cusp of the aortic valve. He was restarted on broad-spectrum antibiotics, intravenous heart failure therapy, and began a twenty-one-day course of combination oral and intravenous steroid therapy. Notably, his plasma glucose levels throughout his clinical course were within normal range (between 90–210 mg/dL) and a ketogenic diet was considered as a possible therapy but was not implemented.

A repeat infectious work-up during this admission was again negative, including multiple sets of blood cultures and additional Karius^© testing. A whole genome sequence was obtained to confirm his diagnosis of GSD IV and rule out other genetic causes of his valve disease. This testing confirmed the diagnosis of GSD IV with two heterozygous variants, a non-maternally inherited mutation and a maternally inherited deletion in the GBE1 gene, but no other genetic abnormalities. On hospital day 10 of readmission, he developed acute respiratory decompensation characterized by worsening dyspnea, hemoptysis, desaturation, and flash pulmonary edema. Given the severity of his mitral valve disease, pulmonary hemorrhage was suspected. He required endotracheal intubation early the following morning. Extracorporeal membrane oxygenation (ECMO) cannulation was considered; however, an echocardiogram at that time demonstrated the prior valvular findings with worsening aortic regurgitation, a posteriorly directed vena contracta, and holo-diastolic flow reversal in the descending aorta, concerning for leaflet rupture (Figure 4). Due to the presence of aortic insufficiency, veno-arterial ECMO was deferred, and the patient underwent urgent surgery for his progressive polyvalvular disease.

Figure 4 Preoperative transesophageal echo images at time of acute decompensation on day 11 of readmission. (A) Mid-esophageal imaging of the tricuspid valve. The four-chamber view shows large coaptation gap, severe tricuspid regurgitation (Nyquist 59 cm/s). (B) Four-chamber view of the mitral valve in diastole shows the highly thickened appearance of the valve. (C) Mitral valve in systole from 110 degrees rotation shows the large coaptation gap and severe mitral regurgitation. (D) 3-dimensional reconstruction of the mitral valve shows the nodular appearance and perforation in the anterior leaflet. (E) Aortic valve irregularity in systole. (F) Severe aortic insufficiency in diastole with color compare. (G) In long axis, a portion of the aortic valve was seen to prolapse below the level of the annulus, consistent with rupture of an aortic valve leaflet.

During surgery a midline sternotomy was performed, and autologous pericardium was harvested for planned valve reconstruction. Cardiopulmonary bypass was initiated via aortic and bicaval venous cannulation, and the patient was cooled to 28 ℃. During cooling, the heart developed fibrillation, prompting placement of both antegrade and retrograde cardioplegia cannulas. Retrograde Del Nido cardioplegia was administered, resulting in complete electromechanical arrest. The aorta was transected, and additional antegrade cardioplegia was delivered directly into the coronary ostia.

The mitral valve was accessed via the interatrial septum. Intraoperative inspection revealed a thickened valve with limited viable tissue and multiple vegetations. The valve was deemed irreparable. Leaflet remnants were resected to the annular level, including several posterior chordae (Figures 5,6). A 31/33 mm Onyx^® mechanical prosthesis was implanted in the mitral position.

Figure 5 Resected mitral valve components with the atrial side up. Chordal attachments are visible along the edges of the leaflet fragments, with arrows marking the locations of chordal and annular attachments. The PML was removed in one large piece, while the anterior leaflet was taken out in smaller fragments due to extensive disease. PML, posterior mitral leaflet.

Figure 6 A magnified image of part of the PML. The ventricular surface is facing upward. Arrows denote the annular attachment and free margin of the leaflet. The nodular lesions and dysplastic nature of the leaflet is appreciated. Histologic analysis of these nodular structures revealed sheets of glycogenated histiocytes admixed with necrosis and fibrinopurulent exudate. PML, posterior mitral leaflet.

Next, the aortic valve was evaluated. The non-coronary cusp appeared abnormal and was debrided; the remaining cusps were intact. The non-coronary leaflet was reconstructed using a patch of autologous pericardium. Following repair, all three cusps had satisfactory height and coaptation.

Examination of the tricuspid valve demonstrated severe regurgitation. The anterior-septal commissure was closed; however, valve testing revealed persistent central insufficiency. A 28-mm Cosgrove annuloplasty ring was implanted to stabilize the annulus. The right atriotomy and aorta were closed, and the cross-clamp was removed, allowing for reperfusion.

Spontaneous cardiac activity resumed with rewarming. Intraoperative transesophageal echocardiography confirmed a well-functioning mitral prosthesis, no aortic stenosis or insufficiency, and mild to moderate residual tricuspid regurgitation. However, ventricular function remained poor, and the patient was placed on veno-arterial ECMO prior to returning to the intensive care unit with an open chest.

Tissue specimens—including mitral and aortic valve leaflets and pericardium—were sent for histopathologic examination and broad-range organism PCR. No microorganisms were identified on microscopy or PCR analysis. Histologic evaluation of the mitral valve showed extensive infiltration with periodic acid-Schiff (PAS)-positive histiocytes and accompanying neutrophilic inflammation (Figures 7-9). The patient underwent a single mediastinal washout before being successfully decannulated from ECMO 2 days later, with subsequent delayed sternal closure.

Figure 7 Mitral valve with large sheets and aggregates of foamy histiocytes denoted by arrows. There is overlying acute inflammatory infiltrates (including neutrophils) and dehyalinized tissue. Hematoxylin and eosin stain: 4× magnification.

Figure 8 Foamy histiocytes in the mitral valve tissue. Hematoxylin and eosin stain: 20× magnification.

