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

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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Alveolar Proteinosis; Mutation Ala393Thr of the MARS Gene; mutationSer567Leu of the MARS Gene
• Intervention / Treatment: 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

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Île-de-France Region
    • Paris, Île-de-France Region, France, 75015
      • Hôpital Necker-Enfants Malades

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Methionine

Drug: Methionine; Administration of methionine from D1 to D60; Drug: Vitamin B12, B9, B6, C supplementation; In case of hyperhomocysteinemia; Diagnostic test: Methionine/homocysteine Dosage; Plasma concentration control of methionine and homocysteine from D0 to D75; Diagnostic test: Thoracic CT scan; At D60; Diagnostic test: Abdominal and liver ultrasound.; At D60; Diagnostic test: Brain MRI; In case of abnormal neurological examination

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: URC-CIC Paris Descartes Necker Cochin
• Investigators: Principal Investigator: Alice HADCHOUEL, PhD, Hôspital Necker Enfants Malades

Publications and helpful links

General Publications

• Hadchouel A, Drummond D, Pontoizeau C, Aoust L, Hurtado Nedelec MM, El Benna J, Gachelin E, Perisson C, Vigier C, Schiff M, Lacaille F, Molina TJ, Berteloot L, Renolleau S, Ottolenghi C, Treluyer JM, de Blic J, Delacourt C. Methionine supplementation for multi-organ dysfunction in MetRS-related pulmonary alveolar proteinosis. Eur Respir J. 2022 Apr 21;59(4):2101554. doi: 10.1183/13993003.01554-2021. Print 2022 Apr.

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2019
• Primary Completion (Actual): June 1, 2020
• Study Completion (Actual): June 1, 2020

Study Registration Dates

• First Submitted: March 12, 2019
• First Submitted That Met QC Criteria: March 21, 2019
• First Posted (Actual): March 22, 2019

Study Record Updates

• Last Update Posted (Actual): November 20, 2025
• Last Update Submitted That Met QC Criteria: November 17, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: methionine; Pulmonary alveolar proteinosis; MARS gene
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Pulmonary Alveolar Proteinosis; Amino Acids, Peptides, and Proteins; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Azoles; Polycyclic Compounds; Amino Acids; Heterocyclic Compounds, 4 or More Rings; Pyrroles; Macrocyclic Compounds; Amino Acids, Essential; Amino Acids, Sulfur; Tetrapyrroles; Amino Acids, Neutral; Corrinoids; Vitamin B 12; Methionine
• Other Study ID Numbers: DC20180338; 2018-004140-28 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No