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Natural history of alpha mannosidosis a longitudinal study.

ABSTRACT: Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of the enzyme alpha-Mannosidase. Clinically it is characterized by hearing impairment, skeletal and neurological abnormalities and mental retardation. In order to characterize the clinical features and disease progression of patients affected by alpha-Mannosidosis, a survey study was conducted. 43 patients from 4 European countries participated in this longitudinal study. Age range of the participants was 3 to 42 years. For each patient a medical history, complete physical and neurological examination, joint range of motion and assessment of physical endurance and of lung function were completed. In addition, serum and urinary oligosaccharide levels were analysed.In this multicenter longitudinal study clinical data of 43 alpha-Mannosidosis patients were collected. In addition to objective clinical measurements biochemical assays were performed.Data analysis revealed a wide spectrum of clinical presentation regarding the severity and disease progression. Most clinical abnormalities were observed in the musculoskeletal and neurological system. All patients showed mental retardation and hearing loss from early childhood. An impairment in physical endurance was revealed by the 6-minute walk and 3-minute stair stair climb tests. There was only slight progression of a few clinical findings: Psychiatric troubles in both groups essentially, and respiratory dysfunction under 18 years. The serum and urinary oligosaccharide levels were increased in all affected individuals and correlated well with the 6-minute walk and 3-minute stair climb test results.This study confirms that alpha-Mannosidosis is a very heterogeneous disorder regarding both, disease severity and progression. As it has been shown that Mannosidosis patients are able to perform lung function tests and the 6MWT and stair-climb test, these clinical parameters apparently can be used as clinical endpoints for clinical trials. Oligosaccharide levels appeared correlated with functional testing and may serve as biomarkers of disease severity, progression and response to treatment.ClinicalTrials.gov Identifier = NCT00498420 and EuropeanCommission FP VI contract LHSM-CT-2006-018692.

SUBMITTER: Beck M

PROVIDER: S-EPMC3691585 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Natural history of alpha mannosidosis a longitudinal study.

Beck Michael M Olsen Klaus J KJ Wraith James E JE Zeman Jiri J Michalski Jean-Claude JC Saftig Paul P Fogh Jens J Malm Dag D

Orphanet journal of rare diseases 20130620

<h4>Background</h4>Alpha-Mannosidosis is a rare lysosomal storage disorder, caused by the deficiency of the enzyme alpha-Mannosidase. Clinically it is characterized by hearing impairment, skeletal and neurological abnormalities and mental retardation. In order to characterize the clinical features and disease progression of patients affected by alpha-Mannosidosis, a survey study was conducted. 43 patients from 4 European countries participated in this longitudinal study. Age range of the partici ...[more]

PMID: 23786919

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Project description:Alpha-mannosidosis is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability. It occurs in approximately 1 of 500,000 live births. The children are often born apparently normal, and their condition worsens progressively. Some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life), skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum), hearing impairment (moderate-to-severe sensorineural hearing loss), gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. The disorder is caused by lysosomal alpha-mannosidase deficiency. Alpha-mannosidosis is inherited in an autosomal recessive fashion and is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12). Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic. Differential diagnoses are mainly the other lysosomal storage diseases like the mucopolysaccharidoses. Genetic counseling should be given to explain the nature of the disease and to detect carriers. Antenatal diagnosis is possible, based on both biochemical and genetic methods. The management should be pro-active, preventing complications and treating manifestations. Infections must be treated frequently. Otolaryngological treatment of fluid in the middle ear is often required and use of hearing aids is invariably required. Early educational intervention for development of social skills is needed and physiotherapy is important to improve bodily function. Orthopedic surgery may be necessary. The long-term prognosis is poor. There is an insidiously slow progression of neuromuscular and skeletal deterioration over several decades, making most patients wheel-chair dependent. No patients manage to be completely socially independent. Many patients are over 50 years of age.

