Trial record 10 of 17 for:    Sandhoff Disease

Biomarker for GM1/GM2 - Gangliosidoses (BioGM1BioGM2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02298647
Recruitment Status : Active, not recruiting
First Posted : November 24, 2014
Last Update Posted : July 3, 2018
Centogene AG Rostock
Information provided by (Responsible Party):
Prof. Dr. Arndt Rolfs, University of Rostock

Brief Summary:
Development of a new MS-based biomarker for the early and sensitive diagnosis of metachromatic leukodystrophy disease from plasma and saliva. Testing for clinical robustness, specificity and long-term stability of the biomarker.

Condition or disease
Gangliosidosis GM1-Gangliosidosis GM2-Gangliosidosis Hexosaminidase Activator Deficiency Tay-Sachs Disease, AB Variant Hexosaminidase A and B Deficiency Sandhoff Disease

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Detailed Description:

Gangliosides are complex compunds consisting of a glycosphingolipid and a sialic acid and are located at the cell surface where they are responsible for detecting extracellular mole-cules. Gangliosides are mainly located in the nervous system.

If gangliosides accumulate pathologically throughout the body this is known as gangliosidoss. There are two main sub-types of gangliosidosis depending on the deficient enzyme, which are known as GM1 and GM2.

GM1-Gangliosidosis GM1 gangliosidosis is an autosomal recessive disease. Genetic counselling should be pro-vided to affected families.

The disorder is caused by mutations in the GLB1-gene coding for beta-galactosidase. To day, more than 165 mutations have been identified. Deficient enzyme activity leads to toxic accumulation of gangliosides in body tissues, and particularly in the central nervous system (CNS).

The disorder is panethnic however the worldwide prevalence is not known. Prevalence at birth is estimated to be approximately 1:100,000 to 200,000 live births. High prevalence has been found in Malta and Brazil, and in the Cypriot and Roma populations.

Deficiency of the lysosomal hydrolase, acid β-galactosidase, causes GM1.Three clinical sub-types of GM1 gangliosidosis are recognized, classified by age of onset, as follows:

  • Infantile (type 1): In the most common infantile form, coarse facial features, hepato-splenomegaly, generalized skeletal dysplasia (dysostosis multiplex), macular cherry-red spots, and developmental delay/arrest (followed by progressive neurologic deteri-oration) usually occur within the first 6 months of life. Nonimmune hydrops fetalis has been reported. An increased incidence of Mongolian spots has also been described. A wide spectrum of variability is observed in the appearance and progression of the typical dysmorphic features. As many as 50% of affected infants have a macular cherry-red spot.
  • Juvenile (type 2): The juvenile form is characterized by a later age of onset, less hepatosplenomegaly (if any), fewer cherry-red spots (if any), dysmorphic features, or skeletal changes (vertebral dysplasia may be detected radiographically).
  • Adult (type 3): The adult form is characterized by normal early neurologic develop-ment, with variable age of clinical presentation. Slowly progressing dementia with parkinsonian features and extrapyramidal disease is common. Intellectual impairment may be initially absent or mild but progresses with time. Generalized dystonia with speech and gait disturbance is the most frequently reported early feature. Typically, no hepatosplenomegaly, cherry-red spots, dysmorphic features, or skeletal changes are present aside from scoliosis (mild vertebral changes may be revealed with radiog-raphy), but short stature is common.

GM2-Gangliosidosis The GM2 gangliosidosis are a group of lysosomal lipid storage disorders caused by mutations in at least 1 of 3 recessive genes: HEXA, HEXB, and GM2A. Normal products of all 3 genes are required for normal catabolism of the GM2 ganglioside substrate. Deficient activity of these enzymes leads to accumulation of the substrate inside neuronal lysosomes, leading to cell death. The products of the 3 genes are, respectively, the alpha subunits of b-hexosaminidase A (Hex A). Hex A is a dimer and has the structure alpha-beta.

β-Hexosaminidase B (Hex B) is a dimer of beta chains. It hydrolyzes GM2 and its neutral asialo derivative GA2. Both subunit precursors acquire the mannose 6-phosphate marker for recognition by lysosomes.

