Long-term follow-up of 17 patients with childhood Pompe disease treated with enzyme replacement therapy.
Ontology highlight
ABSTRACT:
SUBMITTER: van der Meijden JC
PROVIDER: S-EPMC6326992 | biostudies-literature | 2018 Nov
REPOSITORIES: biostudies-literature
Publications
Long-term follow-up of 17 patients with childhood Pompe disease treated with enzyme replacement therapy.
van der Meijden Jan C JC Kruijshaar Michelle E ME Harlaar Laurike L Rizopoulos Dimitris D van der Beek Nadine A M E NAME van der Ploeg Ans T AT
Journal of inherited metabolic disease 20180319 6
<h4>Objectives</h4>Pompe disease is a progressive metabolic myopathy for which enzyme replacement therapy (ERT) was approved in 2006. While various publications have examined the effects of ERT in classic-infantile patients and in adults, little has been published on ERT in children with non-classic presentations.<h4>Study design</h4>This prospective study was conducted from June 1999 to May 2015. Seventeen patients from various countries participated. Outcome measures comprised muscle function ...[more]
Similar Datasets
Project description:BACKGROUND:Enzyme replacement therapy (ERT) has deeply modified the clinical history of Infantile Onset Pompe Disease (IOPD). However, its long-term effectiveness is still not completely defined. Available data shows a close relationship between clinical outcome and patients' cross-reactive immunological status (CRIM), being CRIM-negative status a negative prognostic factor. At the same time limited data are available on the long-term treatment in CRIM-positive infants. METHODS:A retrospective multicentre observational study was designed to analyse the long-term effectiveness of ERT in IOPD. Thirteen Italian centres spread throughout the country were involved and a cohort of 28 patients (15 females, 13 males, born in the period: February 2002-January 2013) was enrolled. IOPD diagnosis was based on clinical symptoms, enzymatic and molecular analysis. All patients received ERT within the first year of life. Clinical, laboratory, and functional data (motor, cardiac and respiratory) were collected and followed for a median period of 71 months (5 years 11 months). RESULTS:Median age at onset, diagnosis and start of ERT were 2, 3 and 4 months, respectively. CRIM status was available for 24/28 patients: 17/24 (71%) were CRIM-positive. Nineteen patients (67%) survived > 2 years: 4 were CRIM-negative, 14 CRIM-positive and one unknown. Six patients (5 CRIM-positive and one unknown) never needed ventilation support (21,4%) and seven (6 CRIM-positive and one unknown: 25%) developed independent ambulation although one subsequently lost this function. Brain imaging study was performed in 6 patients and showed peri-ventricular white matter abnormalities in all of them. Clinical follow-up confirmed the better prognosis for CRIM-positive patients, though a slow, progressive worsening of motor and/or respiratory functions was detected in 8 patients. CONCLUSIONS:These data are the result of the longest independent retrospective study on ERT in IOPD reported so far outside clinical trials. The data obtained confirmed the better outcome of the CRIM-positive patients but at the same time, showed the inability of the current therapeutic approach to reverse or stabilize the disease progression. The results also evidenced the involvement of central nervous system in Pompe disease. To better understand the disease clinical history and to improve treatment efficacy larger multicentre studies are needed as well as the development of new therapeutic approaches.
