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, we hypothesized that treatment of patients with methionine could have beneficial effects on the disease.
Name: Methionine
Description: Administration of methionine from D1 to D60Type: DrugMethionine
Name: Vitamin B12, B9, B6, C supplementation
Description: In case of hyperhomocysteinemiaType: DrugMethionine
Name: Methionine/homocysteine Dosage
Description: Plasma concentration control of methionine and homocysteine from D0 to D75Type: Diagnostic TestMethionine
Name: Thoracic CT scan
Description: At D60Type: Diagnostic TestMethionine
Name: Abdominal and liver ultrasound.
Description: At D60Type: Diagnostic TestMethionine
Name: Brain MRI
Description: In case of abnormal neurological examinationType: Diagnostic TestMethionine
Description: No adverse event from day 0 to day 75.
Measure: Tolerance Assessment Time: From day 0 to day 75Description: number of cycles per minute
Measure: Respiratory rate (cycles /min) Time: At day 0, day 15, day 30, day 45, day 60, day 75Description: Flow in L/min
Measure: Oxygen need (L/min) Time: At day 0, day 15, day 30, day 45, day 60, day 75Description: Presence or absence of signs
Measure: Respiratory signs of struggle Time: At day 0, day 15, day 30, day 45, day 60, day 75Description: Lesions appearance on thoracic CT scan, scored form 0 to 4
Measure: Lung lesions Time: At Day 60Description: Fluid examination
Measure: Lipo-proteinaceous material Time: At each bronchial-alveolar washes during the 2,5 monthsDescription: To evaluate Nutritional status
Measure: Weight Time: At Day 15, Day 30, Day 45, Day 60, Day 75Description: To evaluate Nutritional status
Measure: mid upper arm circumference / head circumference rapport Time: At Day 15, Day 30, Day 45, Day 60, Day 75Description: liver damage evaluate by physician during clinical examination
Measure: Hepatomegaly Time: At Day 0, Day 15, Day 30, Day 45, Day 60, Day 75Description: liver damage evaluate by biological parameters : ASAT, ALAT, GGT, PAL, Bilirubin
Measure: cholestasis and hepatic cytolysis Time: At Day 0, Day 15, Day 30, Day 60, Day 75Description: liver damage evaluate by echography
Measure: Hepatomegaly Time: At Day 0 and Day 60Description: Biological parameters to evaluate Systemic inflammation
Measure: C reactive protein Time: At Day 0, Day 30, Day 60Description: Biological parameters to evaluate Systemic inflammation
Measure: sedimentation rate Time: At Day 0, Day 30, Day 60Description: Biological parameters to evaluate Systemic inflammation
Measure: Immunoglobulin G level Time: At Day 0, Day 30, Day 60Description: Biological parameters to evaluate inflammatory anaemia
Measure: Haemoglobin level Time: At Day 0, Day 30, Day 60Single Group Assignment
There are 2 SNPs
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. --- Ala393Thr ---
Inclusion Criteria: - Minor Patient under the age of 10 with alveolar proteinosis by double mutation Ala393Thr and SER567LEU of the MARS gene, genetically proven. --- Ala393Thr ---
- 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 Inclusion Criteria: - Minor Patient under the age of 10 with alveolar proteinosis by double mutation Ala393Thr and SER567LEU of the MARS gene, genetically proven. --- Ala393Thr ---
- 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 Pulmonary Alveolar Proteinosis Mutation Ala393Thr of the MARS Gene mutationSer567Leu of the MARS Gene Pulmonary Alveolar Proteinosis Pulmonary alveolar proteinosis (PAP) is a rare respiratory disorder. --- Ala393Thr ---
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. --- Ala393Thr --- --- Ser567Leu ---
Inclusion Criteria: - Minor Patient under the age of 10 with alveolar proteinosis by double mutation Ala393Thr and SER567LEU of the MARS gene, genetically proven. --- Ala393Thr --- --- SER567LEU ---
- 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 Inclusion Criteria: - Minor Patient under the age of 10 with alveolar proteinosis by double mutation Ala393Thr and SER567LEU of the MARS gene, genetically proven. --- Ala393Thr --- --- SER567LEU ---