Quantitative muscle MRI to follow up late onset Pompe patients: a prospective study.
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SUBMITTER: Figueroa-Bonaparte S
PROVIDER: S-EPMC6052002 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
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Quantitative muscle MRI to follow up late onset Pompe patients: a prospective study.
Figueroa-Bonaparte Sebastian S Llauger Jaume J Segovia Sonia S Belmonte Izaskun I Pedrosa Irene I Montiel Elena E Montesinos Paula P Sánchez-González Javier J Alonso-Jiménez Alicia A Gallardo Eduard E Illa Isabel I Díaz-Manera Jordi J
Scientific reports 20180718 1
Late onset Pompe disease (LOPD) is a slow, progressive disorder characterized by skeletal and respiratory muscle weakness. Enzyme replacement therapy (ERT) slows down the progression of muscle symptoms. Reliable biomarkers are needed to follow up ERT-treated and asymptomatic LOPD patients in clinical practice. In this study, 32 LOPD patients (22 symptomatic and 10 asymptomatic) underwent muscle MRI using 3-point Dixon and were evaluated at the time of the MRI with several motor function tests an ...[more]
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Project description: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.
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Project description:BackgroundLate-onset Pompe disease (LOPD) is a genetic disorder characterized by progressive degeneration of the skeletal muscles produced by a deficiency of the enzyme acid alpha-glucosidase. Enzymatic replacement therapy with recombinant human alpha-glucosidase seems to reduce the progression of the disease; although at the moment, it is not completely clear to what extent. Quantitative muscle magnetic resonance imaging (qMRI) is a good biomarker for the follow-up of fat replacement in neuromuscular disorders. The aim of this study was to describe the changes observed in fat replacement in skeletal muscles using qMRI in a cohort of LOPD patients followed prospectively.MethodsA total of 36 LOPD patients were seen once every year for 4 years. qMRI, several muscle function tests, spirometry, activities of daily living scales, and quality-of-life scales were performed on each visit. Muscle MRI consisted of two-point Dixon studies of the trunk and thigh muscles. Computer analysis of the images provided the percentage of muscle degenerated and replaced by fat in every muscle (known as fat fraction). Longitudinal analysis of the measures was performed using linear mixed models applying the Greenhouse-Geisser test.ResultsWe detected a statistically significant and continuous increase in mean thigh fat fraction both in treated (+5.8% in 3 years) and in pre-symptomatic patients (+2.6% in 3years) (Greenhouse-Geisser p < 0.05). As an average, fat fraction increased by 1.9% per year in treated patients, compared with 0.8% in pre-symptomatic patients. Fat fraction significantly increased in every muscle of the thighs. We observed a significant correlation between changes observed in fat fraction in qMRI and changes observed in the results of the muscle function tests performed. Moreover, we identified that muscle performance and mean thigh fat fraction at baseline visit were independent parameters influencing fat fraction progression over 4 years (analysis of covariance, p < 0.05).ConclusionsOur study identifies that skeletal muscle fat fraction continues to increase in patients with LOPD despite the treatment with enzymatic replacement therapy. These results suggest that the process of muscle degeneration is not stopped by the treatment and could impact muscle function over the years. Hereby, we show that fat fraction along with muscle function tests can be considered a good outcome measures for clinical trials in LOPD patients.
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Project description:Late-onset Rasmussen encephalitis (LoRE) is a rare unihemispheric progressive inflammatory disorder causing neurological deficits and epilepsy. The long-term radiological evolution has never been fully described. We retrospectively analyzed the MR images of 13 LoRE patients from a total of 136 studies, and searched for focal areas of volume loss or signal intensity abnormality in grey matter or white matter. Each subject had a median of nine MRI studies (IQR 7-13). Frontal and temporal lobes were the most affected regions (13/13 and 8/13, respectively) and showed the greatest worsening over time in terms of atrophic changes (9/13 and 5/8, respectively). A milder cortical atrophy was found in the insular and parietal lobes. The caudate nucleus was affected in seven patients. Hyperintensities of grey matter and white matter on T2-WI and FLAIR images were observed in all patients, and transiently in eight patients. In two cases out of the latter patients, these transient alterations evolved into atrophy of the same region. Disease duration was significantly associated with signal abnormalities in the grey matter at last follow-up. LoRE MRI alterations are milder, and their progression is markedly slower compared to radiological findings described in the childhood form.