| S-EPMC5806382 | biostudies-literature
Project description:This study aimed to evaluate audiological and vestibular involvement in Fabry disease and the effects of enzyme replacement therapy with human alpha-galactosidase A. The study population comprised 20 patients (11 males, 9 females) aged 15-69 years (mean 39.7). Patients underwent a complete clinical and instrumental evaluation before starting and during enzyme replacement therapy. Median follow-up was 51.5 months (range 25-73). Nine patients (45%) complained of hearing symptoms (hearing loss, tinnitus); for six of them the onset and/or progression of the hearing loss were sudden. Vertigo or dizziness was reported by 6 patients (30%). Audiological evaluation showed a sensorineural hearing loss in 18 ears (45%; 10 in male patients, 8 in females). The hearing thresholds for 0.5, 1, 2 and 4 kHz frequencies ranged from 10 to 65 dB HL. Hearing loss was unilateral in 8 cases (40%; 4 in male patients, 4 in females). Also high frequency hearing loss for 4 and 8 kHz was evaluated. No signs of retro-cochlear lesions were observed by means of otoacoustic emissions and auditory brainstem response. Vestibular examinations showed a functional impairment in 7 ears (17.5%, all male patients). During enzyme replacement therapy the auditory function showed some degrees of worsening but no significant changes were observed at statistical analysis. In conclusion involvement of the inner ear is common in men and women with Fabry disease. In this study, a high incidence of cochlear hearing loss was found, which was typically unilateral and showed onset and/or progression by sudden episodes. Vascular or hydropic mechanisms could be hypothesized to explain audiological findings. Vestibular involvement showed a lower incidence and different pattern, thus suggesting that several patho-physiological mechanisms could play a role in determining inner ear damage in Fabry disease. Results obtained show that enzyme replacement therapy may stabilize hearing function; however, further studies on the physiopathology of the inner ear damage are needed.
| S-EPMC2882147 | biostudies-literature
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.
| S-EPMC5760036 | biostudies-literature
Project description:BackgroundTranscatheter aortic valve replacement (TAVR) has become the standard of care in the majority of patients with symptomatic severe aortic stenosis. Data on long-term mortality and durability of transcatheter heart valves (THVs) beyond 5 years are limited. Our study aimed to assess elderly and high-risk patients' long-term outcomes treated with TAVR in a prospective single-centre registry focusing on the durability of THVs.MethodsWe included 795 patients with severe calcific aortic stenosis treated by transfemoral TAVR between 2006 and 2011. Echocardiography was performed at baseline; discharge; 1 year; and afterward, annually, until the longest available follow-up. Mortality rates were estimated for 1, 5, 6, 7, and 8 years. The rates of structural valve deterioration (SVD) and bioprosthetic valve failure (BVF) were assessed in accordance with consensus definitions. Outcome measures were adjudicated according to Valve Academic Research Consortium-2 (VARC-2).ResultsMedian (interquartile range) follow-up time was 1345 (316; 2015) days. One-year, 5-year, 6-year, 7-year, and 8-year overall mortality was 25.4%, 59.0%, 64.6%, 67.9%, and 69.2%, respectively. At 8 years, no significant differences in mortality were found comparing self-expanding vs balloon-expandable valves (69.5% vs 68.0%, P = 0.709) and postdilatation (PD) vs no-PD (69.4% vs 69.2%, P = 0.363). SVD was detected in 26 patients (3.3%), and 19 (2.4%) of the 795 patients had evidence of BVF during follow-up.ConclusionsOur study demonstrates good long-term results for high-risk patients who were alive up to 8 years after TAVR.
| S-EPMC8347830 | biostudies-literature
Project description:BackgroundPompe disease is an autosomal recessive metabolic neuromuscular disorder caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). It has long been believed that the underlying pathology leading to tissue damage is caused by the enlargement and rupture of glycogen-filled lysosomes. Recent studies have also implicated autophagy, an intracellular lysosome-dependent degradation system, in the disease pathogenesis. In this study, we characterize the long-term impact of enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) on lysosomal glycogen accumulation and autophagy in some of the oldest survivors with classic infantile Pompe disease (IPD).MethodsMuscle biopsies from 8 [4 female, 4 male; 6 cross-reactive immunologic material (CRIM)-positive, 2 CRIM-negative] patients with a confirmed diagnosis of classic IPD were examined using standard histopathological approaches. In addition, muscle biopsies were evaluated by immunostaining for lysosomal marker (lysosomal-associated membrane protein-2; LAMP2), autophagosomal marker (microtubule-associated protein 1 light chain 3; LC3), and acid and alkaline ATPases. All patients received rhGAA by infusion at cumulative biweekly doses of 20-40 mg/kg.ResultsMedian age at diagnosis of classic IPD was 3.4 months (range: 0 to 6.5 months; n = 8). At the time of muscle biopsy, the patients' ages ranged from 1 to 103 months and ERT duration ranged from 0 (i.e., baseline, pre-ERT) to 96 months. The response to therapy varied considerably among the patients: some patients demonstrated motor gains while others experienced deterioration of motor function, either with or without a period of initial clinical benefit. Skeletal muscle pathology included fiber destruction, lysosomal vacuolation, and autophagic abnormalities (i.e., buildup), particularly in fibers with minimal lysosomal enlargement. Overall, the pathology reflected clinical status.ConclusionsThis is the first study to investigate the impact of rhGAA ERT on lysosomal glycogen accumulation and autophagic buildup in patients with classic IPD beyond 18 months of treatment. Our findings indicate that ERT does not fully halt or reverse the underlying skeletal muscle pathology in IPD. The best outcomes were observed in the two patients who began therapy early, namely at 0.5 and 1.1 months of age.
