The emerging phenotype of late-onset Pompe disease: A systematic literature review

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Abstract

Background

Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase (GAA). The adult-onset form, late-onset Pompe disease (LOPD), has been characterized by glycogen accumulation primarily in skeletal, cardiac, and smooth muscles, causing weakness of the proximal limb girdle and respiratory muscles. However, increased scientific study of LOPD continues to enhance understanding of an evolving phenotype.

Purpose

To expand our understanding of the evolving phenotype of LOPD since the approval of enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme™/Lumizyme™) in 2006.

Methods

All articles were included in the review that provided data on the charactertistics of LOPD identified via the PubMed database published since the approval of ERT in 2006. All signs and symptoms of the disease that were reported in the literature were identified and included in the review.

Results

We provide a comprehensive review of the evolving phenotype of LOPD. Our findings support and extend the knowledge of the multisystemic nature of the disease.

Conclusions

With the advent of ERT and the concurrent increase in the scientific study of LOPD, the condition once primarily conceptualized as a limb-girdle muscle disease with prominent respiratory involvement is increasingly recognized to be a condition that results in signs and symptoms across body systems and structures.

Introduction

Pompe disease (acid maltase deficiency, glycogen storage disease type II, OMIM ID: 232300) is an autosomal recessive disorder caused by deficiency of the lysosomal glycogen-hydrolyzing enzyme acid α-glucosidase (GAA OMIM ID: 606800), resulting in glycogen accumulation primarily in skeletal, cardiac, and smooth muscle [1], [2], [3], [4]. The clinical spectrum of Pompe disease varies broadly, with significant differences existing in age of onset, rate of disease progression, and overall clinical phenotype. (See Table 1, Table 2.)

Pompe disease represents a continuum of disease spectrum, but in clinical practice two broad subtypes are recognized based on the presence or absence of cardiomyopathy and whether the onset of symptoms is prior to or after one year of age. In classic infantile-onset Pompe disease, GAA activity is absent (or nearly so) and the disease manifests shortly after birth, progressing rapidly to cardiorespiratory failure and death, usually within the first year of life. Due to higher residual GAA activity, late-onset Pompe disease (LOPD) typically presents in adulthood, although cases can present as early as the first year of life. Adults with LOPD typically present with difficulties in ambulation and respiratory involvement [5]. Historically, LOPD has been conceptualized as a proximal limb-girdle myopathy with greater than expected respiratory involvement. However, over the last decade, understanding of the spectrum of phenotypic manifestations of LOPD has broadened substantially. This spectrum includes bulbar muscle involvement manifesting as lingual weakness with dysarthria and dysphagia [6], [7], [8], osteoporosis [9], [10], scoliosis [11], [12], rigid spine syndrome (RSS) [13], sleep apnea and sleep disordered breathing (SDB) [14], small-fiber neuropathy (SFN) [15], sensorineural hearing loss [16], cerebral and intracranial aneurysms [17], [18], cardiac hypertrophy, abnormal cardiac rhythm [19], impaired gastric function and GI motility [20], [21], lower urinary tract (LUT) and anal sphincter involvement [20], [22], [23], pain [24], and fatigue [25].

Pompe disease severity varies by age of onset, extent of organ involvement, degree of myopathy, and rate of progression [6], [25]. The progressive nature of the disease is reflected by the fact that the duration since symptom onset is typically a better predictor than age of disease. Severity and effects on quality of life, than age. Individuals with longer disease duration generally exhibit greater overall disease severity and diminished quality of life [2].

The variable clinical manifestations, broad phenotypic spectrum, rare nature of the condition, and the overlap of signs and symptoms with other neuromuscular diseases make the prompt diagnosis of LOPD challenging [26]. Conditions that are most frequently considered in the differential diagnosis include the limb-girdle muscular dystrophies; Becker muscular dystrophy; facioscapulohumeral muscular dystrophy; scapuloperoneal syndromes; rigid spine syndrome; myasthenia gravis; spinal muscular atrophy; polymyositis; fibromyalgia; chronic fatigue syndrome; glycogen storage diseases types IIIa, IV, V, and VII; Danon disease; rheumatoid arthritis; and mitochondrial myopathies [20], [27].

Residual GAA enzyme activity detected in skin and muscle biopsy has traditionally been used to diagnose LOPD [26]. Measuring acid alpha-glucosidase activity in blood (leukocytes, lymphocytes, or dried-blood spot [DBS]) is now being increasingly utilized due to its reliability, cost-effectiveness, and its less invasive and time-consuming nature [26]. Selective screening for LOPD with the use of DBS assays, in individuals with asymptomatic elevated creatine kinase (CK) or hyperCKemia, has allowed the identification of affected individuals with LOPD [28], [29], [30]. For example, Musumeci and colleagues evaluated 1051 individuals in which 30 (2.9%) were diagnosed with an initial DBS screening. Similarly, 232 individuals (7.6%) of a sample of 3076 individuals with limb girdle muscle dystrophy and hyperCKemia were found to have low GAA activity with DBS [31], [32].

There are several reports that characterize the clinical phenotype of infantile-onset Pompe disease [4], [6], [33], [34], [35], [36], [37], [38], [39], [40]. The objective of this review is to provide a comprehensive review of the signs and symptoms of LOPD reported in the literature, awareness of which has expanded since the advent of ERT, in order to raise awareness of the multiple organ systems that may be involved in individuals with LOPD, as well as the variable presentation of individuals across the disease spectrum, in order to expedite diagnosis and treatment.

Section snippets

Methods

An electronic literature search of the PubMed database was performed for current and past findings of LOPD for the years 2006 through 2016 using the keywords “acid alpha-glucosidase deficiency”, “acid maltase deficiency”, “Pompe disease symptoms”, “adult-onset acid maltase deficiency”, along with the key clinical symptoms of LOPD, as described below. The publications selected were based on whether they reported new or relevant clinical manifestations since the approval of ERT in 2006. When

Results

A total of 213 articles on Pompe disease were found between 2006 and 2016 based on the search described in Methods. One article was discarded for being in another language, 52 animal studies were discarded, and 30 articles were discarded due to information overlap. Thus, including 38 informational and historical articles published prior to 2006, the total number of studies included in this review was 130. This article describes the various systems and manifestations involved in LOPD, including

Conclusion

As described, there is a wide phenotypic spectrum for LOPD. In an effort to clarify the emerging phenotype of LOPD, this comprehensive review describes the expanded features of LOPD identified in the literature since the approval of ERT with alglucosidase afla in 2006, allowing better disease recognition from improvements in survival rates and clinical outcomes. This article details the symptoms and indicators of the disease. As more individuals with Pompe are diagnosed and monitored in

Acknowledgements

Competing interests: JC, ZBK, AKD, SA, and KC have no financial or proprietary interest in the materials presented herein. LHW and HJ receive research support from the Genzyme Corporation for the study of muscle changes in Pompe disease. LHW also receives research support from Valerion Therapeutics for the study of GSD3. LEC has received honoraria from Genzyme Corporation of Sanofi, has participated in research supported by Genzyme Corporation of Sanofi, the Leal Foundation, Biomarin, Roivant

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