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Project description:Background: Late-onset Pompe disease (LOPD) is an autosomal-recessive metabolic myopathy caused by deficiency of the lysosomal enzyme Acid Alpha-Glucosidase (GAA), leading to glycogen accumulation in proximal and axial muscles, and in the diaphragm. Enzyme Replacement Therapy (ERT) with recombinant GAA became available in 2006. Since then, several outcome measures have been investigated for the adequate follow-up of disease progression and treatment response, usually focusing on respiratory and motor function. Prognostic factors predicting outcome have not been identified till now. Methods: In this single Centre, prospective study, we evaluate the response to enzyme replacement therapy in 15 patients (7 males) with LOPD in different stages of disease, aged 49.4 ± 16.1, followed-up for 15 years. Treatment response was measured by the 6-min walking test, vital capacity in supine and upright position, respiratory muscle strength, muscle MRI, manual muscle testing. We investigated the usefulness of Body Impedance Vectorial Analysis for serial body composition assessment. Results: Although most patients with LOPD benefit from long-term treatment, some secondary decline may occur after the first 3-5 years. Some nutritional (lower body mass index, higher fat free mass, higher phase angle) and disease parameters (higher creatinine and shorter disease duration at the beginning of treatment) seem to predict a better motor outcome. Lower Phase Angle, possibly reflecting loss of integrity of skeletal muscle membranes and thus treatment mis-targeting, seems to correlate with worse treatment response on long-term follow-up. Conclusion: Body Impedance Vectorial Analysis is a fast, easily performed and cheap tool that may be able to predict long-term treatment response in patients with LOPD. Low Phase angle may serve as a marker of muscle quality and may be used to predict the response to a muscle-targeted intervention such as ERT, thus improving the identification of patients needing a closer follow-up due to higher fragility and risk of deterioration.
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Project description:Oro-pharyngeal dysphagia commonly occurs in patients with infantile onset Pompe disease (IOPD), which is a rare recessive neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase. Without treatment, death occurs by 1 year of age from cardiorespiratory failure. Enzyme replacement therapy (ERT) has been used to increase life expectancy, however emerging developmental and medical morbidities have become apparent. A case file review of the feeding outcomes of 12 patients with IOPD, managed at a single tertiary centre, was undertaken. Two types of assessment had been completed: clinical feeding assessment (CFA) and instrumental videofluoroscopy swallow study (VFSS). A rating of functional oral intake at every Speech and Language Therapy feeding assessment from initial diagnosis to the most recent assessment was applied using the functional oral intake scale (FOIS).Results indicate, initial diagnosis VFSS predicts long-term feeding outcomes. Even if a patient had an improvement in oral feeding after diagnosis, over a period of time their oral intake returned to the initial diagnosis VFSS level or below. All patients (8/8) who required non-oral feeding support under 6 months of age went on to require non-oral feeding support, even if they had periods of full oral feeding. CRIM negative status predicted significant oral feeding difficulties. An evidence-based follow-up protocol was developed. The information is used at diagnosis to counsel families regarding feeding prognosis and consideration of early gastrostomy when cardiac status allows safe anaesthesia. The results reinforce that feeding changes over time and patients require on-going dysphagia monitoring.
