Ramaekers V T, Thöny B, Sequeira J M, Ansseau M, Philippe P, Boemer F, Bours V, Quadros E V
Division of Paediatric Neurology, Centre Hospitalier Universitaire de Liège, Liège, Belgium; Centre for Autism Liège, Centre Hospitalier Universitaire de Liège, Liège, Belgium.
Division of Metabolism, University Children's Hospital Zurich, Switzerland.
Mol Genet Metab. 2014 Dec;113(4):307-14. doi: 10.1016/j.ymgme.2014.10.002. Epub 2014 Oct 12.
Auto-antibodies against folate receptor alpha (FRα) at the choroid plexus that block N(5)-methyltetrahydrofolate (MTHF) transfer to the brain were identified in catatonic schizophrenia. Acoustic hallucinations disappeared following folinic acid treatment. Folate transport to the CNS prevents homocysteine accumulation and delivers one-carbon units for methyl-transfer reactions and synthesis of purines. The guanosine derivative tetrahydrobiopterin acts as common co-factor for the enzymes producing dopamine, serotonin and nitric oxide.
Our study selected patients with schizophrenia unresponsive to conventional treatment. Serum from these patients with normal plasma homocysteine, folate and vitamin B12 was tested for FR autoantibodies of the blocking type on serial samples each week. Spinal fluid was analyzed for MTHF and the metabolites of pterins, dopamine and serotonin. The clinical response to folinic acid treatment was evaluated.
Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls (3.3%) (χ(2)=21.6; p<0.0001). FRα antibody titers in patients fluctuated over time varying between negative and high titers, modulating folate flux to the CNS, which explained low CSF folate values in 6 and normal values in 7 patients. The mean±SD for CSF MTHF was diminished compared to previously established controls (t-test: 3.90; p=0.0002). A positive linear correlation existed between CSF MTHF and biopterin levels. CSF dopamine and serotonin metabolites were low or in the lower normal range. Administration of folinic acid (0.3-1mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement.
Assessment of FR auto-antibodies in serum is recommended for schizophrenic patients. Clinical negative or positive symptoms are speculated to be influenced by the level and evolution of FRα antibody titers which determine folate flux to the brain with up- or down-regulation of brain folate intermediates linked to metabolic processes affecting homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters. Folinic acid intervention appears to stabilize the disease process.
在紧张型精神分裂症患者中发现了脉络丛处针对叶酸受体α（FRα）的自身抗体，该抗体可阻断N(5)-甲基四氢叶酸（MTHF）向脑内的转运。亚叶酸治疗后幻听消失。叶酸向中枢神经系统的转运可防止同型半胱氨酸蓄积，并为甲基转移反应和嘌呤合成提供一碳单位。鸟苷衍生物四氢生物蝶呤是生成多巴胺、5-羟色胺和一氧化氮的酶的共同辅因子。
我们的研究选取了对传统治疗无反应的精神分裂症患者。对这些血浆同型半胱氨酸、叶酸和维生素B12水平正常的患者的血清，每周对连续样本检测阻断型FR自身抗体。分析脑脊液中的MTHF以及蝶呤、多巴胺和5-羟色胺的代谢产物。评估亚叶酸治疗的临床反应。
18例患者中有15例（83.3%）血清FR自身抗体呈阳性，而30例对照中仅有1例（3.3%）呈阳性（χ(2)=21.6；p<0.0001）。患者的FRα抗体滴度随时间波动，在阴性和高滴度之间变化，调节着叶酸向中枢神经系统的通量，这解释了6例患者脑脊液叶酸值低和7例患者叶酸值正常的原因。与先前确定的对照相比，脑脊液MTHF的平均值±标准差降低（t检验：3.90；p=0.0002）。脑脊液MTHF与生物蝶呤水平之间存在正线性相关。脑脊液多巴胺和5-羟色胺代谢产物水平低或处于正常范围下限。对7例参与研究的患者给予亚叶酸（0.3 - 1mg/kg/天）至少6个月，临床症状得到改善。
建议对精神分裂症患者检测血清FR自身抗体。推测临床阴性或阳性症状受FRα抗体滴度水平及变化的影响，抗体滴度决定了叶酸向脑内的通量，进而上调或下调与影响同型半胱氨酸水平、四氢生物蝶呤合成及神经递质的代谢过程相关的脑叶酸中间产物。亚叶酸干预似乎可稳定疾病进程。