Project description:BackgroundHuman papillomavirus (HPV) infection is one of the most common sexually transmitted infections. However, only a small percentage of high-risk (HR) HPV infections progress to cervical precancer and cancer. In this study, we investigated the role of the cervicovaginal microbiome (CVM) in the natural history of HR-HPV.MethodsThis study was nested within the placebo arm of the Costa Rica HPV Vaccine Trial that included women aged 18-25 years of age. Cervical samples from two visits of women with an incident HR-HPV infection (n = 273 women) were used to evaluate the prospective role of the CVM on the natural history of HR-HPV. We focus specifically on infection clearance, persistence, and progression to cervical intraepithelial neoplasia grade 2 and 3 (CIN2+). The CVM was characterized by amplification and sequencing the bacterial 16S V4 rRNA gene region and the fungal ITS1 region using an Illumina MiSeq platform. OTU clustering was performed using QIIME2. Functional groups were imputed using PICRUSt and statistical analyses were performed using R.ResultsAt Visit 1 (V1) abundance of Lactobacillus iners was associated with clearance of incident HR-HPV infections (Linear Discriminant Analysis (LDA)>4.0), whereas V1 Gardnerella was the dominant biomarker for HR-HPV progression (LDA>4.0). At visit 2 (V2), increased microbial Shannon diversity was significantly associated with progression to CIN2+ (p = 0.027). Multivariate mediation analysis revealed that the positive association of V1 Gardnerella with CIN2+ progression was due to the increased cervicovaginal diversity at V2 (p = 0.040). A full multivariate model of key components of the CVM showed significant protective effects via V1 genus Lactobacillus, OR = 0.41 (0.22-0.79), V1 fungal diversity, OR = 0.90 (0.82-1.00) and V1 functional Cell Motility pathway, OR = 0.75 (0.62-0.92), whereas V2 bacterial diversity, OR = 1.19 (1.03-1.38) was shown to be predictive of progression to CIN2+.ConclusionThis study demonstrates that features of the cervicovaginal microbiome are associated with HR-HPV progression in a prospective longitudinal cohort. The analyses indicated that the association of Gardnerella and progression to CIN2+ may actually be mediated by subsequent elevation of microbial diversity. Identified features of the microbiome associated with HR-HPV progression may be targets for therapeutic manipulation to prevent CIN2+.Trial registrationClinicalTrials.gov NCT00128661.

Project description:BackgroundThe world's most catastrophic epidemic thunderstorm asthma event (ETSA) affected Melbourne in 2016. Little is known about the natural history of individuals affected by such extreme events.ObjectiveIn this single center prospective 3-year longitudinal study, symptomatology and behaviors of individuals affected by ETSA were assessed.MethodsStandardized telephone questionnaire was used to evaluate frequency of asthma symptoms, inhaled corticosteroid preventer use, asthma action plan ownership, and healthcare utilization. Questionnaires were administered at 12, 24, and 36 months after 2016 ETSA. Subgroup analyses of the 'current', 'past', 'possible,' and 'no asthma' subgroups were also conducted.ResultsTwo hundred and eight, 164, and 112 completed questionnaires were analyzed in 2017, 2018, and 2019, respectively. Seventy to eighty five percent of respondents reported ongoing asthma symptoms in any given year, of which 20%-28% experienced weekly symptoms. Nearly 50% of respondents were prescribed preventers, with approximately 45% adherent at least 5 days a week. Less than 40% had an asthma action plan and 15%-20% sought urgent medical attention for asthma over the follow-up period. Among 106 individuals with 3 consecutive years of completed questionnaires, those with no prior doctor diagnosis of asthma were significantly more likely to be asymptomatic on follow-up than those with a prior doctor diagnosis of asthma (p = 0.02). Subgroup analyses suggest that large proportions of respondents with 'past' and 'no asthma' continue to remain symptomatic throughout the 36-month period.ConclusionIn individuals affected by ETSA, we found evidence of ongoing loss of asthma control in those with previously well controlled asthma, and the persistence of symptoms suggestive of asthma in those with no history or symptoms suggestive of prior asthma, even after 36 months from initial ETSA. Low rates of inhaler adherence and asthma action plan ownership may contribute to increased morbidity and mortality from future ETSA events. Further research is required to confirm these findings.

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Natural history of alpha mannosidosis a longitudinal study.

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Natural history of alpha mannosidosis a longitudinal study.

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