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Multisystem late onset Pompe disease (LOPD): an update on clinical aspects.

ABSTRACT: Pompe disease is classified by age of onset, organ involvement, severity, and rate of progression in two main forms: the first one, infantile onset Pompe disease (IOPD), presents before the age of 12 months with generalized muscle weakness, hypotonia, respiratory distress, and hypertrophic cardiomyopathy as main clinical features. The second form, late onset Pompe disease (LOPD), is characterized by an onset at the age of 12 months to adulthood, hyperCKemia, and limb-girdle and axial muscle weakness, often complicated by respiratory muscles degeneration. In the last 10-15 years, an increasing interest in Pompe disease has led to multiple studies in an effort to clarify the emerging clinical aspects, to find out the best diagnostic tools to identify the disease as early as possible, and to offer new therapeutic options apart from enzyme replacement therapy (ERT). Since 2006, ERT-the first treatment for Pompe disease-has been universally accepted in the majority of countries all over the world. Although for years Pompe disease has been primarily considered a muscle disorder, nowadays it is clear that the involvement of several other organs has changed the cultural approach to this entity which is now viewed as a multisystem disorder. The emerging clinical aspects have greatly expanded the spectrum of the disease manifestations. In fact, central, peripheral, and autonomous nervous systems are often involved; vascular malformations and heart involvement are frequently observed; musculoskeletal and bone changes as well as oro-gastrointestinal and urinary tract alterations have been better defined. A great deal of effort has been made to clarify the clinical aspects of Pompe disease, to raise awareness of the LOPD patients' problems and to improve their quality of life.

SUBMITTER: Toscano A

PROVIDER: S-EPMC6642938 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Multisystem late onset Pompe disease (LOPD): an update on clinical aspects.

Toscano Antonio A Rodolico Carmelo C Musumeci Olimpia O

Annals of translational medicine 20190701 13

Pompe disease is classified by age of onset, organ involvement, severity, and rate of progression in two main forms: the first one, infantile onset Pompe disease (IOPD), presents before the age of 12 months with generalized muscle weakness, hypotonia, respiratory distress, and hypertrophic cardiomyopathy as main clinical features. The second form, late onset Pompe disease (LOPD), is characterized by an onset at the age of 12 months to adulthood, hyperCKemia, and limb-girdle and axial muscle weak ...[more]

PMID: 31392196

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Project description:Pompe disease/glycogen storage disease type II, is a rare, lysosomal storage disorder associated with progressive proximal myopathy, causing a gradual loss of muscular function and respiratory insufficiency. Studies of patients with late-onset Pompe disease have used endpoints such as the 6-minute walking test (6MWT) and forced vital capacity (FVC) to assess muscular and respiratory function during disease progression or treatment. However, the relevance of these markers to late-onset Pompe disease and the minimal clinically important difference (MCID) for these endpoints in late-onset Pompe disease have not yet been established. A literature search was carried out to identify studies reporting the MCID (absolute and relative) for the 6MWT and FVC in other diseases. The MCIDs determined in studies of chronic respiratory diseases were used to analyze the results of clinical studies of enzyme replacement therapy in late-onset Pompe disease. In 9 of the 10 late-onset Pompe disease studies reviewed, changes from baseline in the 6MWT were above or within the MCID established in respiratory diseases. Clinical improvement was perceived by patients in 6 of the 10 studies. In 6 of the 9 late-onset Pompe disease studies that reported FVC, the changes from baseline in percentage predicted FVC were above or within the MCID established in respiratory diseases and the difference was perceived as either an improvement or stabilization by patients. However, applying the 6MWT and FVC MCIDs from studies of chronic respiratory diseases to late-onset Pompe disease has several important limitations. Outcome measures in muscular dystrophies include composite measures of muscle function and gait, as well as Rasch-designed and validated tools to assess disease-related quality of life and activities of daily living. Given that the relevance to patients with late-onset Pompe disease of the 6MWT or FVC MCIDs established for chronic respiratory diseases is unclear, these measures should be evaluated specifically in late-onset Pompe disease and alternative outcome measures more specific to neuromuscular disease considered.

