Severe tracheal and bronchial collapse in adults with type II mucopolysaccharidosis

Background: Mucopolysaccharidosis type II (MPSII) patients frequently suffer from dyspnoea caused by restrictive airway disease due to skeletal abnormalities as well as glycosaminoglycans (GAG) accumulation at different levels of the airway, including the trachea. In this study we describe the extent of the tracheal and bronchial narrowing, the changes in airway diameter during respiration and the effects of these obstructions on respiratory function in adult MPSII patients. Methods: Five adult MPSII patients (mean age 40 years) were included. Pulmonary function tests and in- and expiratory chest CT scans were obtained. Cross-sectional areas of trachea and main bronchi were measured at end-inspiration and -expiration and percentage collapse was calculated. Results: There was diffuse narrowing of the entire intra-thoracic trachea and main bronchi and severe expiratory collapse of the trachea in all patients. At 1 cm above the aortic arch the median % collapse of the trachea was 68 (range 60 to 77 %), at the level of the aortic arch 64 (range 21-93 %), for the main bronchi this was 58 (range 26-66 %) on the left and 44 (range 9-76 %) on the right side. The pulmonary function tests showed that this airway collapse results in obstructive airway disease in all patients, which was severe (forced expiratory volume <50 % of predicted) in four out of five patients. Conclusion: In adult MPS II patients, central airways diameters are strikingly reduced and upon expiration there is extensive collapse of the trachea and main bronchi. This central airways obstruction explains the severe respiratory symptoms in MPSII patients

Hearing in adults with Pompe disease

Hearing loss has been recognized as an important cause of morbidity in infants with Pompe disease, a metabolic disorder caused by deficiency of acid α-glucosidase. It is unknown whether hearing is also affected in adult Pompe patients. We have studied the prevalence, severity, and type of hearing loss in 58 adult patients using tympanometry and pure-tone audiometry. Compared to normative data (International Organisation for Standardisation standard 7029), 72% of patients had impaired hearing thresholds at one or more frequencies in at least one ear. All measured frequencies were equally affected. All patients had a sensorineural type of hearing loss, pointing to cochlear or retrocochlear pathology. Categorised according to the standards of the World Health Organisation 21% of patients had a clinically relevant hearing loss (16% slight, 3% moderate, 2% profound). Though this suggests that hearing loss occurs in a considerable number of patients with Pompe disease, this prevalence is similar to that in the general population. Therefore, we conclude that hearing loss is not a specific feature of Pompe disease in adults

Lung MRI and impairment of diaphragmatic function in Pompe disease

Background: Pompe disease is a progressive metabolic myopathy. Involvement of respiratory muscles leads to progressive pulmonary dysfunction, particularly in supine position. Diaphragmatic weakness is considered to be the most important component. Standard spirometry is to some extent indicative but provides too little insight into diaphragmatic dynamics. We used lung MRI to study diaphragmatic and chest-wall movements in Pompe disease. Methods: In ten adult Pompe patients and six volunteers, we acquired two static spirometer-controlled MRI scans during maximum inspiration and expiration. Images were manually segmented. After normalization for lung size, changes in lung dimensions between inspiration and expiration were used for analysis; normalization was based on the cranial-caudal length ratio (representing vertical diaphragmatic displacement), and the anterior-posterior and left-right length ratios (representing chest-wall movements due to thoracic muscles). Results: We observed striking dysfunction of the diaphragm in Pompe patients; in some patients the diaphragm did not show any displacement. Patients had smaller cranial-caudal length ratios than volunteers (p < 0.001), indicating diaphragmatic weakness. This variable strongly correlated with forced vital capacity in supine position (r = 0.88) and postural drop (r = 0.89). While anterior-posterior length ratios also differed between patients and volunteers (p = 0.04), left-right length ratios did not (p = 0.1). Conclusions: MRI is an innovative tool to visualize diaphragmatic dynamics in Pompe patients and to study chest-walland diaphragmatic movements in more detail. Our data indicate that diaphragmatic displacement may be severely disturbed in patients with Pompe disease

The quick motor function test: a new tool to rate clinical severity and motor function in Pompe patients

Pompe disease is a lysosomal storage disorder characterized by progressive muscle weakness. With the emergence of new treatment options, psychometrically robust outcome measures are needed to monitor patients’ clinical status. We constructed a motor function test that is easy and quick to use. The Quick Motor Function Test (QMFT) was constructed on the basis of the clinical expertise of several physicians involved in the care of Pompe patients; the Gross Motor Function Measure and the IPA/Erasmus MC Pompe survey. The test comprises 16 items. Validity and test reliability were determined in a cohort of 91 Pompe patients (5 to 76 years of age). In addition, responsiveness of the scale to changes in clinical condition over time was examined in a subgroup of 18 patients receiving treatment and 23 untreated patients. Interrater and intrarater reliabilities were good (intraclass correlation coefficients: 0.78 to 0.98 and 0.76 to 0.98). The test correlated strongly with proximal muscle strength assessed by hand held dynamometry and manual muscle testing (rs= 0.81, rs=0.89), and showed significant differences between patient groups with different disease severities. A clinical-empirical exploration to assess responsiveness showed promising results, albeit it should be repeated in a larger group of patients. In conclusion, the Quick Motor Function Test can reliably rate clinical severity and motor function in children and adults with Pompe disease