Figure 9 20× magnification of mitral valve tissue and foamy histiocytes. PAS stain after diastase treatment with intracellular resistance to diastase digestion. PAS, periodic acid-Schiff.

The patient was eventually extubated and experienced a prolonged recovery in the hospital before being discharged home. His convalescence was complicated by significant critical illness myopathy, requiring intensive inpatient rehabilitation. He was home for 5 days before returning to the emergency department with persistent fever, hemoptysis, and a supratherapeutic international normalized ratio (INR). Imaging revealed multiple fluid collections throughout the body, suspicious for abscesses or hematomas. Shortly after readmission, he experienced acute pulmonary hemorrhage. Given the severity of his comorbid conditions and elevated bleeding risk, he was deemed unsuitable for ECMO support. In accordance with the family’s wishes, care was transitioned to comfort-focused measures. Life-sustaining therapies were withdrawn 26 days after this final readmission, and 78 days following his initial cardiac operation. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient and his guardian for publication of this case report and accompanying images. A copy of written consent is available for review by the editorial office of this journal.

Discussion

This case of GSD IV is unique in its clinical presentation. GSD IV encompasses a spectrum of pathology, most commonly affecting the liver, cardiac muscle, peripheral musculature, and nervous system (1,3). Cardiac manifestations are well documented, with reported phenotypes ranging from hydrops fetalis in utero to the development of hypertrophic or dilated cardiomyopathy in later childhood. Prior case reports and case series involving cardiac involvement in GSD IV describe amylopectin-like glycogen and PAS-positive deposits within myocardial tissue identified on autopsy or biopsy (2,5,6). To our knowledge, this is the first reported case demonstrating these histopathologic findings within valvular tissue in a patient with GSD IV, which may have important clinical implications.

This case underscores the importance of a comprehensive and modern approach to the diagnosis of IE, while recognizing that not all echocardiographic findings of valvular vegetations and inflammation are attributable to infection. In 2023, the International Society for Cardiovascular Infectious Diseases convened a working group to revise the diagnostic criteria for IE. A key update included the incorporation of cell-free DNA PCR testing, such as the Karius^© test, into the diagnostic algorithm (7). Reported sensitivity and specificity of Karius^© testing compared to standard diagnostic modalities are 92.9% and 62.7%, respectively, with performance improving in proportion to the detected pathogen DNA load (8,9).

Numerous case reports and series have demonstrated the utility of pathogen DNA PCR in evaluating culture-negative endocarditis. When combined with conventional blood cultures, this approach offers high sensitivity and specificity for diagnosing IE (10). In our case, the final diagnostic modality employed was broad-range and specific bacterial PCR on excised valvular tissue. Previous studies have shown that PCR on valve specimens provides superior diagnostic yield, as bacterial DNA concentrations are typically higher in tissue than in serum. Using this method, causative organisms can be identified in up to 62.7% of culture-negative IE cases (11). Given the extent of our negative infectious work-up including serial blood cultures, multiple Karius^© tests, and tissue PCR, we concluded that this patient’s presentation was most consistent with a unique form of noninfectious endocarditis.

Noninfectious endocarditis is most commonly associated with hypercoagulable or hyperinflammatory states, including antiphospholipid syndrome and systemic lupus erythematosus (SLE) (12). Due to its rarity and distinct pathophysiology, the diagnosis and management of noninfectious endocarditis are not well defined, with available data limited primarily to small observational studies and case reports. In general, treatment focuses on managing the underlying systemic condition, initiating anticoagulation when appropriate, and addressing surgical indications using approaches similar to those for IE (12). In cases where the underlying pathology is inflammatory in nature, such as SLE, there is at least one reported case demonstrating resolution of valvular pathology with systemic corticosteroid therapy alone (13).

Noninfectious endocarditis was considered in this patient after a negative infectious work-up and prolonged empiric antibiotic therapy failed to yield clinical improvement. Given these findings, an extensive rheumatologic evaluation was pursued to investigate possible underlying conditions commonly associated with noninfectious endocarditis, such as SLE, antiphospholipid syndrome, and systemic vasculitides; however, all results were negative. Ultimately, histopathologic analysis of the mitral valve demonstrated extensive inflammatory cell infiltration, absence of organisms on broad-range tissue PCR, and prominent glycogen deposition. These findings support the possibility that this represents a novel form of noninfectious endocarditis directly associated with GSD IV, potentially as a progression of the primary metabolic disorder.

Given the known spectrum of cardiac involvement in GSD IV, current recommendations for cardiovascular surveillance include annual echocardiography, electrocardiography, and laboratory markers of heart failure such as brain natriuretic peptide (BNP) or N-terminal pro-BNP, with cardiac magnetic resonance imaging (MRI) considered when feasible (14). Although this case alone does not warrant changes to established guidelines, it highlights the importance of recognizing that valvular degeneration may represent an additional cardiac manifestation of GSD IV. In some patients, this process may be both progressive and clinically significant, warranting closer monitoring and early consideration of valvular involvement.

Conclusions

This case of a patient with long-standing GSD IV presenting with progressive valvular degeneration in the setting of a negative comprehensive infectious and rheumatologic work-up, represents a novel form of cardiac involvement in GSD IV. Clinicians involved in both inpatient and outpatient care should be aware of this potential complication and consider valvular pathology in the differential diagnosis when evaluating GSD IV patients with evolving cardiac symptoms.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-393/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-393/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-393/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient and his guardian for publication of this case report and accompanying images. A copy of written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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