Elsevier

Molecular Genetics and Metabolism

Volume 120, Issues 1–2, January–February 2017, Pages 96-100
Molecular Genetics and Metabolism

Alglucosidase alfa enzyme replacement therapy as a therapeutic approach for a patient presenting with a PRKAG2 mutation

https://doi.org/10.1016/j.ymgme.2016.09.006Get rights and content

Abstract

Objective

PRKAG2 syndrome, an autosomal dominant disorder, is characterized by severe infantile hypertrophic cardiomyopathy and heart rhythm disturbances to cases with a later presentation and a spectrum of manifestations including cardiac manifestations, myopathy and seizures. The cardiac features of PRKAG2 resemble the cardiac manifestations of Pompe disease. We present a patient who was initially diagnosed with Pompe disease and treated with alglucosidase-alfa enzyme replacement therapy (ERT); however, he was eventually diagnosed to carrying a PRKAG2 pathogenic gene mutation; he did not have Pompe disease instead he was a carrier for the common adult leaky splice site mutation in the GAA gene.

Case report

At 2.5 months, the patient had hypotonia/generalized muscle weakness, a diagnosis of non-classic infantile Pompe disease was made based on low acid alpha-glucosidase activity and the patient started on ERT at 11 months. However, 1 month later, the patient began to have seizures. As the patient's medical history was somewhat unusual for infantile Pompe disease, further evaluation was initiated and included a glycogen storage disease sequencing panel which showed that the patient had a pathogenic mutation in PRKAG2 which had been reported previously. ERT was discontinued and patient had a progression of motor deficits. ERT was reinitiated by the treating physician, and a clinical benefit was noted.

Conclusion

This report outlines the benefits of ERT with alglucosidase alfa in a patient with PRKAG2 syndrome, the decline in his condition when the ERT infusions were discontinued, and the significant positive response when ERT was reinitiated.

Introduction

In humans, glycogen is a polymer of glucose that is stored in liver, skeletal muscle, and heart cells. There are a number of enzymes involved in the synthesis and breakdown of glycogen within the body. Deficiency or dysfunction of one of these enzymes results in a group of diseases called glycogen storage diseases (GSDs), in which the clinical hallmark is excessive glycogen accumulation in various tissues [1]. One such GSD is PRKAG2 syndrome, which is caused by mutations in the PRKAG2 gene that encodes the γ2 subunit of AMP-activated protein kinase (AMPK). AMPK is a crucial cellular energy sensor that regulates a number of vital cellular metabolic cascades and lipid/glucose metabolic pathways [2], [3], [4]. PRKAG2 syndrome is an autosomal dominant disorder with a wide spectrum of symptoms. The disease phenotype is a spectrum that is characterized by severe infantile hypertrophic cardiomyopathy and heart rhythm disturbances to cases with a later presentation (age range 8 to 42 years of age) of cardiac manifestations such as increased left ventricular wall thickness and ventricular pre-excitation [5]. Also, symptoms of myalgia, myopathy, and seizures have been reported further expanding the phenotype and characterization of it beyond a cardiac syndrome as was previously thought [6], [7]. Mutations in the PRKAG2 gene cause chronic activation of AMPK and the underlying mechanism of excess glycogen accumulation in PRKAG2 syndrome is illustrated in Fig. 1 [2], [8], [9]. The clinical cardiac features and muscle weakness of PRKAG2 syndrome closely resemble the cardiac and muscle manifestations of Pompe Disease (GSD Type II). Pompe disease is an autosomal recessive metabolic disorder that is characterized by glycogen accumulation in lysosomes of cardiac, skeletal, and smooth muscles due to the deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA) [10]. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA, Alglucosidase alfa, Genzyme, Boston, MA, USA) is currently the only FDA approved treatment for Pompe disease.

With the phenotypic similarity of PRKAG2 syndrome to Pompe disease, there is the potential for a misdiagnosis for either of these disorders, especially the infantile form of Pompe disease. Here, we present an interesting case of a patient initially diagnosed with Pompe disease and started on ERT with alglucosidase alfa, which improved his condition. However, over the course of the therapy, the patient began to develop inconsistent symptoms that led his physicians to question the diagnosis. Through further medical tests, he was diagnosed with PRKAG2, carrying a pathogenic mutation in the gene, and being a carrier of Pompe disease and not affected. This case report outlines the benefits that the patient showed while on ERT treatment, the decline to his condition when his infusions were discontinued due to his updated diagnosis, and the significant positive response when alglucosidase alfa ERT was reinitiated. This case study provides several key messages: 1) the importance of confirming the diagnosis of Pompe disease via gene sequencing and doing enzyme analysis in a lab with experience before ERT initiation, 2) our group's previous work showing the potential of GAA as a treatment approach for cytoplasmic GSDs [11] such as PRKAG2, and 3) it also supports the expanded phenotype of PRKAG2 depicting a case with myopathy, seizures, and minimal cardiac involvement.

Section snippets

Case presentation

This male patient was born by caesarian section at 38 weeks gestation as a result of the nuchal cord being wrapped around his neck. At age 2 1/2 months, the patient was noted to have hypotonia and generalized muscle weakness. He was areflexic and had feeding difficulties. At age 4 months, the patient began developing severe lower respiratory infections which led to frequent admissions to the hospital. Labs at 11 months of age showed a mild increase in creatine kinase (CK) at 197 IU/L (normal range:

Discussion

Due to similar symptomatic phenotypes, rare PRKAG2 cases can be misdiagnosed with infantile Pompe disease. PRKAG2 should be in the differential diagnosis of cases with cardiomyopathy. Interestingly, the patient in our case study only exhibited mild cardiac hypertrophy. There is variability of cardiac involvement in PRKAG2 as shown in Table 1. He did have a family member die of a sudden cardiac event, and based on current literature, there is a broader clinical spectrum of this disorder beyond

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