Burden of illness of Pompe disease in patients only receiving supportive care

Background: Pompe disease is an orphan disease for which enzyme replacement therapy (ERT) recently became available. This study aims to estimate all relevant aspects of burden of illness-societal costs, use of home care and informal care, productivity losses, and losses in health-related quality of life (HRQoL)-for adult Pompe patients only receiving supportive care. Methods: We collected data on all relevant aspects of burden of illness via a questionnaire. We applied a societal perspective in calculating costs. The EQ-5D was used to estimate HRQoL. Results: Eighty adult patients (87% of the total Dutch adult Pompe population) completed a questionnaire. Disease severity ranged from mild to severe. Total annual costs were estimated at €22,475 (range €0-169,539) per adult Pompe patient. Patients on average received 8 h of home care and 19 h of informal care per week. Eighty-five percent of the patients received informal care from one or more caregivers; 40% had stopped working due to their disease; another 20% had reduced their working hours. HRQoL for Pompe patients who only received supportive care was estimated at 0.72, 17% lower than the Dutch population at large. Conclusions: Adult Pompe disease is associated with a considerable burden of illness at both the societal and patient levels. The disease leads to substantial costs and dependency on medical devices, home care, and informal care, and has a high impact on the patient's social network. In addition, patients are limited in their ability to work and have significantly reduced HRQoL

Hearing loss in Pompe disease revisited: results from a study of 24 children

Little information is available regarding the auditory function in Pompe patients. Hearing loss has been reported in classic infantile patients, but it is still unknown whether central nervous system involvement interferes with auditory function and whether enzyme replacement therapy can improve hearing. Audi

PAS-positive lymphocyte vacuoles can be used as diagnostic screening test for Pompe disease

Screening of blood films for the presence of periodic acid-Schiff (PAS)-positive lymphocyte vacuoles is sometimes used to support the diagnosis of Pompe disease, but the actual diagnostic value is still unknown. We collected peripheral blood films from 65 untreated Pompe patients and 51 controls. Lymphocyte vacuolization was quantified using three methods: percentage vacuolated lymphocytes, percentage PAS-positive lymphocytes, and a PAS score depending on staining intensity. Diagnostic accuracy of the tests was assessed using receiver operating characteristic (ROC) curves. All three methods fully discerned classic infantile patients from controls. The mean values of patients with milder forms of Pompe disease were significantly higher than those of controls, but full separation was not obtained. The area under the ROC curve was 0.98 for the percentage vacuolated lymphocytes (optimal cutoff value 3; sensitivity 91%, specificity 96%) and 0.99 for the percentage PAS-positive lymphocytes and PAS score (optimal cutoff value 9; sensitivity 100%, specificity 98%). Our data indicate that PAS-stained blood films can be used as a reliable screening tool to support a diagnosis of Pompe disease. The percentage of PAS-positive lymphocytes is convenient for use in clinical practice but should always be interpreted in combination with other clinical and laboratory parameters

Increased aortic stiffness and blood pressure in non-classic Pompe disease

Vascular abnormalities and glycogen accumulation in vascular smooth muscle fibres have been described in Pompe disease. Using carotid-femoral pulse wave velocity (cfPWV), the gold standard methodology for determining aortic stiffness, we studied whether aortic stiffness is increased in patients with Pompe disease. Eighty-four adult Pompe patients and 179 age- and gender-matched volunteers participated in this cross-sectional case-controlled study. Intima media thickness and the distensibility of the right common carotid artery were measured using a Duplex scanner. Aortic augmentation index, central pulse pressure, aortic reflexion time and cfPWV were assessed using the SphygmoCor® system. CfPWV was higher in patients than in volunteers (8.8 versus 7.4 m/s, p < 0.001). This difference was still present after adjustment for age, gender, mean arterial blood pressure (MAP), heart rate and diabetes mellitus (p = 0.001), and was shown by subgroup analysis to apply to the 40-59 years age group (p = 0.004) and 60+ years age group (p = 0.01), but not to younger age groups (p = 0.99). Except for a shorter aortic reflexion time (p = 0.02), indirect indicators of arterial stiffness did not differ between patients and volunteers. Relative to volunteers (20 %), more Pompe patients had a history of hypertension (36 %, p = 0.005), and the MAP was higher than in volunteers (100 versus 92 mmHg, p < 0.001). This study shows that patients with non-classic Pompe disease have increased aortic stiffness and blood pressure. Whether this is due to glycogen accumulation requires further investigation. To reduce the potential risk of cardiovascular diseases, we recommend that blood pressure and other common cardiovascular risk factors are monitored regularly

A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease

Abstract Background Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA. Results Reveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was <1.2 h. Eighteen of 22 subjects completed 72 weeks of treatment. The most common adverse events were hypoglycemia (63%), dizziness, fall, headache, and nausea (55% for each). Serious adverse events included hypersensitivity (n = 1), symptomatic hypoglycemia (n = 2), presyncope (n = 1), and acute cardiac failure (n = 1). In the dose-escalation study, all treated subjects tested positive for anti-reveglucosidase alfa, anti-rhGAA, anti-IGF1, and anti-IGF2 antibodies at least once. Subjects receiving 20 mg/kg of reveglucosidase alfa demonstrated increases in predicted maximum inspiratory pressure (13.9%), predicted maximum expiratory pressure (8.0%), forced vital capacity (−0.4%), maximum voluntary ventilation (7.4 L/min), and mean absolute walking distance (22.3 m on the 6-min walk test) at 72 weeks. Conclusions Additional studies are needed to further assess the safety and efficacy of this approach. Improvements in respiratory muscle strength, lung function, and walking endurance in subjects with LOPD may make up for the risk of hypersensitivity reactions and hypoglycemia. Reveglucosidase alfa may provide a new treatment option for patients with late-onset Pompe disease. Trial registration ISRCTN01435772 and ISRCTN01230801 , registered 27 October 2011