Administration of Methionine in Patients With Pulmonary Alveolar Proteinosis by Mutation of the MARS Gene.

Study Overview
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Brief Summary
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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
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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.

Official Title
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Oral or Enteral Administration of Methionine in Patients With Pulmonary Alveolar Proteinosis by Mutation of the MARS Gene.

Conditions
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Pulmonary Alveolar Proteinosis, Mutation Ala393Thr of the MARS Gene, mutationSer567Leu of the MARS Gene

Intervention / Treatment
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* Drug: Methionine
* Drug: Vitamin B12, B9, B6, C supplementation
* Diagnostic Test: Methionine/homocysteine Dosage
* Diagnostic Test: Thoracic CT scan
* Diagnostic Test: Abdominal and liver ultrasound.
* Diagnostic Test: Brain MRI


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methionine<br> | Drug: Methionine<br>* Administration of methionine from D1 to D60<br>Drug: Vitamin B12, B9, B6, C supplementation<br>* In case of hyperhomocysteinemia<br>Diagnostic Test: Methionine/homocysteine Dosage<br>* Plasma concentration control of methionine and homocysteine from D0 to D75<br>Diagnostic Test: Thoracic CT scan<br>* At D60<br>Diagnostic Test: Abdominal and liver ultrasound.<br>* At D60<br>Diagnostic Test: Brain MRI<br>* In case of abnormal neurological examination<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerance Assessment | No adverse event from day 0 to day 75. | From day 0 to day 75 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Respiratory rate (cycles /min) | number of cycles per minute | At day 0, day 15, day 30, day 45, day 60, day 75 | 
| Oxygen need (L/min) | Flow in L/min | At day 0, day 15, day 30, day 45, day 60, day 75 | 
| Respiratory signs of struggle | Presence or absence of signs | At day 0, day 15, day 30, day 45, day 60, day 75 | 
| Lung lesions | Lesions appearance on thoracic CT scan, scored form 0 to 4 | At Day 60 | 
| Lipo-proteinaceous material | Fluid examination | At each bronchial-alveolar washes during the 2,5 months | 
| Weight | To evaluate Nutritional status | At Day 15, Day 30, Day 45, Day 60, Day 75 | 
| mid upper arm circumference / head circumference rapport | To evaluate Nutritional status | At Day 15, Day 30, Day 45, Day 60, Day 75 | 
| Hepatomegaly | liver damage evaluate by physician during clinical examination | At Day 0, Day 15, Day 30, Day 45, Day 60, Day 75 | 
| cholestasis and hepatic cytolysis | liver damage evaluate by biological parameters : ASAT, ALAT, GGT, PAL, Bilirubin | At Day 0, Day 15, Day 30, Day 60, Day 75 | 
| Hepatomegaly | liver damage evaluate by echography | At Day 0 and Day 60 | 
| C reactive protein | Biological parameters to evaluate Systemic inflammation | At Day 0, Day 30, Day 60 | 
| sedimentation rate | Biological parameters to evaluate Systemic inflammation | At Day 0, Day 30, Day 60 | 
| Immunoglobulin G level | Biological parameters to evaluate Systemic inflammation | At Day 0, Day 30, Day 60 | 
| Haemoglobin level | Biological parameters to evaluate inflammatory anaemia | At Day 0, Day 30, Day 60 | 
| Plasma concentration of methionine | Variation of the concentration for each patient | From Day 0 to Day 75 | 
| Plasma concentration of homocysteine | Variation of the concentration for each patient | From Day 0 to Day 75 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary alveolar proteinosis, MARS gene, methionine