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Project description:ObjectivesEnzyme replacement therapy has shown to be effective for childhood/adult onset Pompe disease (AOPD). The discovery of biomarkers useful for monitoring disease progression is one of the priority research topics in Pompe disease. Muscle MRI could be one possible test but the correlation between muscle MRI and muscle strength and function has been only partially addressed so far.MethodsWe studied 34 AOPD patients using functional scales (Manual Research Council scale, hand held myometry, 6 minutes walking test, timed to up and go test, time to climb up and down 4 steps, time to walk 10 meters and Motor Function Measure 20 Scale), respiratory tests (Forced Vital Capacity seated and lying, Maximun Inspiratory Pressure and Maximum Expiratory Pressure), daily live activities scales (Activlim) and quality of life scales (Short Form-36 and Individualized Neuromuscular Quality of Life questionnaire). We performed a whole body muscle MRI using T1w and 3-point Dixon imaging centered on thighs and lower trunk region.ResultsT1w whole body muscle MRI showed a homogeneous pattern of muscle involvement that could also be found in pre-symptomatic individuals. We found a strong correlation between muscle strength, muscle functional scales and the degree of muscle fatty replacement in muscle MRI analyzed using T1w and 3-point Dixon imaging studies. Moreover, muscle MRI detected mild degree of fatty replacement in paraspinal muscles in pre-symptomatic patients.ConclusionBased on our findings, we consider that muscle MRI correlates with muscle function in patients with AOPD and could be useful for diagnosis and follow-up in pre-symptomatic and symptomatic patients under treatment.Take home messageMuscle MRI correlates with muscle function in patients with AOPD and could be useful to follow-up patients in daily clinic.
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Project description:BackgroundIn 2011 a 12 weeks personalized exercise training program in 23 mildly affected adult late onset Pompe patients (age 19.6-70.5 years) improved endurance, muscle strength and function. Data on long-term effects of this program or of other physical activity in Pompe disease are absent. This retrospective cohort study aimed to explore effects of long-term healthy physical activity according to the WHO norm and the former exercise training program on the disease course.ResultsA total of 29 adult late onset Pompe patients were included: 19 former exercise training program participants and 10 comparable control patients. Patients, who based on interviews, met the 2010 WHO healthy physical activity norm (active, n = 16) performed better on endurance (maximal cardiopulmonary exercise test), muscle strength and function compared to patients not meeting this norm (inactive, n = 13) (p < 0.05). Majority of the outcomes, including endurance and manually tested muscle strength, tended to be higher in the active patients of the 2011 training cohort who continued the program compared to active control patients (p > 0.05).ConclusionIn Pompe disease long-term healthy physical activity according to the 2010 WHO norm leads to physical benefits and a personalized exercise training program may have additional favorable effects and both should be recommended as standard of care.
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Project description:ObjectiveThe objective of this study was to evaluate a quantitative method based on conventional T1-weighted magnetic resonance (MR) imaging to assess fatty muscular degeneration in patients with late-onset Pompe disease and to compare it with semi-quantitative visual evaluation (the Mercuri score). In addition, a long-term retrospective data analysis was performed to evaluate treatment response to enzyme replacement therapy with alglucosidase alfa.MethodsMR images of the lumbar spine were acquired in 41 patients diagnosed with late-onset Pompe disease from 2006 through 2015. Two independent readers retrospectively evaluated fatty degeneration of the psoas and paraspinal muscles by applying the Mercuri score. Quantitative semi-automated muscle and fat tissue separation was performed, and inter-observer agreement and correlations with clinical parameters were assessed. Follow-up examinations were performed in 13 patients treated with alglucosidase alfa after a median of 39 months; in 7/13 patients, an additional follow-up examination was completed after a median of 63 months.ResultsInter-observer agreement was high. Measurements derived from the quantitative method correlated well with Medical Research Council scores of muscle strength, with moderate correlations found for the 6-minute walk test, the 4-step stair climb test, and spirometry in the supine position. A significant increase in the MR-derived fat fraction of the psoas muscle was found between baseline and follow-up 1 (P = 0.016), as was a significant decrease in the performance on the 6-minute walk test (P = 0.006) and 4-step stair climb test (P = 0.034), as well as plasma creatine kinase (P = 0.016). No statistically significant difference in clinical or MR-derived parameters was found between follow-up 1 and follow-up 2.ConclusionsQuantification of fatty muscle degeneration using the semi-automated method can provide a more detailed overview of disease progression than semi-quantitative Mercuri scoring. MR-derived data correlated with clinical symptoms and patient exercise capacity. After an initial worsening, the fat fraction of the psoas muscle and performance on the 6-minute walk test stayed constant during long-term follow-up under enzyme replacement therapy.
