Adult Pompe Patients Research Articles

Lysosomal storage disorders identified in adult population from India: Experience of a tertiary genetic centre and review of literature.

Lysosomal storage disorders (LSDs) in adults have milder phenotype and variable age at presentation. Several studies have described the phenotype, genotype and treatment outcomes for adult-onset LSDs like Gaucher, Fabry, Pompe disease and others. We describe the first systematic study on the occurrence of LSDs in an adult population from India. It describes, the key clinical signs seen in these patients and those from literature review that can aid in early detection. Of 2102 biochemically diagnosed LSDs cases, 32 adult patients were identified with LSDs. Based on the clinical suspicion, screening test and enzyme study was carried out. Twenty-two patients were subjected to a genetic study to identify the causative variant in a respective gene. Of the 32 adult patients, we observed a maximum percentage of 37.5% (n = 12) cases with Gaucher disease, followed by 13% (n = 4) with Fabry disease. We found 10% of cases with MPS IVA and MPS I, and 9% cases with Pompe. Single case of adult mucolipidosis III and two cases each of Type 1 Sialidosis, Niemann-Pick disease B and metachromatic leukodystrophy were identified. We observed two common variants p.Leu483Pro and p.Ala487Thr in the GBA1 gene in 23% of Indian patients with adult Gaucher disease. No common variants were observed in other aforementioned LSDs. Study identified 50% of Fabry patients and 4% of Gaucher patients diagnosed at our centre to be adults. The prevalence of adult Pompe patients was low (3.4%) as compared to 80% reported in the Caucasian population. Adult LSDs such as, MPS III, GM1/GM2 gangliosidosis and Krabbe disease were not identified in our cohort.

Home-Based Infusion of Alglucosidase Alfa Can Safely be Implemented in Adults with Late-Onset Pompe Disease: Lessons Learned from 18,380 Infusions.

Enzyme replacement therapy (ERT) with alglucosidase alfa is the treatment for patients with Pompe disease, a hereditary metabolic myopathy. Home-based ERT is unavailable in many countries because of the boxed warning alglucosidase alfa received due to the risk of infusion-associated reactions (IARs). Since 2008, home infusions have been provided in The Netherlands. This study aimed to provide an overview of our experience with home-based infusions with alglucosidase alfa in adult Pompe patients, focusing on safety, including management of IARs. We analysed infusion data and IARs from adult patients starting ERT between 1999 and 2018. ERT was initially given in the hospital during the first year. Patients were eligible for home treatment if they were without IARs for multiple consecutive infusions and if a trained home nurse, with on-call back-up by a doctor, was available. The healthcare providers graded IARs. We analysed data on 18,380 infusions with alglucosidase alfa in 121 adult patients; 4961 infusions (27.0%) were given in hospital and 13,419 (73.0%) were given at home. IARs occurred in 144 (2.9%) hospital infusions and 113 (0.8%) home infusions; 115 (79.9% of 144) IARs in hospital and 104 (92.0% of 113) IARs at home were mild, 25 IARs (17.4%) in hospital and 8 IARs (7.1%) at home were moderate, and very few severe IARs occurred (4 IARs in hospital [2.8%] and 1 IAR at home [0.9%]). Only one IAR in the home situation required immediate clinical evaluation in the hospital. Given the small numbers of IARs that occurred with the home infusions, of which only one was severe, we conclude that alglucosidase alfa can be administered safely in the home situation, provided the appropriate infrastructure is present.

Physical training and high-protein diet improved muscle strength, parent-reported fatigue, and physical quality of life in children with Pompe disease.

Exercise has proven to be an effective adjuvant treatment to enzyme replacement therapy (ERT) in mildly affected adult Pompe patients. The aim of this study was to investigate the effects of a 12-week tailored lifestyle intervention, consisting of physical training and a high protein diet (2 grams/kg), in children with Pompe disease. This randomized controlled semi-crossover trial investigated the effects of a lifestyle intervention on the primary outcome: exercise capacity. Secondary outcomes were: muscle strength, core stability, motor function, physical activity levels, quality of life, fatigue, fear of exercise, caloric intake, energy balance, body composition, and safety. Fourteen Pompe patients with a median age of 10.6 [IQR: 7.2-14.5], of whom six classic infantile patients, participated in the lifestyle intervention. At baseline, patients had a lower exercise capacity compared to healthy peers (median 70.3% [IQR: 54.8%-98.6%] of predicted). After the intervention, absolute Peak VO2 improved significantly (1279 mL/min [1012.5-2006] vs. 1352 mL/min [1101.5-2069], p = 0.039), but not compared to the control period. Muscle strength of the hip flexors, hip abductors, elbow extensors, neck extensors, knee extensors, and core stability improved significantly compared to the control period. Children reported a significant increase on the change in health domain of quality of life, parents reported significantly better scores on the quality of life domains: physical functioning, change in health, family cohesion, and fatigue. A 12-week tailored lifestyle intervention for children with Pompe disease seemed safe and led to improvements in muscle strength, core stability, quality of life, and parent-reported fatigue. Pompe patients with a stable disease trajectory seemed to benefit the most from the intervention.