Hexosaminidase S (Hex S) is a dimer of alpha chains; it is a normal constituent of plasma and degrades a wide range of glycoconjugates containing β-linked N-acetylhexosaminyl res-idues. With lack of beta-subunits the increased polymerization of alpha subunits leads to the increased formation of Hex S in Tay - Sachs disease.

GM2A is a cofactor required for the normal function of Hex A; it´s disruption likewise leads to a reduced function of Hex A.

New methods, like mass-spectrometry give a good chance to characterize specific metabolic alterations in the blood (plasma) of affected patients that allow diagnosing in the future the disease earlier, with a higher sensitivity and specificity.

Therefore it is the goal of the study to validate this new biochemical marker from the plasma of the affected patients helping to benefit other patients by an early diagnose and thereby with an earlier treatment. Examining saliva samples will allow determining whether measurement is feasible in saliva samples and will further promote early detection of GM1/GM2 disease.

Study Type : Observational
Actual Enrollment : 137 participants
Observational Model: Cohort
Time Perspective: Prospective
Study Start Date : November 2014
Actual Primary Completion Date : July 2018
Estimated Study Completion Date : July 2018

Patients with a diagnosis of Gangliosidosis type GM1/GM2 based upon biochemical and/or genetic criteria or profound suspicion for Gangliosidosis type GM1/GM2

Primary Outcome Measures :
  1. Development of a new MS-based biomarker for the early and sensitive diagnosis of GM1/GM2 -gangliosidoses from plasma and saliva using [ Time Frame: 36 month ]

Secondary Outcome Measures :
  1. Testing for clinical robustness, specificity and long-term stability of the biomarker [ Time Frame: 36 month ]

Biospecimen Retention:   Samples With DNA
For the development of the new biomarkers using the technique of Mass-spectometry 10ml EDTA blood, sputum tube and a dry blood spot filter card are taken. To proof the correct diagnosis in those patients where up to the enrollment in the study no genetic testing has been done, sequencing will be done. The analyses are done in the Albrecht-Kossel-Institute for Neuroregeneration (AKos), POB 100 888, Gehlsheimer Str. 20, 18055 Rostock (Germany)

Information from the National Library of Medicine

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Ages Eligible for Study:   2 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Patients with GM1/GM2- Gangliosidoses or high-grade suspicion for GM1/GM2 -Gangliosidoses

Inclusion Criteria:

  • Informed consent will be obtained from the parents before any study related proce-dures.
  • Patients of both genders aged 2 months and older
  • The patient has a diagnosis of GM1/GM2 -gangliosidoses or a high-grade suspicion for GM1/GM2 -gangliosidoses

High-grade suspicion for GM1 or GM2 pre-sent, if one or more inclusion criteria are valid:

  • Positive family anamnesis for GM1 or GM2 disease
  • Neurodegenerative symptoms
  • Skeletal symptoms
  • Cherry Red Spot

Exclusion Criteria:

  • No Informed consent from the parents be-fore any study related procedures.
  • No diagnosis of GM1/GM2 disease or no valid criteria for profound suspicion of GM1/GM2 -disease
  • Patients of both genders younger than 2 months

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02298647

Albrecht-Kossel-Institute for Neuroregeneration (AKos) Centre for Mental Health Disease University of Rostock
Rostock, Germany, 18147
Sponsors and Collaborators
University of Rostock
Centogene AG Rostock
Principal Investigator: Arndt Rolfs, Prof. University of Rostock, Albrecht-Kossel-Institute for Neuroregeneration

Additional Information:
Responsible Party: Prof. Dr. Arndt Rolfs, Prof. Dr. med., University of Rostock Identifier: NCT02298647     History of Changes
Other Study ID Numbers: BGM 03-2014
First Posted: November 24, 2014    Key Record Dates
Last Update Posted: July 3, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Prof. Dr. Arndt Rolfs, University of Rostock:
Lysosomal Storage Diseases

Additional relevant MeSH terms:
Tay-Sachs Disease
Sandhoff Disease
Tay-Sachs Disease, AB Variant
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Gangliosidoses, GM2
Gangliosidosis, GM1
Metabolism, Inborn Errors
Lipid Metabolism, Inborn Errors