Clinical Biomarkers in Alpha-mannosidosis

Brief Title

Clinical Biomarkers in Alpha-mannosidosis

Official Title

Clinical Biomarkers in Alpha-Mannosidosis

Brief Summary

      Background:

      - Alpha-mannosidosis is a rare inherited disorder. It causes problems in many organs and
      tissues of the body. It can occur in children and adults. Because there is no treatment for
      this disease, researchers want to find out more about it.

      Objective:

      - To learn more about Alpha-mannosidosis.

      Eligibility:

      - People ages 5-60 with Alpha-mannosidosis.

      Design:

        -  Participants will be recruited from patient support organizations and medical genetics
           clinics.

        -  Participants will have 3 study visits, about once a year. A final evaluation will be
           made after 3 years.

        -  Participants will have a medical history and a physical exam.

        -  Blood samples and a urine sample will be collected.

        -  Cerebrospinal fluid will be collected. A small area of the lower back will be numbed
           with medicine. A thin needle will be inserted between the spine bones. About 2
           tablespoons of spinal fluid will be removed.

        -  Brain magnetic resonance spectroscopy (MRS) scans will be done at each visit. MRS uses a
           strong magnetic field and radio waves to take pictures of chemicals in the brain with a
           scanner. The participant will lie on a table that can slide in and out of the cylinder.
           While in the scanner the participant will hear loud knocking noises. They will get
           earplugs or earmuffs to muffle the sound. Medicines might be used to keep the
           participant asleep during the MRS.

        -  Participants will have a skin biopsy at the first visit only. A small area of the
           participant s skin will be numbed. A small circle of skin will be removed with a biopsy
           tool.
    

Detailed Description

      Alpha-mannosidosis (AMD) is an inherited lysosomal storage disorder caused by mutations in
      the LAMAN gene, which encodes lysosomal alpha-mannosidase and is characterized by
      neurodevelopmental delay, mild immune deficiency, facial and skeletal abnormalities, hearing
      impairment, intellectual disability, muscle weakness and ataxia. The progression of
      neuromuscular and skeletal deterioration is insidious, occurring over several decades,
      rendering most patients wheel-chair dependent. No consistently successful treatment is
      available. To better characterize the biochemical phenotype and natural history of this
      disorder, we will study 15 patients with AMD, ranging in age from five to 60 years, recruited
      from Departments of Biochemical Genetics and Medical Genetics at university medical centers
      mainly in the US and Canada or referred by the Intl Society for Mannosidosis & Related
      Diseases. Participants in the study will visit the NIH Clinical Center 2-3 days on an
      outpatient basis and will undergo clinical and biochemical evaluations to establish reliable
      clinical

      benchmarks and to identify cerebrospinal fluid biomarkers that could serve as candidate

      surrogate markers of treatment effect in future clinical trials. The protocol will take
      advantage of the NICHD Biomedical Mass Spectrometry Facility to generate CSF proteomic
      profiles. Patients will also undergo MR spectroscopy (under sedation/anesthesia, if
      appropriate) in order to establish the phenotypic baseline and for possible utility as a
      guide for natural history and/or treatment outcomes in future studies. If the pre-clinical
      components of this proposal prove promising, the prospect of a recombinant adeno-associated
      viral gene therapy trial involving a brain-directed (intrathecal) approach for AMD would be
      possible within 3 years.
    


Study Type

Observational


Primary Outcome

Identify cerebrospinal fluid biomarkers that could serve as candidate surrogate markers of treatment effect in a future clinical trial.

Secondary Outcome

 Establish reliable clinical benchmarks for alpha-mannosidosis.

Condition

Alpha-Mannosidosis



Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

11

Start Date

July 24, 2014

Completion Date

November 29, 2019

Primary Completion Date

November 29, 2019

Eligibility Criteria

        -  INCLUSION CRITERIA:

               1. Must have a verifiable diagnosis of AMD based on clinical, biochemical and/or
                  molecular grounds, including increased urinary excretion of mannose-rich
                  oligosaccharides, decreased acidic -mannosidase activity in leukocytes or other
                  nucleated cells, and/or mutations in two alleles of the LAMAN gene.

               2. Must be at least five years old.

        EXCLUSION CRITERIA:

          1. Significant systemic or major disease including congestive heart failure, coronary
             artery disease, cerebrovascular disease and pre-existing or recent onset pulmonary
             disease, renal failure, organ transplantation, decompensated liver disease, serious
             psychiatric disease, or malignancy that in the opinion of the investigator would
             preclude successful participation..

          2. Pregnancy. We will perform a urine pregnancy test on all post-menarcheal female
             subjects on the same day as the history and physical exam, prior to MRI. If pregnancy
             is identified, we will follow Maryland state law in place at the time concerning
             parental notification. In the event a woman becomes pregnant during the study, she
             will be withdrawn from all study procedures, but the study team will follow up with
             the participant regarding the pregnancy outcome.
      

Gender

All

Ages

5 Years - 60 Years

Accepts Healthy Volunteers

No

Contacts

Stephen G Kaler, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02141503

Organization ID

140106

Secondary IDs

14-CH-0106

Responsible Party

Sponsor

Study Sponsor

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)


Study Sponsor

Stephen G Kaler, M.D., Principal Investigator, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)


Verification Date

November 29, 2019