VP.29 Safety analysis of home-based enzyme replacement therapy with alglucosidase alfa in Pompe disease; a prospective study

Pompe disease is a progressive lysosomal storage disease treated with life-long weekly or biweekly enzyme replacement therapy (ERT). Home-based ERT diminishes the burden of treatment in Pompe patients and has been provided in the Netherlands since 2008. The COVID-19 pandemic has prompted the need for home-based ERT. We conducted a prospective survey to map infusion associated reactions (IARs) and validate safety of home-based ERT during one year. Patients with Pompe disease currently receiving alglucosidase alfa infusions at home were included. Prospective data on the occurrence, severity and management of IARs related to the home-infusion of alglucosidase alfa were collected by means of questionnaires. Patients received this questionnaire every three months during one year. Data on 120 patients were collected; 18 classic infantile, 18 childhood onset, and 84 adult onset Pompe patients. In total 116 of these patients filled in 423 questionnaires (overall response rate: 88%). Health problems during or within 48 hours from infusion were reported 27 times in 17 patients (5 classic infantile, 1 childhood onset, 11 adult onset). None of the infusion associated reactions that occurred warranted immediate care in hospital. Our data demonstrate that home-based ERT in Pompe disease is safe as few IARs occurred and those that occurred could be managed with no or minor interventions. Insights gained from this study can be used as a base for implementation of home-infusions in other countries and for further optimization of the protocol for home-based therapy with ERT in Pompe disease.

MRI changes in diaphragmatic motion and curvature in Pompe disease over time

ObjectivesTo evaluate changes in diaphragmatic function in Pompe disease using MRI over time, both during natural disease course and during treatment with enzyme replacement therapy (ERT).MethodsIn this prospective study, 30 adult Pompe patients and 10 healthy controls underwent pulmonary function tests and spirometry-controlled MRI twice, with an interval of 1 year. In the sagittal view of 3D gradient echo breath-hold acquisitions, diaphragmatic motion (cranial-caudal ratio between end-inspiration and end-expiration) and curvature (diaphragm height and area ratio) were calculated using a machine learning algorithm based on convolutional neural networks. Changes in outcomes after 1 year were compared between Pompe patients and healthy controls using the Mann-Whitney test.ResultsPulmonary function outcomes and cranial-caudal ratio in Pompe patients did not change significantly over time compared to healthy controls. Diaphragm height ratio increased by 0.04 (−0.38 to 1.79) in Pompe patients compared to −0.02 (−0.18 to 0.25) in healthy controls (p = 0.02). An increased diaphragmatic curvature over time was observed in particular in untreated Pompe patients (p = 0.03), in those receiving ERT already for over 3 years (p = 0.03), and when severe diaphragmatic weakness was found on the initial MRI (p = 0.01); no progression was observed in Pompe patients who started ERT less than 3 years ago and in Pompe patients with mild diaphragmatic weakness on their initial MRI.ConclusionsMRI enables to detect small changes in diaphragmatic curvature over 1-year time in Pompe patients. It also showed that once severe diaphragmatic weakness has occurred, improvement of diaphragmatic muscle function seems unlikely.Key Points• Changes in diaphragmatic curvature in Pompe patients over time assessed with 3D MRI may serve as an outcome measure to evaluate the effect of treatment on diaphragmatic function.• Diaphragmatic curvature showed a significant deterioration after 1 year in Pompe patients compared to healthy controls, but the curvature seems to remain stable over this period in patients who were treated with enzyme replacement therapy for less than 3 years, possibly indicating a positive effect of ERT.• Improvement of diaphragmatic curvature over time is rarely seen in Pompe patients once diaphragmatic motion shows severe impairment (cranial-caudal inspiratory/expiratory ratio < 1.4).

