Profound Cerebral Folate Deficiency as a Clinical Model for Identification of MRI and Biochemical Signatures of Choroid Plexus Dysfunction
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 65
- 试验地点
- 4
- 主要终点
- Identify a clinico-radio-proteo-metabolic profile indicative of choroid plexus dysfunction based on observation of LHIPFOLD patients as an experimental model.
研究概览
简要总结
Cerebral folate deficiency (CFD), a partially treatable condition defined by a low folate cerebrospinal fluid (CSF) concentration, can be linked to genetic defects of folate metabolism or be secondary to various diseases without clear causal link. The team identified a neurological syndrome (named LHIPFOLFD) characterized by deep CFD and a specific leukoencephalopathy, related to several possible gene defects never involving folate metabolism. The team hypothesize that CFD in LHIPFOLD is due to a Choroid Plexus (CP) dysfunction, a brain organ that expresses transporters regulating flux between blood and CSF of numerous metabolites (including folate), and secretes CSF and specific proteins. Consequently, other potentially treatable biochemical abnormalities due to PC dysfunction may exist in LHIPFOLD, beyond CFD. Currently, there is no available clinical explorations to evaluate CP functions, whereas the team consider LHIPFOLD a very useful model to validate the capacity of some relevant diagnostic tools to do so. The objectives are to identify a CP-related MRI and biochemical signature in LHIPFOLD patients, using morphological and functional imaging (CP capillary permeability and CP macrovascular perfusion), and metabolomics/proteomics approaches (untargeted then targeted validation of candidate biomarkers related to CP physiology); and to set-up imaging and biochemical diagnostic tests for clinical practice. For this, brain MRI data and blood/CSF samples will be collected during 2 years from LHIPFOLD patients and controls. Some experimental data indicate that the innovative concept of generalized PC dysfunction as part of a more global pathophysiology has the potential to be applied to other neurological diseases like Alzheimer's disease. Therefore, efficient diagnostic tools exploring CP function will be of great utility not only in LHIPFOLD but also in more common neurological diseases, potentially leading to original therapeutic approaches.
详细描述
Cerebral folate deficiency (CFD) is a condition defined by low concentration (<41 nM) of 5-methyltetrahydrofolate (5MTHF, the biologically active form of folate) in the cerebrospinal fluid (CSF) 1. CFD is considered to be of "primary" origin if it is associated with several genetic diseases involving folate metabolism, leading to severe motor and cognitive manifestations. CFD can also be "secondary", i.e. associated with various definite diseases such as genetic mitochondrial diseases and also unidentified diseases. In secondary CFD, the cause of CFD is not understood. In the center, the team identified 16 CFD patients with common characteristics: deep secondary CFD (5MTHF<10nM whereas blood folate is normal), high protein CSF >1g/L (N<0.5), and a specific involvement of brain white matter, hyperintense on T2-weighted MRI. The team called this syndrome "LHIPFOLD" for Leukoencephalopathy with CSF HIgh Protein and FOLate Deficiency (confidential, planned submission in end of 2022). Within the French metabolic biochemistry labs network, the team identified 6 additional LHIPFOLDpat (LHIPFOLD patients). They have a mean age of 42 to 14 years (min 15; max 77), and a sex ratio of 1.8 (M/F). 9/22 had either a large mitochondrial DNA deletion (Kearns-Sayre) or bi-allelic POLG mutations (mitochondrial DNA replication defect). The other 13 patients were all undiagnosed until recently, but the team found in a research context and validated in vitro bi-allelic variants in 4/7 tested patients within genes from MRPS family, coding for sub-units of the mitoribosome.
LHIPFOLD patients clearly have a defect of intracerebral 5MTHF transport, but without mutation of the brain folate transporters. Since folate is exclusively transported from blood to the brain by the choroid plexus (CP)2, the team hypothesize that CFD in LHIPFOLD is due to CP dysfunction. CP, localized in the brain ventricles, is a vascularized epithelial organ that acts as a blood-CSF barrier, expressing numerous transporters for molecules transfer from the blood to the CSF and vice versa (removing waste products from brain cells). CP also secretes CSF and expresses CSF-secreted proteins related to various functions3.
High protein CSF due to a blood brain barrier alteration, and reported abnormal CP morphology from brain autopsy in two Kearns-Sayre patients are also in favor of CP dysfunction in LHIPFOLD 4. In addition, in two LHIPFOLDpat, the team found very high concentrations of CSF sialic acid without the involvement of sialic acid-related genes whereas CP strongly expresses the sialic acid efflux transporter. The team also recently measured strongly decreased CP size after automatic segmentation in two other LHIPFOLD pat. All these data strongly argue for CP dysfunction in LHIPFOLD .
