Review
The respiratory neuromuscular system in Pompe disease

https://doi.org/10.1016/j.resp.2013.06.007Get rights and content

Highlights

Abstract

Pompe disease is due to mutations in the gene encoding the lysosomal enzyme acid α-glucosidase (GAA). Absence of functional GAA typically results in cardiorespiratory failure in the first year; reduced GAA activity is associated with progressive respiratory failure later in life. While skeletal muscle pathology contributes to respiratory insufficiency in Pompe disease, emerging evidence indicates that respiratory neuron dysfunction is also a significant part of dysfunction in motor units. Animal models show profound glycogen accumulation in spinal and medullary respiratory neurons and altered neural activity. Tissues from Pompe patients show central nervous system glycogen accumulation and motoneuron pathology. A neural mechanism raises considerations about the current clinical approach of enzyme replacement since the recombinant protein does not cross the blood-brain-barrier. Indeed, clinical data suggest that enzyme replacement therapy delays symptom progression, but many patients eventually require ventilatory assistance, especially during sleep. We propose that treatments which restore GAA activity to respiratory muscles, neurons and networks will be required to fully correct ventilatory insufficiency in Pompe disease.

Section snippets

Overview of Pompe disease

The clinical features of Pompe disease were originally described by J.C. Pompe (1932) and subsequently the disease pathophysiology is considered the prototypical lyosomal storage disease (Cori, 1954, Hers, 1963). This neuromuscular disorder results from mutations in the GAA gene which has been mapped to the long arm of chromosome 17 (17q25.2–q25.3). More than 350 different mutations have been described, and the genotype–phenoype relationship is a subject of active investigation (Kroos et al.,

Respiratory insufficiency in Pompe disease

Respiratory insufficiency is extremely common in both the infantile and late-onset forms of Pompe disease (Burghaus et al., 2006, Mellies and Lofaso, 2009, Mellies et al., 2005, Pellegrini et al., 2005). Infants typically present at 4–6 months of age, and “respiratory difficulty” is often noted as the first symptom (van den Hout et al., 2003). Considerable CO2 retention (e.g. PaCO2 > 60 mmHg) can be present during spontaneous breathing in Pompe infants (Hogan et al., 1969), and cardiorespiratory

Respiratory muscle function in Pompe disease

It is well accepted that skeletal muscle weakness is prominent in Pompe disease (Mellies and Lofaso, 2009, Mellies et al., 2001, Prigent et al., 2012). Muscular pathology is evident on histological exam, and electron microscopy reveals extensive accumulation of glycogen in muscle cell lysosomes in Pompe patients (Baudhuin et al., 1964, Hudgson and Fulthorpe, 1975). In the early phases of the disease, glycogen is also found dispersed in the cytoplasm and intrafibrillary spaces. In advanced Pompe

The upper airway and Pompe disease

In addition to the primary and accessory respiratory “pump” muscles which actively change the volume of the thoracic or abdominal cavities, breathing also involves activation of pharyngeal and laryngeal muscles (Feldman and Del Negro, 2006). Hypoglossal (XII) motoneurons are of particular importance to upper airway patency since they regulate the shape, stiffness and position of the tongue (Bailey and Fregosi, 2004, Fregosi and Fuller, 1997, Gestreau et al., 2005, Remmers, 1978). Contraction of

The central nervous system, breathing, and Pompe disease

Motor problems in Pompe disease, including impaired breathing, have historically been attributed to muscular pathology (Raben et al., 2002). We emphasize that respiratory muscle pathology and dysfunction are prominent features of Pompe disease (see above) that contribute to respiratory impairments as the disease progresses. However, the genetic mutation in Pompe disease is not restricted to muscle tissues, and accordingly CNS pathology must be considered. Indeed, neural pathology is prominent

Enzyme replacement therapy (ERT) – impact on breathing in Pompe disease

Therapies aimed at altering glycogen synthesis (e.g. high-protein diet, steroids) have failed to reduce glycogen accumulation in Pompe disease (Isaacs et al., 1986). Other treatment approaches with limited or no clinical impact include bone marrow transplantation and administration of unphosphorylated GAA (de Barsy et al., 1973). The only currently FDA-approved treatment for Pompe disease involves bi-weekly intravenous (i.v.) infusion of recombinant GAA enzyme (Beck, 2009, Byrne et al., 2011a).

The future of Pompe respiratory therapy

The current standard of care in Pompe disease therapy is muscle-directed ERT and other supportive measures, including ventilatory assistance. Aside from the problems related to the feasibility of life-long ERT and managing complications of immune responses to the recombinant protein, it is important to emphasize that the long-term treated population of patients continue to lose ventilatory function. The substantial effort needed for bi-weekly ERT treatment, the associated high cost (>$500,000

Conclusion

Respiratory dysfunction is prominent in both early and late onset Pompe disease patients. While respiratory muscular pathology and dysfunction are prominent, a growing basic science and clinical literature supports the hypothesis that neural dysfunction also contributes to respiratory insufficiency. The relative contribution of muscular vs. neural pathology to respiratory dysfunction in Pompe disease is difficult to ascertain because both components of the motor unit are affected by the

Acknowledgments

We thank Dr. Reordan O DeJesus for comments on Fig. 1, Dr. William H. Donnelly Jr. for processing the tissues shown in Fig. 2, Dr. Michael A. Lane for discussion of Fig. 2, Fig. 3, and Dr. Elisa Gonzalez-Rothi for assistance with Fig. 4. This work was supported by the Parker B. Francis Foundation (MKE) and the NIH: 201HD052682-06A1 (DDF, BJB), MDA 216676 (DJF), K12HD055929 (BKS), and PO1 HL59412 (BJB)

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    This paper is part of a special issue entitled “Clinical Challenges to Ventilatory Control”, guest-edited by Dr. Gordon Mitchell, Dr. Jan-Marino Ramirez, Dr. Tracy Baker-Herman and Dr. Dr. David Paydarfar.

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