Diaphragmatic dysfunction in neuromuscular disease, an MRI study

The aim of this exploratory study was to evaluate diaphragmatic function across various neuromuscular diseases using spirometry-controlled MRI. We measured motion of the diaphragm relative to that of the thoracic wall (cranial-caudal ratio vs. anterior posterior ratio; CC-AP ratio), and changes in the diaphragmatic curvature (diaphragm height and area ratio) during inspiration in 12 adults with a neuromuscular disease having signs of respiratory muscle weakness, 18 healthy controls, and 35 adult Pompe patients – a group with prominent diaphragmatic weakness. CC-AP ratio was lower in patients with myopathies (n=7, 1.25±0.30) and motor neuron diseases (n=5, 1.30±0.10) than in healthy controls (1.37±0.14; p=0.001 and p=0.008), but not as abnormal as in Pompe patients (1.12±0.18; p=0.011 and p=0.024). The mean diaphragm height ratio was 1.17±0.33 in patients with myopathies, pointing at an insufficient diaphragmatic contraction. This was also seen in patients with Pompe disease (1.28±0.36), but not in healthy controls (0.82±0.33) or patients with motor neuron disease (0.82±0.24). We conclude that spirometry-controlled MRI enables us to investigate respiratory dysfunction across neuromuscular diseases, suggesting that the diaphragm is affected in a different way in myopathies and motor neuron diseases. Whether MRI can also be used to evaluate progression of diaphragmatic dysfunction requires additional studies.

Exercise, nutrition and enzyme replacement therapy are efficacious in adult Pompe patients: report from EPOC Consortium.

Pompe Disease, also known as glycogenosis type 2, is due to deficiency in lysosomal alpha- glucosidase, a lysosomal hydrolase, which presents infantile and late onset subtypes (LOPD). The myopathy in LOPD can be reversed by Enzyme Replacement Therapy (ERT), but might benefit from a concomitant low carbohydrate - high protein diet and aerobic exercise treatment. From 65 Late onset Pompe cases, we were able to obtain in 58 a self-reported evaluation, most of them gave a positive efficacy evaluation of Enzyme Replacement Therapy and they were classified by a self-administered scale as Responders or non-Responders. A cooperative study of a clinical group on LOPD monitored age, sex, BMI, Gardner-Medwin-Walton scale and six minute walking test (6MWT). The only clinical parameters that were significantly associated with a Responder category were the pre-ERT walking distance (p<0.035) and the use of regular diet, exercise or both (p<0.029). The present study shows that in LOPD this condition can be treated by ERT, but also benefits from concomitant diet and aerobic exercise therapy.

Positive association between physical outcomes and patient-reported outcomes in late-onset Pompe disease: a cross sectional study

BackgroundPompe disease is a rare, progressive metabolic myopathy. The aim of this study is to investigate the associations of physical outcomes with patient-reported outcome measures (PROMs) in late-onset Pompe disease.MethodsWe included 121 Dutch adult patients with Pompe disease.Physical outcomes comprised muscle strength (manual muscle testing using Medical Research Council [MRC] grading, hand-held dynamometry [HHD]), walking ability (6-min walk test [6MWT]), and pulmonary function (forced vital capacity [FVC] in upright and supine positions).PROMs comprised quality of life (Short Form 36 health survey [SF-36]), participation (Rotterdam Handicap Scale [RHS]) and daily-life activities (Rasch-Built Pompe-Specific Activity [R-PAct] Scale).Analyses were cross-sectional: the time-point before, and closest to, start of Enzyme Replacement Therapy was chosen. Associations between PROMs and physical outcomes were investigated using linear regression models.ResultsRHS and R-PAct scores were better in patients with higher FVC supine and upright, HHD, MRC and 6MWT scores, accounting for the effect of sex, disease duration, use of wheelchair and ventilator support. While the SF-36 Physical Component Summary (PCS) was correlated positively with FVC upright, HHD, MRC and 6MWT scores, there was no significant relationship between the SF-36 Mental Component Summary (MCS) and any of the physical outcomes.ConclusionsParticipation, daily-life activities, and the physical component of quality of life of adult Pompe patients are positively correlated to physical outcomes. This work serves as a first step towards assessing how changes over time in physical outcomes are related to changes in PROMs, and to define the minimal change in physical outcomes required to make an important difference for the patient.

