Successful heart transplantation in a patient with glycogen storage disease

Abstract

Background

Polyglucosan body myopathy is a type of glycogen storage disease characterized by abnormal glycogen structure formation. Progressive heart failure is the primary cause of mortality in affected patients

Case Summary

Here, we present a rare case of an Azeri teenage boy with advanced, decompensated heart failure associated with a novel sporadic variant mutation in the RBCK1 gene, displaying a polyglucosan body myopathy phenotype. Following multidisciplinary consensus, the patient underwent successful heart transplantation, resulting in discharge two weeks post-transplantation and excellent health at a one-year follow-up

Discussion

Heart transplantation represents the ultimate treatment option for patients with advanced heart failure and increased mortality risk. It remains a viable and beneficial strategy, even for those with cardiomyopathy secondary to multi-organ diseases.

Learning Objectives

1. Heart transplantation could be a reasonable and life-saving choice in patients with genetic glycogen storage disease.

2. When considering heart transplantation in patients with glycogen storage disease, it is important to be mindful that other possible affected organs should also be under close evaluation.

Introduction

Polyglucosan body myopathy (PGBM) with RanBP-type and C3HC4-type zinc finger-containing 1 (RBCK1) gene mutations is a type of glycogen storage disease characterized by abnormal glycogen structure formation. These structures accumulate mainly in skeletal and cardiac muscle tissues, resulting in severe cardiomyopathy [1]. It is a rare clinical condition, and our knowledge is based on a few case reports.

Like other myopathies with cardiac involvement, progressive heart failure is the primary cause of mortality in affected patients. Beyond guideline-directed medical therapies (GDMT), heart transplantation may be considered an option for patients with severe heart failure who do not respond to medical treatments. The average age of death in these patients who underwent heart transplantation was 25.3 years, while the average age of death in patients with cardiomyopathy who did not undergo heart transplantation was 17.6 years [2]. The survival benefit of transplantation in carefully chosen patients is supported by these data, even though they came from a small report. However, persistent skeletal muscle weakness and other possible systemic symptoms may make long-term care and post-transplant recovery more difficult.

Considering this precarious balance between the potential for improved survival and the uncertainties of a rare systemic disease, each case contributes invaluable insights.

Here, we report a case of polyglucosan body myopathy (PGBM) with peripheral and cardiac involvement, refractory to GDMT, who successfully underwent heart transplantation.

Case Report

The patient was a 14-year-old boy referred to our center for heart transplantation because of stage D heart failure (HF) and no response to fully tolerated GDMT.

His symptoms started when he was 5 years old, and he suffered from muscle weakness, fatigue, and difficulty running. He was unable to do routine physical exercises like his schoolmates. He was diagnosed with myopathic disorder, but wasn’t worked up until the age of 14 when he developed shortness of breath, peripheral edema, dry cough, and orthopnea. The progression of his symptoms indicated several diagnostic tests and procedures, including an electrocardiogram and chest x-ray, as shown in Fig. 1. Trans thoracic echocardiography confirmed severe bi-ventricular dilation and dysfunction with moderate mitral regurgitation, and the left ventricular (LV) ejection fraction was equal to 20%. Laboratory tests are presented in Table 1. Moreover, cardiac MRI findings were compatible with dilated cardiomyopathy. Regarding the evidence of a systemic myopathic disease, further specific procedures were executed to determine the etiology of the myopathy. Electromyography (EMG) and nerve-conducting velocity (NCV) were performed in the first place, with negative results for any myopathy. Considering the high probability of systemic myopathy and the low sensitivity of EMG and NCV tests, a biopsy of the left vastus lateralis muscle was done. Immunohistochemistry tests of the muscle fragments showed evidence of glycogen storage disease.

Figure 1.

Pre-transplant patient’s electrocardiogram. Normal sinus rhythm, wide QRS complexes, deep S waves in pericardial leads.

Table 1.

Summary of clinical findings of our patient during hospitalization.

Laboratory tests	At admission	At discharge
White Blood Cell	10.74 × 109/l	8.26 × 109/l
Hemoglobin	13.8gr/dl	8.6gr/dl
Mean corpuscular volume	73.3 fl	78.9 fl
Platelet Count	483 × 109/l	340 × 109/l
Creatinine	0.6 mg/dl	0.4 mg/dl
Echocardiography main results	Dilated LV, severe RV enlargement, Moderate to severe MR, Severe TR,	50% LVEF, Normal LV size, Normal RV size with preserved function.

In the next step, whole-exome sequencing (WES) was done to define the type of glycogen storage disease.

WES showed a homozygous mutation variant in exon 9 of the RBCK1 gene (c.1111dup), revealing polyglucosan body myopathy type 1. Moreover, immunological tests were performed to assess immunological status, and all were within a normal range.

Laboratory and liver enzyme tests were taken, and did not show evidence of abnormality.

Unfortunately, his general condition got worse, and he didn’t respond to standard medical treatment; therefore, he was referred for a heart transplantation. Due to low cardiac output, cardiogenic shock, and a rise of creatinine to 3.3 mg/dl with oliguria (as a sign of renal failure), treatment with two inotropic and vasopressor drugs, and continuous renal replacement therapy (CRRT) were started. After 4 days, he underwent a successful heart transplantation.