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Project description:Late-onset Pompe disease (LOPD) is a rare treatable lysosomal storage disorder characterized by progressive lysosomal glycogen accumulation and muscle weakness, with often a limb-girdle pattern. Despite published guidelines, testing for LOPD is often overlooked or delayed in adults, owing to its low frequency compared to other muscle disorders with similar muscle patterns. Next-generation sequencing has the capability to test concurrently for several muscle disorders. This could potentially lead to increased diagnosis of LOPD, disorders with non-specific muscle weakness or atypical patients.We developed a gene panel to further study its clinical utility in a cohort of patients with suspected muscle disorders. We designed a gene panel to analyze the coding sequences and splice site junctions of GAA causing LOPD, along with 77 other genes causing muscle disorders with overlapping phenotypes.At a median coverage of ~200X (sequences per base), all GAA exons were successfully covered with >20X and only 0.3 % of exons across all genes were <20X. The panel showed an excellent sensitivity (100 %) and specificity (98 %) across all selected genes, using known variations in Pompe patients and controls. We determined its clinical utility by analyzing 34 patients with suspected muscle disorders of undetermined etiology and various muscle patterns, who were referred or followed in neuromuscular and genetics clinics. A putative diagnosis was found in up to 32 % of patients. The gene panel was instrumental in reaching a diagnosis in atypical patients, including one LOPD case. Acid alpha-glucosidase activity was used to confirm the molecular results in all patients.This work highlights the high clinical utility of gene panels in patients with suspected muscle disorders and its potential to facilitate the diagnosis of patients showing non-specific muscle weakness or atypical phenotypes. We propose that gene panels should be used as a first-tier test in patients with suspected muscle disorders of undetermined etiology, which could further increase overall diagnosis of muscle conditions, and potentially reduce diagnostic delay. Further studies are necessary to determine the impact of first-tier gene panels on diagnostic delay and on treatment outcome for LOPD.
| S-EPMC4727295 | biostudies-literature
Project description:Mutations in the acidic alpha-glucosidase (GAA) coding gene cause Pompe disease. Late-onset Pompe disease (LOPD) is characterized by progressive proximal and axial muscle weakness and atrophy, causing respiratory failure. Enzyme replacement therapy (ERT), based on recombinant human GAA infusions, is the only available treatment; however, the efficacy of ERT is variable. Here we address the question whether proteins at variance in LOPD muscle of patients before and after 1 year of ERT, compared withhealthy age-matched subjects (CTR), reveal a specific signature. Proteins extracted from skeletal muscle of LOPD patients and CTR were analyzed by combining gel based (two-dimensional difference gel electrophoresis) and label-free (liquid chromatography-mass spectrometry) proteomic approaches, and ingenuity pathway analysis. Upstream regulators targeting autophagy and lysosomal tethering were assessed by immunoblotting. 178 proteins were changed in abundance in LOPD patients, 47 of them recovered normal level after ERT. Defects in oxidative metabolism, muscle contractile protein regulation, cytoskeletal rearrangement, and membrane reorganization persisted. Metabolic changes, ER stress and UPR (unfolded protein response) contribute to muscle proteostasis dysregulation with active membrane remodeling (high levels of LC3BII/LC3BI) and accumulation of p62, suggesting imbalance in the autophagic process. Active lysosome biogenesis characterizes both LOPD PRE and POST, unparalleled by molecules involved in lysosome tethering (VAMP8, SNAP29, STX17, and GORASP2) and BNIP3. In conclusion this study reveals a specific signature that suggests ERT prolongation and molecular targets to ameliorate patient's outcome.
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