European Alpha-Mannosidosis Participant

Terminated

• Conditions: Immunodeficiency; Deafness; Facial Dysmorphism; Skeletal Abnormalities; Mental Retardation; Gingival Hypertrophy

• Registration Number: NCT03651245
• Lead Sponsor: CENTOGENE GmbH Rostock

Brief Summary

International, multicenter, observational, longitudinal monitoring study to investigate the prevalence of Alpha-Mannosidosis in participants at risk for Alpha-Mannosidosis.

Detailed Description

Alpha-Mannosidosis is a lysosomal storage disorder of the Glycoprotein family of diseases and is closely related to Mucopolysaccharidoses.It is a rare inherited disorder that causes problems in many organs and tissues of the body. Affected individuals may have intellectual disability, distinctive facial features, and skeletal abnormalities. Characteristic facial features can include a large head, prominent forehead, low hairline, rounded eyebrows, large ears, flattened bridge of the nose, protruding jaw, widely spaced teeth, overgrown gums, and large tongue. The skeletal abnormalities that can occur in this disorder include reduced bone density (osteopenia), thickening of the bones at the top of the skull (calvaria), deformations of the bones in the spine (vertebrae), bowed legs or knock knees, and deterioration of the bones and joints.

Affected individuals may also experience difficulty in coordinating movements (ataxia); muscle weakness (myopathy); delay in developing motor skills such as sitting and walking; speech impairments; increased risk of infections; enlargement of the liver and spleen (hepatosplenomegaly); a buildup of fluid in the brain (hydrocephalus); hearing loss; and a clouding of the lens of the eye (cataract).

Alpha-Mannosidosis is estimated to occur in approximately 1 in 500,000 people worldwide. Mutations in the MAN2B1 gene cause Alpha-Mannosidosis. This gene provides instructions for making the enzyme alpha-mannosidase. Mutations in the MAN2B1 gene interfere with the ability of the alpha-mannosidase enzyme to perform its role in breaking down mannose-containing oligosaccharides. These oligosaccharides accumulate in the lysosomes and cause cells to malfunction and eventually die. Tissues and organs are damaged by the abnormal accumulation of oligosaccharides and the resulting cell death, leading to the characteristic features of Alpha-Mannosidosis.

Modern methods, as DBS based mass-spectrometry give a great opportunity to

* Simplify the diagnostic process

* Simplify the logistics

* Increases stability and reproducibility

* Characterize specific metabolic alterations in the blood of affected patients that allow diagnosing the disease earlier, with a higher sensitivity and specificity.

A more specific diagnosis that permits earlier detection of the disease, as well as assessment of the disease activity and progression, would also permit improved chances for earlier treatment of those patients suffering from the disease.

It is the goal of this international, multicentre, epidemiological study to explore and analyse the prevalence of Alpha-Mannosidosis disease in a cohort of 1.000 patients with a suspicion of Alpha-Mannosidosis disease, based on the patient's clinical symptoms.

Study Timeline

• Study Start: 2018-08-20
• Study First Submitted: 2018-08-24
• Study First Submitted QC: 2018-08-27
• Study First Posted: 2018-08-29
• Primary Completion: 2022-05-30
• Study Completion: 2022-05-30
• Status Verified: 2022-06
• Last Update Submitted: 2022-06-10
• Last Update Posted: 2022-06-13

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 667

Inclusion Criteria

• Informed consent is obtained from the participant's parent/legal guardian
• The participant is aged between 2 months and 18 years of age
• The participant has a family history of Alpha-Mannosidosis or is at risk for Alpha-Mannosidosis according to one or more of the following symptoms: recurrent infections, skeletal abnormalities, hearing impairment-deafness, progressive neurological symptoms, impairment of mental functions, gingival hypertrophy, dysmorphic facial features, motoric disturbances of no obvious etiology