If the hypothesis is correct, it means that beyond CFD, other CSF abnormalities probably exist as a consequence of generalized CP dysfunction. This may be very interesting in terms of therapeutic approach, as folate supplementation has a clear but limited therapeutic effect, especially in some patients. Unfortunately, to assess our hypothesis, there is no available clinical exploration to evaluate CP functions, whereas CP dysfunction/alteration is suggested as a potential pathogenesis contributor in several common neurological diseases (for the following text the team will use dysfunction for both dysfunction and alteration). As the team think that in LHIPFOLD the CP dysfunction is particularly severe, as suggested by the deep CFD, the team consider LHIPFOLD syndrome a very useful clinical model to validate the capacity of some relevant diagnostic tools to evaluate CP function. Therefore, the objectives of the project are:
- Prove CP dysfunction in LHIPFOLD, through the identification of specific and CP-related MRI and biochemical signatures, using CP-centered imaging and metabolomics and proteomics approaches.
- Identify CP-related biochemical biomarkers in LHIPFOLD directly amenable to treatment.
- Set-up imaging and biochemical diagnostic tests for evaluating CP function in clinical practice (biomarkers-based CP-dysfunction score).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •For LHIPFOLD patients:
- •Suspicion of diagnosis or diagnosis of LHIPFOLD syndrome documented in the medical record, i.e. presence of these three manifestations: severe intrathecal deficiency in 5MTHF< 10 nmol/L, hyperproteinorachia > 1 g/L, and white matter abnormalities on cerebral MRI.
- •Patient covered by Social Security or Complementary Health Insurance or any equivalent scheme (including AME).
- •For Neurological Controls (NC) :
- •No chronic pathology (notably no renal, cardiac, pulmonary or hepatic disease)
- •Patients with one of the following neurological pathologies (confirmed diagnosis or strong suspicion), investigated in the course of routine clinical practice: Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, intracranial hypertension, normal pressure hydrocephalus, frontotemporal dementia.
- •For Healthy Volunteers (VS):
- •No chronic pathology (in particular, no renal, cardiac, pulmonary, hepatic or psychiatric disease)
- •No history of neurological pathology
- •No chronic alcohol intoxication
- •No consumption of toxic substances in the week preceding the inclusion visit
- •No neurological or psychotropic medication.
排除标准
- •For all research participants:
- •Pregnant and breast-feeding women.
- •Participant unable to give informed consent.
- •Participant with a contraindication to MRI: implantable cardiac defibrillators, prostheses, transdermal patches, catheters; implantable pumps; artificial heart valves; implants to treat deafness (if incompatible with MRI); surgical neurostimulator clips., pregnancy, extreme claustrophobia.
- •Participants with contraindications to contrast injection: known allergy to gadolinium chelates, severe renal insufficiency, pregnancy (BHCG for women of childbearing age prior to MRI), breast-feeding.
- •Participants with contraindications to LP: haemostasis abnormalities (PT<50%, platelets < 40*109/L), mass syndrome on brain imaging, suspected infection at or near the needle insertion site, coagulopathy, cardiopulmonary insufficiency or respiratory distress.
- •For NC and VS :
- •Participant under legal protection (guardianship, curatorship)
- •Participant not covered by Social Security or Complementary Health Insurance or any equivalent scheme (excluding AME).
- •Taking folate, vitamin C or dietary supplements containing vitamins (excluding vitamin D and E) in the two months prior to inclusion.
研究组 & 干预措施
Population
- LHIPFOLD patients
- Patients with neurologic disease
- healthy volunteers
干预措施: Biologic samples and MRI (Other)
结局指标
主要结局
Identify a clinico-radio-proteo-metabolic profile indicative of choroid plexus dysfunction based on observation of LHIPFOLD patients as an experimental model.
时间窗: 37 months
Characterization of a specific combined biochemical and radiological signature associated with choroid plexus damage observed in LHIPFOLD patients considered as "cases", comprising a limited number of biomarkers (target 5 to 6).
次要结局
- Development of a simple MRI diagnostic strategy (acquisition and analysis) that can be used routinely for the radiological identification of choroid plexus damage, based on the observation of LHIPFOLD patients as an experimental model.(37 months)
- Development of a simple diagnostic strategy based on biochemistry (metabolites/proteins) of blood and CSF discriminating choroid plexus alteration, using LHIPFOLD patients as an experimental model.(37 months)
- Identification of therapeutic targets, i.e. blood and CSF biochemical biomarkers indicating choroid plexus dysfunction AND likely to be modulated by therapeutic intervention (e.g. supplementation of DFIC with folinic acid).(37 months)