Project description:BackgroundPompe disease is a lysosomal storage disorder caused by the deficiency of enzyme acid alpha-glucosidase (GAA) which results in accumulation of glycogen, particularly in the skeletal, cardiac, and smooth muscles. The late-onset form with symptoms presenting in childhood through adulthood, is characterized by proximal muscle weakness, respiratory insufficiency, and unlike the infantile-onset form often with no cardiac involvement.MethodsWe report our experience with 18 adult patients (14 males/4 females) with Pompe disease, several of whom had unique findings and novel pathogenic variants. Patients ranged in ages from 22-74 years (mean 53.7 years) and were diagnosed at an age range of 11-65 years (mean 43.6 years), often after a history of progressive muscle disease of several years' duration. All 18 patients were treated with alglucosidase alfa (Lumizyme) and their response to treatment was monitored by measurements of their pulmonary function and muscle weakness, six-minute walk test (6MWT), and other functional studies.ResultsGenetic sequencing revealed that 16 out of 18 individuals had the common c.-32-13T>G splicing variant, and six patients, including two sibships had four novel pathogenic variants: c.1594G>A, c.2655_2656delCG, c.1951-1952delGGinsT, and c.1134C>G. A male with the c.1594G>A variant developed an intracerebral aneurysm at the age of 43 years treated with surgery. Two siblings with the c.2655_2656delCG developed very high antibody titers, one of whom developed a severe infusion reaction. Other clinical features included BiPAP requirement in twelve, tinnitus in seven, scoliosis in five, cardiomyopathy in three, one individual was diagnosed with a cerebral aneurysm who underwent successful Penumbra coil placement, and another individual was diagnosed with both Graves' disease and testicular cancer.ConclusionsOur study illustrates significant variability in the range of clinical features, and the variable clinical response to enzyme replacement therapy. It also alerts us to the importance of careful monitoring and early management of complications. Possible genotype-phenotype associations with the novel mutations identified may emerge with larger studies.

Project description:BackgroundThe late-onset form of Pompe disease (LOPD) is characterized by muscle weakness, locomotor limitations and a risk of falls. The mechanisms responsible for altered locomotion in adults with LOPD are unknown. The identification of clinical biomarkers is essential for clinical follow-up and research.ObjectivesTo identify muscle determinants of impaired locomotor performance, gait stability and gait pattern, and biomechanical determinants of falls in adults with LOPD.MethodsIn this cross-sectional, case-control study, LOPD and control participants underwent 3D gait analysis, locomotor performance tests and muscle strength measurements (isokinetic dynamometer). We explored the muscular determinants of locomotor performance (gait speed, 6-minute walk test distance and timed up and go test), gait stability (spatiotemporal gait variables) and the gait pattern. We also explored biomechanical gait determinants of falls. After intergroup comparisons, determinants were sought to use forward stepwise multiple regression.ResultsEighteen participants with LOPD and 20 control participants were included. Locomotor performance, gait stability, and the gait pattern were significantly altered in LOPD compared to control participants. Hip abductor strength was the main common determinant of locomotor performance, gait stability and pelvic instability. Hip flexor strength was the main determinant of abnormal gait kinematics at the hip and knee. Percentage duration of single support phase during the gait cycle was the main determinant of falls.ConclusionsHip abductor strength and percentage duration of single support during gait were the major determinants of locomotor performance, gait stability, falls and the gait pattern in LOPD. These new clinical biomarkers should therefore be systematically assessed using instrumented tools to improve the follow-up of adults with LOPD. They should also be considered in future studies to accurately assess the effects of new therapies. Hip abductor strength and single support phase should also be priority targets for rehabilitation.

Dataset Information

Multisystem late onset Pompe disease (LOPD): an update on clinical aspects.

Publications

Multisystem late onset Pompe disease (LOPD): an update on clinical aspects.

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