Peroxisome Biogenesis Disorders
Conditions
Keywords
Peroxisome Biogenesis Disorder, PBD, neonatal adrenoleukodystrophy, infantile Refsum disease, PEX1 mutation, Betaine
Brief summary
The PBD are a rare group of inherited disorders due to the failure to form functional cellular peroxisomes. Most patients have progressive hearing and visual loss, leading to deafness and blindness, as well as neurological deterioration. There are no therapies for this disorder. A misfolded protein with residual function, PEX1-Gly843Asp, represents one third of all mutant alleles. Using patient cell lines with this mutation, we reported the recovery of peroxisome functions by treatment with Betaine, acting as a nonspecific chemical chaperone for the misfolded PEX1 protein. Betaine, or trimethylglycine, is a Health Canada and FDA approved orphan drug for the treatment of homocystinuria and is used by us safely and regularly in genetic medicine. We will perform a 6 month pilot study with 12 patients to test the hypothesis that Betaine, at recommended doses, can recover peroxisome biochemical functions in blood.
Detailed description
Peroxisome biogenesis disorders (PBD) are a group of inherited conditions caused by faulty assembly of peroxisomes, structures located inside cells that regulate levels of important fats and lipids in the body. When there is faulty peroxisome assembly, as in PBD, these important fats and lipids either accumulate or are not made. There is no specific treatment for these disorders, and management is supportive. In order to complement existing supportive therapies, physicians and researchers are still actively looking for new treatments acting on the root cause of PBD: the peroxisome function. To identify drugs that help recover peroxisome function a group of scientists developed a laboratory-based research test aimed at reviewing the activity of the large number of potential treatments. Using this test, they have uncovered that Betaine can improve the function of the peroxisome, when the defect is caused by a PEX1-Gly843Asp mutation, and as such may improve the overall health of child suffering from PBD. Betaine is a medication already available as a powder for oral solution, for another rare disease. It is approved in many countries, including Health Canada for Canada and the Food and Drug Administration for the USA. Paediatric genetic physicians are used to prescribing this medication and know it well. At the current stage of scientific knowledge, it is a critical next step to evaluate the benefit of betaine in children having a PBD due to a PEX1-Gly843Asp mutation, to ensure that the medication is safe and to measure the level of improvement of the function of the peroxisome. Thus, the principal objective of the study is to determine the improvement in the key peroxisome functions (plasma very long chain fatty acid profiles red cell plasmalogen levels, plasma pipecolic acid levels and plasma bile acid profiles). Another objective is to measure the growth of your child and his / her development.
Interventions
DRUGBetaine
Betaine will be given orally (mixed with food or dissolved in water, juice, milk, or formula) or through gastrostomy tube as follows: * 6 g/day in children \< 30 kg, in 3 divided doses (2 g at meal time) * 12 g/day in children \> 30 kg, in 4 divided doses (3 g at meal time and bed time).
Sponsors
Children's Hospital and Medical Center, Omaha, Nebraska
McGill University Health Centre/Research Institute of the McGill University Health Centre
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Males or females * Any age * Peroxisome Biogenesis Disorder (PBD) confirmed by biochemical analysis of at least two peroxisomal enzyme parameters: * Elevated plasma VLCFA (C26/22) \> 0.02 * Elevated plasma branched chain pristanic acid \> 0.3 μg/ml * Reduced red blood cell plasmalogen levels (C16:0DMA/C16:0 Fatty acid) \< 0.07 * PBD clinical syndromes: neonatal adrenoleukodystrophy (NALD) or infantile Refsum disease (IRD) * Genotype PEX1-G843D/G843D, PEX1-G843D/I700fs, or PEX1-G843D and any second PEX1 mutation that is predicted to be null * Expected survival of at least 6 months
Exclusion criteria
* Genotypes other than PEX1 G843D/G843D, PEX1-G843D//I700fs, or PEX1-G843D and any second PEX1 mutation that is predicted to be null * Patient already treated with betaine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peroxisome Biochemical Functions as Measured by Plasma Very Long Chain Fatty Acid | 6 months | C26/C22 ratio in plasma is a recognized biomarker for very long chain fatty acid (normal range: 0.002-0.018). It was measured twice before the beginning of treatment and measured once at the end. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Developmental Status | 6 months | Denver Developmental Screening Test expressed in years and months. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Betaine Betaine will be given orally to all participants and dose will be adjusted to body weight.
Betaine: Betaine given orally (mixed with food or dissolved in water, juice, milk, or formula) or through gastrostomy tube:
* 6 g/day in children \< 30 kg, in 3 divided doses (2 g at meal time)
* 12 g/day in children \> 30 kg, in 4 divided doses (3 g at meal time and bed time). | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Betaine |
|---|---|
| Age, Categorical <=18 years | 11 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 4.75 years |
| Mutation status PEX1 G843D homozygous mutation | 2 participants |
| Mutation status PEX1 G843D/null mutations | 10 participants |
| Region of Enrollment Canada | 2 participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Peroxisome Biochemical Functions as Measured by Plasma Very Long Chain Fatty Acid
C26/C22 ratio in plasma is a recognized biomarker for very long chain fatty acid (normal range: 0.002-0.018). It was measured twice before the beginning of treatment and measured once at the end.
Time frame: 6 months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Betaine | Peroxisome Biochemical Functions as Measured by Plasma Very Long Chain Fatty Acid | Baseline | 0.180 ratio |
| Betaine | Peroxisome Biochemical Functions as Measured by Plasma Very Long Chain Fatty Acid | At 6 months | 0.188 ratio |
Secondary
Developmental Status
Denver Developmental Screening Test expressed in years and months.
Time frame: 6 months
Population: The Denver Developmental Screening Test was not performed.