Screening of Pulmonary Veino Occlusive Disease in Heterozygous EIF2AK4 Mutation Carriers

Study Overview
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Brief Summary
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Pulmonary Veino Occlusive Disease (PVOD) is a rare form of pulmonary arterial hypertension, characterised by a poor prognosis. Recent studies demonstrated that heritable form of pulmonary veino occlusive diseaseis due to bi-allelic mutations in EIF2AK4 gene. heritable pulmonary veino occlusive disease is an autosomal recessive disease. In the french referal center of severe PH, ulmonary veino occlusive disease patients carriers of bi-allelic mutations in EIF2AK4 gene were identified. Genetic counselling in these families allowed to identified herozygous carriers of a single mutation in EIF2AK4 gene. However, to date, nothing is known about the risk of these persons of developping pulmonary diseases. It appears essential to determine the clinical, functional, echocardiographic and radiologics characteristics of these persons, and their risk of developping Pulmonary veino occlusive disease

Detailed Description
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the investigators will evaluate the subjects at inclusion after informed by a clinical evaluation (dyspnea assessed by New York Heart Association functional class (I-IV), signs of right heart failure), a 6min walk test, a Computerized Tomography scan of the chest, an electrocardiogram, an echocardiography , an abdomina ulstrasound, a Cardiopulmonary exercise testing, a lung function tests , arterial blood gases. At one and two years, a phone call will be made to to participants evaluate dyspnea and intercurrent events in all subjects. In the presence of pulmonary veino occlusive diseaseis symptoms, a new evaluation will be proposed in order to confirm of not pulmonary veino occlusive diseaseis.

Official Title
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Screening of Pulmonary Veino Occlusive Disease in Heterozygous EIF2AK4 Mutation Carriers

Conditions
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Mutation, Genetic Syndrome

Intervention / Treatment
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* Other: Screening of adult without diagnosis of PH carrying an heterozygous EIF2AK4 mutation.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female adult (age ≥18 years of age at the date of inclusion), With an identification of the presence of a mutation of the EIF2AK4 gene in the heterozygous state, Having given free and informed consent. Exclusion Criteria: Minor (age <18 years), Patient with known Pulmonary veino occlusive disease or Pulmonary arterial hypertension Woman having started a pregnancy or breastfeeding protected adult persons, Persons deprived of their liberty, People in emergency, Those who refused or were unable to give informed consent, Contraindication to the exercise test (acute coronary syndrome, syncope, tight stenotic valve disease ...) See the list of relative and absolute contraindications to the exercise test (chapter 6.2). No affiliation to a social security scheme (beneficiary or beneficiary).

Ages Eligible for Study
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Minimum 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: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Adults without diagnosis of PH<br>Adults without diagnosis of PH carrying an heterozygous EIF2AK4 | Other: Screening of adult without diagnosis of PH carrying an heterozygous EIF2AK4 mutation.<br>* will be performed : a clinical evaluation (dyspnea assessed by New York Heart Association functional class (I-IV), signs of right heart failure), a 6min walk test, a Computerized Tomography scan of the chest, an electrocardiogram, an echocardiography (measurement of the velocity of tricuspid regurgitation, measurement of Tricuspid Annular Plane Systolic Excursion (TAPSE) and Tei index, pericardial effusion, dilatation and hypertrophy of the right ventricle), an abdomina ulstrasound, a stress Test (ventilation oxygen peak and ventilation oxygen specific, minute ventilation, dead-space ventilation / dead space, ventilatory reserve, alveolar-arterial gradient, pulse oxygen, PaO2), a lung function tests and measurement of Diffusing capacity or transfer factor of the Lung for Carbon mOnoxide (DLCO) and Nitric Oxide (DLNO), and a blood sample.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolution of characteristics of asymptomatic heterozyous EIF2AK4 mutation carriers and monitor these subjects' clinical, functional, biological, echocardiographic | frequency of abnormalities observed | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| predictive factors of the occurrence of PVOD follow prospectively a cohort of asymptomatic heterozyous EIF2AK4 mutation carriers to determine predictive factors of the occurrence of VOD | number of heterozygous EIF2AK4 mutation carriers who will develop Pulmonary Veno-Occlusive Disease | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary veino occlusive disease, pulmonary hypertension