Discontinuation of enzyme replacement therapy in adults with Pompe disease: Evaluating the European POmpe Consortium stop criteria

Enzyme replacement therapy for Pompe disease received market authorization in 2006. To implement this costly treatment in the Netherlands in the most sensible way, a multidisciplinary expert committee was installed. We evaluated decision making in adult patients in relation to the European POmpe Consortium stop criteria. Of 125 adult Pompe patients, 111 started treatment; subsequently treatment stopped in 24 patients (21%). In 10 patients, treatment was discontinued for medical or personal reasons, as defined in the six stop criteria (median treatment duration: 2.1 years, range: 0.3–14.6 years). Three of these patients continued follow-up (follow-up: 1.3–8.0 years), these patients did not display a more rapid decline after discontinuation. In 14 of 24 patients, therapy ended at time of death. In 10 patients death was related to Pompe disease (median treatment duration: 7.2 years, range: 0.4–10.3 years). All 10 patients were severely affected at start of treatment, treatment had elicited positive effects in eight. The European POmpe Consortium guidelines worked well in decision making on stopping treatment. However, (re)evaluation of the rationale for continuation of treatment in advanced disease stage is not addressed. We suggest to add this to the treatment evaluation and to handle treatment decisions in a multidisciplinary expert team.

O.23A 10 year prospective study on the effects of enzyme replacement therapy in adult Pompe patients

Enzyme-replacement therapy (ERT) with alglucosidase alfa has become standard of care in the treatment of patients with Pompe disease and is known to benefit walking ability, muscle strength and respiratory function in studies up to 5 years' follow-up. The aim of this study was to determine the effects of 10 years' ERT, focusing on individual variability in treatment response.

PDGF-BB serum levels are decreased in adult onset Pompe patients

Adult onset Pompe disease is a genetic disorder characterized by slowly progressive skeletal and respiratory muscle weakness. Symptomatic patients are treated with enzymatic replacement therapy with human recombinant alfa glucosidase. Motor functional tests and spirometry are commonly used to follow patients up. However, a serological biomarker that correlates with the progression of the disease could improve follow-up. We studied serum concentrations of TGFβ, PDGF-BB, PDGF-AA and CTGF growth factors in 37 adult onset Pompe patients and 45 controls. Moreover, all patients performed several muscle function tests, conventional spirometry, and quantitative muscle MRI using 3-point Dixon. We observed a statistically significant change in the serum concentration of each growth factor in patients compared to controls. However, only PDGF-BB levels were able to differentiate between asymptomatic and symptomatic patients, suggesting its potential role in the follow-up of asymptomatic patients. Moreover, our results point to a dysregulation of muscle regeneration as an additional pathomechanism of Pompe disease.

Enzyme replacement therapy reduces the risk for wheelchair dependency in adult Pompe patients

BackgroundPompe disease is a rare metabolic myopathy. In adult patients, progressive weakness of limb-girdle and respiratory muscles often leads to wheelchair and respirator dependency. Clinical studies have shown enzyme replacement therapy (ERT) to positively affect motor and respiratory outcomes. Here we investigate whether ERT reduces patients’ risk of needing a wheelchair or respirator.MethodsData were collected as part of a prospective international survey, the IPA/Erasmus MC Pompe survey, which was conducted annually between 2002 and 2016. We excluded patients who were already using a wheelchair or respirator, those under 18 at survey entry, and those who had missing information. Time-dependent Cox proportional hazard models were used.ResultsThe inclusion criteria for analyzing the risk of wheelchair use were met by 189 patients (median age 47 years; range 18–75). During follow-up, 126 (67%) started ERT. Over 1120 person-years of follow-up (median 5 years), 46 became wheelchair dependent, 16 of whom used ERT. After adjustment for disease duration, sex and country, ERT reduced the risk for wheelchair use (HR 0.36; 95% CI 0.17–0.75). For analyses of respirator use, 177 patients met the inclusion criteria (median age 46 years; range 18–73). Over 1190 person-years of follow-up (median 6 years), 125 patients (71%) were treated and 48 started respiratory support, 28 of whom received ERT. We found no association between ERT and the risk for respirator use (HR 1.23; 95% CI 0.61–2.47).ConclusionsOur study found that ERT reduced the risk for wheelchair dependency. We could not demonstrate an effect on respiratory support.