Exclusion Criteria

• Informed consent is not provided by the partici-pant's parent/legal guardian
• The participant is younger than 2 months or older than 18 years
• The participant has no family history of Alpha-Mannosidosis and is not at risk for Alpha-Mannosidosis (represents none of the following symptoms): recurrent infections, skeletal abnormalities, hearing impairment-deafness, progressive neurological symptoms, impairment of mental functions, gingival hypertrophy, dysmorphic facial features, motoric disturbances of no obvious etiology

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Epidemiological analysis of the prevalence of Alpha-Mannosidosis disease in a cohort of patients with suspicion for Alpha-Mannosidosis, based on their clinical symptoms.	3 years	Number of identified Alpha-Mannosidosis patients, showing a mutation/pathogenic variant in the MAN2B1-Gene, within a cohort of 1000 suspected cases using respective patient's dry-blood sample for confirmatory genetic testing (NGS-based sequencing of MAN2B1-gene)

Secondary Outcome Measures

Name	Time	Method
Establishment of biomarker/s in MAN2B1 positive cohort.	3 years	Alpha-Mannosidosis-positive samples will be validated for the identification of potential biomarkers (based on MS/MS-Tandem spectroscopy) and compared with the merged control samples in order establish a disease-specific biomarker.

Trial Locations

Locations (19)

Universitätsklinikum Halle Universitätsklinik und Poliklinik für Pädiatrie I; 🇩🇪 Halle, Germany

Carl-Thiem-Klinikum Cottbus GmbH, Klinik für Kinder und Jugendmedizin; 🇩🇪 Cottbus, Germany

Universitätsklinikum Essen, Klinik für Hals-Nasen und Ohrenheilkunde; 🇩🇪 Essen, Germany

Sozialpädiatrisches Zentrum der HTZ Neuwied gGmbH; 🇩🇪 Neuwied, Germany

Zentrum für Kinder und Jugendliche Sozialpädiatrisches Zentrum (SPZ) im Marien-Hospital; 🇩🇪 Wesel, Germany

Uniklinik RWTH Aachen Klinik für Kinder- und Jugendmedizin; 🇩🇪 Aachen, Germany

Evangelisches Krankenhaus Hamm, Klinik für Kinder-und Jugendmedizin; 🇩🇪 Hamm, Germany

Universitätsklinikum Jena, Klinik für Neuropädiatrie; 🇩🇪 Jena, Germany

Elblandkliniken Stiftung & Co. KG - Elblandklinkum Riesa Sozialpädiatrisches Zentrum und Frühförderstelle; 🇩🇪 Riesa, Germany

Inselspital Bern Universitätsklinik für Neurologie; 🇨🇭 Bern, Switzerland

Charité - Universitätsmedizin Berlin, Leitung Sozialpädiatrisches Zentrum, Klinik für Pädiatrie m.S. Neurologie; 🇩🇪 Berlin, Germany

Universitätsklinikum Gießen, Zentrum für Kinderheilkunde und Jugendmedizin, Abteilung für Kinderneurologie, Sozialpädiatrie und Epileptologie; 🇩🇪 Gießen, Germany

Medizinische Hochschule Hannover, Deutsches HörZentrum Hannover; 🇩🇪 Hannover, Germany

Universitätsklinikum Jena, Klinik für Hals-, Nasen- und Ohrenheilkunde; 🇩🇪 Jena, Germany

UKE - Universitätsklinikum Hamburg-Eppendorf Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde; 🇩🇪 Hamburg, Germany

UNIVERSITÄTSKLINIKUM LEIPZIG AöR, Klinik und Poliklinik für Hals-, Nasen-, Ohrenheilkunde; 🇩🇪 Leipzig, Germany

Evangelisches Krankenhaus Oberhausen, Sozialpädiatrisches Zentrum; 🇩🇪 Oberhausen, Germany

Klinik für Kinder-und Jungendmedizin des Universitätsklinikums Ulm; 🇩🇪 Ulm, Germany

HNO-Universitätsklinik, Universitätsspital Basel; 🇨🇭 Basel, Switzerland