Clinical Biomarkers in Alpha-mannosidosis
| Status: | Suspended |
|---|---|
| Healthy: | No |
| Age Range: | 5 - 60 |
| Updated: | 4/4/2019 |
| Start Date: | May 15, 2014 |
| End Date: | December 31, 2020 |
Clinical Biomarkers in Alpha-Mannosidosis
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.
- 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.
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.
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.
- 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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
Phone: 800-411-1222
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