The respiratory neuromuscular system in Pompe disease

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.

Keywords: Motoneurons; Pathology; Plasticity; Pompe; Respiratory; Therapy.

Fig. 1

A midsagittal T1-weighted MRI image of a five month old male with Pompe disease. Macroglossia is suggested by enlargement of the tongue, particularly at the base (*). The enlarged tongue is displacing the epiglottis posteriorly (arrow) which partially occludes the airway.

Fig. 2

Semi-thin plastic embedded sections from the mid-cervical spinal cord of an 18-month-old child with Pompe disease. Cervical spinal tissue was obtained on autopsy, plastic embedded, cut at 2μm thickness and stained with toluidine blue. The patient had been treated with recombinant enzyme replacement therapy for the preceding 12 months but experienced respiratory failure. Panel A depicts the ventrolateral cervical spinal cord at the junction of the white and gray matter. Myelinated axons are clearly discerned in the left part of the image, and the asterisks highlight four ventral horn neurons (putative motoneurons). Panel B shows a higher magnification of the neuron indicated by the asterisk in A. Panel C shows another ventral horn neuron from an adjacent tissue section. Note that the neurons are swollen and nuclei (when visible) were displaced from the center of the cell – histopathological features characteristic of central chromatolysis. Scale bars: (A) 200 μm; (B–C) 50 μm.

Fig. 3

Hypoglossal motoneurons in wild type (129) and Pompe (Gaa^−/−) mice. Tissues were processed with an antibody against GAA protein, and were counter-stained with cresyl violet. Tissue from a wild type 129 mouse shows positive GAA immunostaining staining (brown) in hypoglossal motoneurons, as expected. In contrast, motoneurons from the Gaa^−/− mouse show a complete absence of positive GAA staining. Note the difference in the histological appearance of cells in panel A vs. B. Specifically, Gaa^−/− motoneurons are larger with a swollen appearance. Scale bars: 50 μm.

Fig. 4

A conceptual model of the mechanisms leading to respiratory failure in Pompe disease. In this model, we hypothesize three critical periods in the development of respiratory failure in Pompe disease. Importantly, the model recognizes the contribution of both skeletal muscle contractile dysfunction and neuropathology to the development of respiratory insufficiency. Critical period 1: Glycogen accumulation begins in respiratory motor units (e.g., myofibers, motoneuron soma, axons, etc.). Pathological processes are beginning during this phase, but no symptoms are apparent. Critical period 2: Myofiber contractile dysfunction begins to develop. Impaired respiratory muscle function is initially met with compensatory increases in respiratory drive. Critical period 3: Neural and muscular pathology reach a critical threshold, and neural compensation for respiratory muscle dysfunction is no longer possible. The resulting respiratory failure (*) necessitates mechanical ventilation. Therapies which improve muscle function (e.g., ERT, gene therapy) or neural function (e.g., gene therapy) will prevent or minimize the declines in neuromotor function, and delay the onset of respiratory failure. Please see the text for a more detailed discussed of the hypothesized critical periods.