Pompe disease affects patients of all ages and is always characterized by progressive musculoskeletal degeneration (proximal and respiratory). The rate of progression varies, ranging from a rapidly progressive course that is usually fatal by 1 year of age to a more variable, but still relentless, progressive course, resulting in significant morbidity and often premature mortality. The infantile-onset form of Pompe disease (IOPD), is characterized by a rapid rate of progression and a generally poor prognosis. Children and adults with the late-onset form of the disease (LOPD) usually display more gradual and varied rates of disease progression; however, the prognosis is unpredictable. Information on mortality in LOPD patients is lacking, and these patients generally have a higher mortality rate than the population at large with one study estimating a 2.2x higher rate of mortality. Generally, survival in LOPD patients depends less on age than it does on level of disability. Figures 1B and C demonstrate that when LOPD patients require both ambulatory and respiratory support, or when their disability level is high, the 5-year survival rate is lower than that of LOPD patients who are healthier and retain more physical ability and independence.
Figure 1.Median estimated survival rates in LOPD patients stratified by (A) number of years following diagnosis, (B) RHS score (P = .002), and (C) level of disability (ie, need for use of ambulatory and/or respiratory support; P = .002). The Rotterdam Handicap Scale consists of 9 questions regarding ability to carry out various daily activities (mobility, domestic tasks, leisure activities, work, school, travel). Patients grade their abilities on a scale of 1 (unable to fulfill the activity) to 4 (completely able to fulfill the activity). Scores will range from 9 (lowest) to 36 (highest), with an average score being 18. Median RHS score at study entry was 27 (range, 9-36). The scores are divided into tertiles: 1; <23, 2; 23-30, 3; >30. Dx, diagnosis; RHS, Rotterdam Handicap Scale; RS = respiratory support; WC, wheelchair use.
The progression of LOPD is related to skeletal muscle dysfunction. Proximal (lower limb) and paraspinal muscles are typically affected first, followed by the diaphragm and other accessory muscles used for breathing. However, muscle weakness and dysfunction may not follow this order of progression in all patients, and variations in symptom order or severity does not rule out a diagnosis of Pompe disease. Progressive weakening of limb girdle and proximal lower limb muscles will usually result in the requirement for ambulation assistance (cane, walker, wheelchair). Progressive loss of diaphragm function leads to respiratory insufficiency ranging from mild (fatigue and headaches from sleep apnea or sleep-disordered breathing) to severe, and eventually life-threatening symptoms (hypoventilation during waking hours, hypoxia, and cor pulmonale in the end stages). Respiratory symptoms lead to the requirement for breathing assistance in the form of respiratory management (airway clearance, cough assist devices), non-invasive ventilator support (CPAP, BiPAP), or mechanical ventilatory support. Respiratory weakness may be a primary symptom preceding limb muscle weakness, or early respiratory symptoms may be subtle. The degree of respiratory function does not consistently correlate with the degree of motor muscle weakness. Whether respiratory symptoms manifest early or late in the course of the disease, it is generally accepted that patients with LOPD will eventually succumb to respiratory failure.
While the symptoms of IOPD are generally homogenous, the same is not true for LOPD. Progressive muscle weakness and atrophy lead to mobility problems. The more severe the weakness, the more the symptoms will interfere with a patient’s daily life. Difficulties running, lifting, or climbing stairs may be a patient’s primary complaints. As symptoms progress, patients may face the difficulties of balancing the desire to maintain independence while recognizing the need to request and accept assistance from others.
The burden of illness is large; apart from physical limitations, societal as well as monetary costs are associated with medical expenditures and loss of wages. A survey of Dutch patients with Pompe disease receiving only supportive care (ie, costs associated with medication not assessed) from the Erasmus Medical Center demonstrated substantial costs associated with medical devices, home care, and limitations in ability to work as well as unfavorable impact on social networks and quality of life (Fig. 2).
Figure 2. . Results of a questionnaire to determine burden of illness in 80 adult patients with LOPD from the Center for Lysosomal and Metabolic Diseases at Erasmus Medical Center from January 2005 to October 2009. Researchers asked patients to fill out a health economic questionnaire and assessed the patients’ HRQol with the EQ-5D instrument. The HRQoL measured 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) on a scale of 3 levels: no limitations, some limitations, and severe limitations. When combined with health states such as “unconscious” and “death,” the instrument describes 245 distinct health states, with utilities derived from these health states ranging from 0 (death) to 1 (perfect health). Informal care was valued using the shadow price method, which used professionals’ wage rates to value informal caregivers’ time. HRQoL, health-related quality of life.CLICK TO ENLARGE
The Pompe Registry was designed to develop a better understanding of the natural history and outcomes in patients with Pompe disease. The Registry contains the largest collection of data on patients diagnosed with Pompe disease. Physical investigators worldwide can enroll any patient with a confirmed diagnosis (documented GAA deficiency from any tissue source and/or documentation of 2 GAA gene mutations) of Pompe disease, regardless of age, symptoms, or how the patient was managed. Patient participation in the Pompe Registry is voluntary, and participating physicians and healthcare team members involved in managing enrolled patients voluntarily report clinical information.
If a diagnosis is eventually confirmed, consider the Pompe Registry for your patient and their family. Registries have proven to be especially valuable in gathering information and contributing to scientific publications for rare diseases like Pompe disease.
The Pompe Registry is sponsored and administered by Sanofi Genzyme®. Information submitted to the Pompe Registry will be maintained as confidential.