Efficient therapy for refractory Pompe disease by mannose 6-phosphate analogue grafting on acid α-glucosidase

Pompe disease is a rare disorder due to deficiency of the acid α-glucosidase (GAA) treated by enzyme replacement therapy. The present authorized treatment with rhGAA, the recombinant human enzyme, provides an important benefit in the infantile onset; however, the juvenile and adult forms of the disease corresponding to >80% of the patients are less responsive to this treatment. This resistance has been mainly attributed to an insufficiency of mannose 6-phosphate residues in rhGAA to address lysosomes through the cation-independent mannose 6-phosphate receptor (CI-M6PR). As yet, several attempts to improve the enzyme delivery by increasing the number of mannose 6-phosphate on the enzyme were poorly effective on the late onset form of the disease. Here, we show that chemical conjugation of a synthetic analogue of the mannose 6-phosphate, named AMFA, onto rhGAA improves the affinity for CI-M6PR and the uptake of the enzyme in fibroblasts and myoblasts of adult Pompe patients. More importantly, only the conjugated rhGAA-AMFA was effective in aged Pompe mice when compared to rhGAA. Weekly treatment with 5–20mg·kg−1 rhGAA-AMFA provided major improvements of the motor function and of the myofiber structure, whereas rhGAA was inactive. Finally, AMFA addition did not induce supplementary immune response to the enzyme. This modified enzyme, displaying a muscle recovery in aged Pompe mice that was never attained before, could be considered as a potential therapy for the late onset Pompe disease.

P.219 - Long-term efficacy of enzyme-replacement therapy in 102 adult Pompe patients: a 5-year nationwide prospective cohort study

P.219 - Long-term efficacy of enzyme-replacement therapy in 102 adult Pompe patients: a 5-year nationwide prospective cohort study

Response to Herbert et al.

__To the Editor:__ We thank Herbert et al. for their interest in our work. Their laboratory has shown to be instrumental in studying the effects of enzyme replacement therapy (ERT) in infants with Pompe disease. However, there are some misunderstandings about our study on adult Pompe patients and antibody formation. Below we explain these in detail.

Pattern and prognostic value of cardiac involvement in patients with late-onset pompe disease: a comprehensive cardiovascular magnetic resonance approach

BackgroundPompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal α–1,4-glucosidase leading to accumulation of glycogen in target tissues with progressive organ failure. While the early infantile-onset form is characterized by early severe hypertrophic cardiomyopathy with cardiac and respiratory failure, clinically relevant cardiomyopathy seems to be uncommon in patients with late-onset Pompe disease, and the prevalence and nature of myocardial abnormalities are still to be clarified.MethodsSeventeen patients with genetically proven late-onset Pompe disease (50 ± 18 years, 11 male) and 18 age- and gender-matched healthy controls (44 ± 10 year, 12 male) underwent comprehensive cardiovascular magnetic resonance (CMR) including conventional and advanced techniques: cine and feature tracking-based strain imaging for depiction of (even subtle) systolic LV dysfunction as well as late gadolinium enhancement (LGE) and myocardial extracellular volume fraction (ECV) quantification for focal and diffuse fibrosis detection.ResultsAll patients had normal left ventricular (LV) and right ventricular (RV) volumes and normal LV and RV ejection fraction. In comparison to healthy controls, neither conventional cine nor advanced feature-tracking based-strain imaging could depict any (subclinical) myocardial systolic dysfunction. Three (18%) of the patients had non-ischemic LGE in the basal inferolateral wall and 21% demonstrated elevated global ECV values suggestive of interstitial myocardial fibrosis. Non-specific abnormalities such as left atrial (LA) dilatation were present in two patients, while LV hypertrophy was seen only in one. Two of the three LGE-positive patients were also hypertensive and demonstrated high global ECV values (>30%) in addition to dilated LA. After a median follow-up of 25 (11–29) months, only one cardiovascular event occurred: one of the LGE-positive patients with a high cardiovascular risk profile suffered an acute coronary syndrome.ConclusionIn contrast to the early infantile-onset form of Pompe disease, mild and rather non-specific cardiac abnormalities can be detected by CMR only in a small proportion of patients with late-onset Pompe disease. The observed structural abnormalities seem to result from an interplay between the storage disease and other comorbidities and they did not affect short-term to mid-term prognosis in adult Pompe patients.

Safety and efficacy of exercise training in adults with Pompe disease: evalution of endurance, muscle strength and core stability before and after a 12 week training program.

