ReviewThe respiratory neuromuscular system 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.