After transplantation, he received immunosuppressive drugs (anti-thyroglobulin (for the first three days), corticosteroid (methyl prednisolone for the first three days and then continued by prednisolone), mycophenolate mofetil (as Cellcept), and tacrolimus as a calcineurin inhibitor), inotropic support for 2 days with milrinone and epinephrine, and therapeutic antibiotics along with prophylactic (amikacin, vancomycin, meropenem, and cotrimoxazole), antifungal (itraconazole), antiviral (valganciclovir), and other supportive medications. Rehabilitation started immediately after our patient’s extubation.

The patient had a good post-op course without complications and was discharged in acceptable condition.

After 3 months, he was diagnosed with hyperglycemia. Therefore, tacrolimus and prednisone dosages were adjusted, and antihyperglycemic (metformin) agents were prescribed. Now, one year after his transplantation, his follow-up echocardiograms and laboratory results are all acceptable, and he efficiently attends school and enjoys cycling. Endomyocardial biopsy was also performed at several time points, and none of them showed any evidence of rejection or abnormal accumulations.

Discussion

Here, we described a case of successful heart transplantation in a 14-year-old boy with a rare genetic glycogen storage disease associated with RBCK1 deficiency.

Our patient presented with early-onset skeletal muscle weakness in childhood, which was not further investigated until adolescence, when he developed severe biventricular dysfunction and refractory stage D heart failure. The diagnosis was confirmed through muscle biopsy, demonstrating glycogen accumulation and genetic testing that identified a homozygous frameshift variant in exon 9 of RBCK1 (c.1111dup), consistent with PGBM1. Although electromyography and nerve conduction studies were inconclusive, this reflects the limited sensitivity of these modalities in glycogen storage diseases and underscores the importance of genetic sequencing when systemic myopathy is suspected.

Polyglucosan body myopathy type 1 (PGBM1) is a glycogen storage disorder caused by autosomal recessive variants in the RBCK1 gene. The disease is characterized by defective glycogen branching and accumulation of polyglucosan bodies within skeletal and cardiac muscle, leading to progressive neuromuscular impairment and, in many cases, dilated cardiomyopathy [3].

The disease onset is usually in childhood and early adulthood [2]. Nevertheless, his sibling is a 17-year-old boy who is symptom-free without any muscle or cardiac problems. We suggested that his sibling be checked for PGBM.

Polyglucosan is a poorly branched defective glycogen that cannot be effectively metabolized by α-amylase [4]. Polyglucosan has fewer branches and can aggregate into dense inclusion bodies, known as polyglucosan bodies. Under normal physiological conditions, polyglucosan can accumulate to a certain extent in various tissues, but its abnormal accumulation is a marker of glycogen metabolism-related diseases [5]. PGBM1 is a glycogen accumulation disease characterized by abnormal accumulation of polyglucosan in tissues [5]. This is an autosomal recessive genetic disease caused by homozygous or compound heterozygous variations in the RBCK1 gene. The RBCK1 gene is located on chromosome 20p13. According to the location and region of RBCK1 variants, clinical phenotypes of the disease can be different. The N-terminus variant of RBCK1 mainly causes immune dysfunction, while mid or C-terminus region variants may be more likely to cause cardiomyopathy and neuromuscular symptoms [1, 6]. In addition, nonsense variants often lead to more severe phenotypes [1].

A literature review, which was done by Qiqing Sun et al, revealed that till now, a total of 24 cases of PGBM1 have been reported, with a total of 24 variant sites detected, mostly C-terminal and intermediate region variants. The main manifestations were progressive proximal muscle weakness and dilated cardiomyopathy [2]. Immunodeficiency and recurrent infections secondary to the N-terminal variant were less reported in that review.

Standard medical treatment for heart failure is recommended in case of cardiac involvement. Unfortunately, no effective medical or genetic treatment for PGBM1 is available. Considering that cardiomyopathy is the main cause of death, early cardiac transplantation could be suggested in patients with progressive heart failure to avoid rapid deterioration, as seen in our presented case.

Our study’s limitation is the short follow-up period of one year. Long-term results are important for managing these patients and considering the most beneficial treatment option. This is mainly a concern as further abnormal glycogen accumulation in the transplanted heart may be suspected.

By presenting this case and expanding our knowledge of RBCK1 gene mutation variants, we aimed to address the fact that, although rare, heart transplantation could be a reasonable and life-saving choice in patients with genetic glycogen storage disease and should preferably be performed early, as the course can be unexpectedly expedited. Moreover, it is important to be mindful that other possible affected organs should be under close evaluation to determine the optimum treatment strategy.

Authors’ contribution

HY-K: patient management, data gathering, and writing the original draft.

BS-K: supervision and editing.

Z-HA: patient management and editing.

MTS: patient management and editing.

AJ: patient management.

LS: patient coordination.

SS: supervision and editing.

FN: conceptualization, patient management, review, and editing.

Conflict of interest

None.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval

Our institution does not require ethics approval for reporting individual cases or case series.

Consent

Written informed consent was obtained for anonymized patient information to be published in this article.

Guarantors

None.