Oral or Enteral Administration of Methionine in Patients With Pulmonary Alveolar Proteinosis by Mutation of the MARS Gene.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Tolerance Assessment
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Methionine
干预措施: Thoracic CT scan (Diagnostic Test)
Methionine
干预措施: Abdominal and liver ultrasound. (Diagnostic Test)
Methionine
干预措施: Brain MRI (Diagnostic Test)
Methionine
干预措施: Methionine/homocysteine Dosage (Diagnostic Test)
Methionine
干预措施: Methionine (Drug)
Methionine
干预措施: Vitamin B12, B9, B6, C supplementation (Drug)
结局指标
主要结局
Tolerance Assessment
时间窗: From day 0 to day 75
No adverse event from day 0 to day 75.
次要结局
- mid upper arm circumference / head circumference rapport(At Day 15, Day 30, Day 45, Day 60, Day 75)
- Hepatomegaly(At Day 0 and Day 60)
- sedimentation rate(At Day 0, Day 30, Day 60)
- Immunoglobulin G level(At Day 0, Day 30, Day 60)
- Haemoglobin level(At Day 0, Day 30, Day 60)
- cholestasis and hepatic cytolysis(At Day 0, Day 15, Day 30, Day 60, Day 75)
- C reactive protein(At Day 0, Day 30, Day 60)
- Respiratory rate (cycles /min)(At day 0, day 15, day 30, day 45, day 60, day 75)
- Plasma concentration of methionine(From Day 0 to Day 75)
- Plasma concentration of homocysteine(From Day 0 to Day 75)
- Oxygen need (L/min)(At day 0, day 15, day 30, day 45, day 60, day 75)
- Lipo-proteinaceous material(At each bronchial-alveolar washes during the 2,5 months)
- Weight(At Day 15, Day 30, Day 45, Day 60, Day 75)
- Respiratory signs of struggle(At day 0, day 15, day 30, day 45, day 60, day 75)
- Lung lesions(At Day 60)