Pulmonary Alveolar Proteinosis, Mutation Ala393Thr of the MARS Gene, mutationSer567Leu of the MARS Gene
Conditions
Keywords
Pulmonary alveolar proteinosis, MARS gene, methionine
Brief summary
The purpose of this study is to determine the safety and tolerance of an oral administration of methionine in the treatment of pulmonary alveolar proteinosis due to the double mutation Ala393Thr / Ser567Leu in the MARS gene. This disease is very severe and especially leads to chronic respiratory insufficiency. There is no curative treatment for this disease. The MARS gene encodes the methionine tRNA synthetase (MetRS). Mutations in this gene leads to a defect in MetRS function. In cultured mutated yeast, addition of methionine in culture medium restores MetRS function. Therefore, the investigators hypothesized that treatment of patients with methionine could have beneficial effects on the disease.
Detailed description
Pulmonary alveolar proteinosis (PAP) is a rare respiratory disorder. Recently, a genetic cause has been identified for a specific form of PAP predominant on La Reunion Island. This form is characterized by a multisystem phenotype including PAP, failure to thrive, hepatic involvement and chronic inflammation. This is a severe disease without any specific treatment and a high rate of mortality related to end-stage respiratory insufficiency. Two recurrent mutations were isolated in the MARS gene that encodes the methionine tRNA synthetase (MetRS). This enzyme catalyzes the ligation of methionine to tRNA and is critical for protein biosynthesis. Functional studies on mutated yeast show an altered growth and protein synthesis as compared to control yeast. Addition of methionine in culture medium corrects these defects. Complementary experiments on human purified MetRS show altered enzymatic catalytic parameters in mutated forms. Increasing blood concentration of methionine in patients could correct these parameters and potentially improve patients' phenotype in this severe disorder where no curative treatment exists. The main objective of this protocol is to determine the tolerance of a prolonged daily supplementation of methionine in patients presenting a MARS related PAP. The secondary objectives are to determine the efficiency of such treatment on respiratory, hepatic, inflammatory and growth status. To meet the objectives of the study, enrolled patients will receive daily oral or enteral methionine administration at increasing doses, under surveillance of plasma levels of methionine and homocysteine, and possible clinical side effects, until determining the ideal dose for each patient. Once daily dosage determined for each patient, this dosage will be continued for a total of 2 months with daily clinical monitoring of tolerance and bi-monthly plasma levels surveillance of methionine and homocysteine.
Interventions
DRUGMethionine
Administration of methionine from D1 to D60
DRUGVitamin B12, B9, B6, C supplementation
In case of hyperhomocysteinemia
DIAGNOSTIC_TESTMethionine/homocysteine Dosage
Plasma concentration control of methionine and homocysteine from D0 to D75
DIAGNOSTIC_TESTThoracic CT scan
At D60
DIAGNOSTIC_TESTAbdominal and liver ultrasound.
At D60
DIAGNOSTIC_TESTBrain MRI
In case of abnormal neurological examination
Sponsors
URC-CIC Paris Descartes Necker Cochin
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
Inclusion criteria
* Minor Patient with alveolar proteinosis by double mutation Ala393Thr and SER567LEU of the MARS gene, genetically proven. * Patient in need of prolonged hospitalization in Necker for treatment of bronchial-alveolar washes in the context of care. * Patient for which methionine can be administered orally or by enteral probe (Nasogastric or gastrostomy probe) * Signed Informed consent form by parents / legal guardian
Exclusion criteria
* Patient with alveolar proteinosis by other mutations of the MARS gene * Patient with alveolar proteinosis secondary to another etiology or without identified cause * Refusal to participate in the study * High blood pressure requiring drug treatment * Heart failure * Known hypersensitivity to one of the substances used or potentially used in the study: methionine, vitamins B6, B12, B9 and C * Pre-Hypermethioninemia (Methioninemia \> + 2 DS of normal for age) whatever the cause
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tolerance Assessment | From day 0 to day 75 | No adverse event from day 0 to day 75. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| mid upper arm circumference / head circumference rapport | At Day 15, Day 30, Day 45, Day 60, Day 75 | To evaluate Nutritional status |
| Hepatomegaly | At Day 0, Day 15, Day 30, Day 45, Day 60, Day 75 | liver damage evaluate by physician during clinical examination |
| Respiratory rate (cycles /min) | At day 0, day 15, day 30, day 45, day 60, day 75 | number of cycles per minute |
| Oxygen need (L/min) | At day 0, day 15, day 30, day 45, day 60, day 75 | Flow in L/min |
| Respiratory signs of struggle | At day 0, day 15, day 30, day 45, day 60, day 75 | Presence or absence of signs |
| Lung lesions | At Day 60 | Lesions appearance on thoracic CT scan, scored form 0 to 4 |
| Lipo-proteinaceous material | At each bronchial-alveolar washes during the 2,5 months | Fluid examination |
| Weight | At Day 15, Day 30, Day 45, Day 60, Day 75 | To evaluate Nutritional status |
| C reactive protein | At Day 0, Day 30, Day 60 | Biological parameters to evaluate Systemic inflammation |
| sedimentation rate | At Day 0, Day 30, Day 60 | Biological parameters to evaluate Systemic inflammation |
| Immunoglobulin G level | At Day 0, Day 30, Day 60 | Biological parameters to evaluate Systemic inflammation |
| Haemoglobin level | At Day 0, Day 30, Day 60 | Biological parameters to evaluate inflammatory anaemia |
| Plasma concentration of methionine | From Day 0 to Day 75 | Variation of the concentration for each patient |
| Plasma concentration of homocysteine | From Day 0 to Day 75 | Variation of the concentration for each patient |
| cholestasis and hepatic cytolysis | At Day 0, Day 15, Day 30, Day 60, Day 75 | liver damage evaluate by biological parameters : ASAT, ALAT, GGT, PAL, Bilirubin |
Countries
France
Outcome results
None listed