| S-EPMC3691834 | biostudies-literature
Project description:BackgroundWith improved childhood cancer cure rate, long term sequelae are becoming an important factor of quality of life. Signs of cardiovascular disease are frequently found in long term survivors of cancer. Cardiac damage may be related to irradiation and chemotherapy.We have evaluated simultaneous influence of a series of independent variables on the late cardiac damage in childhood cancer survivors in Slovenia and identified groups at the highest risk.Methods211 long-term survivors of different childhood cancers, at least five years after treatment were included in the study. The evaluation included history, physical examination, electrocardiograpy, exercise testing and echocardiograpy. For analysis of risk factors, beside univariate analysis, multivariate classification tree analysis statistical method was used.Results and conclusionPatients treated latest, from 1989-98 are at highest risk for any injury to the heart (73%). Among those treated earlier are at the highest risk those with Hodgkin's disease treated with irradiation above 30 Gy and those treated for sarcoma. Among specific forms of injury, patients treated with radiation to the heart area are at highest risk of injury to the valves. Patients treated with large doses of anthracyclines or concomitantly with anthracyclines and alkylating agents are at highest risk of systolic function defect and enlarged heart chambers. Those treated with anthracyclines are at highest risk of diastolic function defect. The time period of the patient's treatment is emerged as an important risk factor for injury of the heart.
| S-EPMC2430718 | biostudies-literature
Project description:BACKGROUND:It remains unclear to what extent the brain is affected by Maroteaux-Lamy syndrome (MPS VI), a progressive lysosomal storage disorder. While enzyme replacement therapy (ERT) elicits positive effects, the drug cannot cross the blood-brain barrier. We therefore studied cognitive development and brain abnormalities in the Dutch MPS VI patient population treated with ERT. METHODS:In a series of 11 children with MPS VI (age 2 to 20 years), we assessed cognitive functioning and brain magnetic resonance imaging prospectively at the start of ERT and at regular times thereafter up to 4.8 years. We also assessed the children's clinical characteristics, their siblings' cognitive development, and their parents' educational levels. RESULTS:The patients' intelligence scores ranged from normal to mentally delayed (range test scores 52-131). In 90%, their scores remained fairly stable during follow-up, generally lying in the same range as their siblings' test scores (median for patients?=?104, median for siblings?=?88) and comparing well with the parental educational levels. Native-speaking patients had higher intelligence test scores than non-native-speaking patients. Two patients, both with high baseline glycosaminoglycan levels in their urine and severe mutations in the arylsulfatase B gene, scored clearly lower than expected. Patients with pY210C performed best. Brain abnormalities were aspecific, occurring more in patients with severe symptoms. CONCLUSION:Our study shows that cognitive development in MPS VI patients is determined not only by familial and social-background factors, but, in patients with a severe form of the disease, also by the disease itself. Therefore in patients with severe disease presentation cognition should be monitored carefully.