BackgroundPompe disease is a proximal myopathy. We investigated whether exercise training is a safe and useful adjuvant therapy for adult Pompe patients, receiving enzyme replacement therapy.MethodsTraining comprised 36 sessions of standardized aerobic, resistance and core stability exercises over 12 weeks. Before and after, the primary outcome measures safety, endurance (aerobic exercise capacity and distance walked on the 6 min walk test) and muscle strength, and secondary outcome measures core stability, muscle function and body composition, were evaluated.ResultsOf 25 patients enrolled, 23 successfully completed the training. Improvements in endurance were shown by increases in maximum workload capacity (110 W before to 122 W after training, [95 % CI of the difference 6 · 0 to 19 · 7]), maximal oxygen uptake capacity (69 · 4 % and 75 · 9 % of normal, [2 · 5 to 10 · 4]), and maximum walking distance (6 min walk test: 492 meters and 508, [−4 · 4 to 27 · 7] ). There were increases in muscle strength of the hip flexors (156 · 4 N to 180 · 7 N [1 · 6 to 13 · 6) and shoulder abductors (143 · 1 N to 150 · 7 N [13 · 2 to 35 · 2]). As an important finding in secondary outcome measures the number of patients who were able to perform the core stability exercises rose, as did the core stability balancing time (p < 0.05, for all four exercises). Functional tests showed small reductions in the time needed to climb four steps (2 · 4 sec to 2 · 1, [− 0 · 54 to −0 · 04 ]) and rise to standing position (5 · 8 sec to 4 · 8, [−2 · 0 to 0 · 0]), while time to run, the quick motor function test results and body composition remained unchanged.ConclusionsOur study shows that a combination of aerobic, strength and core stability exercises is feasible, safe and beneficial to adults with Pompe disease.

Homozygosity for the common GAA gene splice site mutation c.-32-13T>G in Pompe disease is associated with the classical adult phenotypical spectrum

Homozygosity for the common Caucasian splice site mutation c.-32-13T>G in intron 1 of the GAA gene is rather rare in Pompe patients. We report on the clinical, biochemical, morphological, muscle imaging, and genetic findings of six adult Pompe patients from five unrelated families with the c.-32-13T>G GAA gene mutation in homozygous state. All patients had decreased GAA activity and elevated creatine kinase levels. Five patients, aged between 43 and 61 years (median 53 years), initially presented with myalgia, hyperCKaemia, and/or exercise induced fatigue at an age of onset (12–55 years). All but one had proximal lower limb weakness combined with axial weakness and moderate respiratory insufficiency; the sixth patient presented with hyperCKaemia only. Muscle biopsies showed PAS-positive vacuolar myopathy with lysosomal changes and reduced GAA activity. Muscle MRI of lower limb muscles revealed a moderate adipose substitution of the gluteal muscles, biceps femoris and slight fatty infiltration of all thigh muscles. One MRI of the respiratory muscles revealed a diaphragmatic atrophy with unilateral diaphragm elevation. So, the common Caucasian, so called mild, splice site mutation c.-32-13T>G in intron 1 of the GAA gene in a homozygote status reflects the full adult Pompe disease phenotype severity spectrum.

Lung MRI and impairment of diaphragmatic function in Pompe disease.

BackgroundPompe 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.MethodsIn 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).ResultsWe 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).ConclusionsMRI 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12890-015-0058-3) contains supplementary material, which is available to authorized users.

Skeletal muscle quantitative nuclear magnetic resonance imaging follow-up of adult Pompe patients.

Adult late-onset Pompe disease is most often a slowly progressive limb-girdle and spine extensor muscle dystrophy, due to defective lysosomal acid maltase. With the exception of the few patients who present with a dramatically accelerated clinical course, standard diagnostic imaging fail to detect and evaluate disease progression between two successive visits. In muscle dystrophy of very rapid evolution, like the Duchenne disease, quantitative NMR imaging has successfully demonstrated its capacity to objectivate both disease activity and degenerative changes progression over short follow-up periods. The purpose of this retrospective monocentric open-label study was to investigate whether quantitative NMR imaging can monitor disease progression in adult Pompe patients despite its very slow nature. Quantitative imaging of Pompe patients succeeded in demonstrating that muscle fatty infiltration increased on average by 0.9 %/year, with the hamstring and adductor muscles showing the fastest degradation. Muscle water T2 mapping revealed that 32 % of all muscles had abnormally high T2 in at least one of two successive examinations. When muscle water T2 was abnormal, fatty degenerative changes were further increased by 0.61 %/year. Enzyme replacement therapy resulted in 0.68 %/year slowdown of the muscle fatty infiltration, in both muscles with normal and high T2s.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-015-9825-9) contains supplementary material, which is available to authorized users.