| S-EPMC4754322 | biostudies-literature
Project description:BackgroundThe aim of this study was to examine the long-term effect of shortening after a midshaft clavicular fracture on strength deficiency in the shoulder.MethodThis study included 18 participants (14 males, 4 females) with a conservatively treated midshaft clavicular fracture. Mean age was 52.2 ± 13.8 years, range 32-76 years). The mean follow-up time was 13.5 ± 0.4 years. Participants filled in a QUICKDASH questionnaire and both clavicle lengths were measured using a caliper. The isometric strengths in internal rotation, external rotation and abduction of both arms were measured with a handheld dynamometer.ResultsAverage shortening of the clavicle in this group was 1.09 cm (SD 0.53). Nearly all strength measurements showed no significant difference between the shortened and the unaffected side. Multiple regression revealed a small (3N per mm length difference) but statistically significant relationship on external rotation between the relative extent of shortening of the clavicle, dominant side of the fracture and the isometric force difference between the unaffected and affected arm, F(2,15) = 5.746, p < .05, adj. R2 = .358. Over 14 years there was a reduction in mean DASH-score of 4.4 (8.8 ± 12.3; current DASH = 4.4 ± 7.7)In this group, long term effects of clavicular shortening were small. Based on these results we conclude that on the long term clavicular shortening will not result in significant strength loss.
| S-EPMC7068017 | biostudies-literature
Project description:BackgroundEnzyme replacement therapy (ERT; alglucosidase alfa) has improved the prospects for patients with classic infantile Pompe disease considerably. However, over time we noticed that many of these children exhibit distal muscle weakness at an early age, which is in contrast to the primarily proximal and axial muscle weakness in patients with late-onset Pompe disease. This was reason to study the prevalence and severity of distal muscle weakness, and the sequence of muscle involvement over time in patients that had learned to walk under ERT.MethodsIn this prospective, single-center cohort study, we studied 16 classic infantile patients. We used video recordings that were made during regular standardized assessments to investigate distal muscle function (active dorsiflexion of the feet during walking; ability to use a pincer grasp/actively extend the fingers) and proximal muscle function (standing up from a supine position; raising the arms above the head).ResultsMedian age at start of ERT was 3.2 months (0.1-5.8 months), median age at study end was 5.6 years (2.9-18.2 years). Six patients (6/16, 38%) initially had no evident signs of distal muscle weakness and developed a gait with active dorsiflexion of the feet. The other 10 patients never exhibited active dorsiflexion of the feet during walking. At study-end two patients showed no loss of distal muscle function. A subset of five patients (5/16, 31%) developed also weakness of the hands, particularly of the extensors of the 3rd and 4th digit.ConclusionsWe found that the majority (14/16, 88%) of patients who had learned to walk exhibited distal muscle weakness of the lower extremities, while a subset (5/16, 31%) also developed weakness of the hands. The distal muscle weakness was often more serious than, and preceded the development of, the proximal muscle weakness.
| S-EPMC7488760 | biostudies-literature
Project description:ObjectivesTo explore whether a conceptual model of patient satisfaction previously developed 1-2 years post-total knee replacement (TKR) is still relevant 3-4 years post-TKR. Specifically, (i) what is the stability in satisfaction levels 3-4 years post-TKR? and (ii) does the existing conceptual model of patient satisfaction after TKR apply at this later follow-up?DesignA constructivist grounded theory qualitative follow-up study. The present study was theoretically governed by the findings of the initial qualitative inquiry. One-on-one semi-structured interviews were used to test the assumptions of the model developed from the findings of the previous study.SettingAn urban Australian public hospital PARTICIPANTS: From 40 people who participated in the original study, 11 participants were purposively sampled based on their level of satisfaction and factors driving satisfaction as reported in their first interview. There were six women and five men, the average time since TKR was 3 years and 5 months, and the average age at time of interview was 77 years.ResultsSatisfaction levels were mostly stable with the exception of three participants; two transitioned in a positive direction; one in a negative direction. The meaning of satisfaction and the factors that influenced satisfaction were consistent with the original findings. However, beliefs relating to the influence of ageing on persistent knee symptoms and functional limitations were more dominant in the present study.ConclusionsThe findings provide support for patient satisfaction being a multifactorial construct that is potentially modifiable over time. Clinicians may apply the conceptual model we have described to optimise satisfaction in patients up to 3-4 years post-TKR.
| S-EPMC8609943 | biostudies-literature