Folate receptor α deficiency – Myelin-sensitive MRI as a reliable biomarker to monitor the efficacy and long-term outcome of a new therapeutic approach

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Steffi Dreha-Kulaczewski, Prativa Sahoo, Matthias Preusse, Irini Gkalimani, Peter Dechent, Gunther Helms, Sabine Hofer, Robert Steinfeld, Jutta Gärtner
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引用次数: 0

Abstract

Cerebral folate transport deficiency, caused by a genetic defect in folate receptor α, is a devastating neurometabolic disorder that, if untreated, leads to epileptic encephalopathy, psychomotor decline and hypomyelination. Currently, there are limited data on effective dosage and duration of treatment, though early diagnosis and therapy with folinic acid appears critical. The aim of this long-term study was to identify new therapeutic approaches and novel biomarkers for assessing efficacy, focusing on myelin-sensitive MRI. Clinical, biochemical, structural and quantitative MRI parameters of seven patients with genetically confirmed folate receptor α deficiency were acquired over 13 years. Multimodal MRI approaches comprised MR-spectroscopy (MRS), magnetization transfer (MTI) and diffusion tensor imaging (DTI) sequences. Patients started oral treatment immediately following diagnosis or in an interval of up to 2.5 years. Escalation to intravenous and intrathecal administration was performed in the absence of effects. Five patients improved, one with a presymptomatic start of therapy remained symptom-free, and one with inconsistent treatment deteriorated. While CSF 5-methyltetrahydrofolate and MRS parameters normalized immediately after therapy initiation, myelin-sensitive MTI and DTI measures correlated with gradual clinical improvement and ongoing myelination under therapy. Early initiation of treatment at sufficient doses, considering early intrathecal applications, is critical for favorable outcome. The majority of patients showed clinical improvements that correlated best with MTI parameters, allowing individualized monitoring of myelination recovery. Presymptomatic therapy seems to ensure normal development and warrants newborn screening. Furthermore, the quantitative parameters of myelin-sensitive MRI for therapy assessments can now be used for hypomyelination disorders in general.

Abstract Image

叶酸受体α缺乏症--髓鞘敏感核磁共振成像是监测新疗法疗效和长期结果的可靠生物标志物。
由叶酸受体α基因缺陷引起的脑叶酸转运缺乏症是一种破坏性神经代谢疾病,如不及时治疗,会导致癫痫性脑病、精神运动功能衰退和骨髓营养不良。目前,有关有效治疗剂量和疗程的数据十分有限,但早期诊断和使用亚叶酸治疗似乎至关重要。这项长期研究的目的是确定新的治疗方法和评估疗效的新型生物标志物,重点是髓鞘敏感核磁共振成像。研究人员历时13年,采集了7名经基因证实的叶酸受体α缺乏症患者的临床、生化、结构和定量磁共振成像参数。多模态磁共振成像方法包括磁共振光谱(MRS)、磁化传递(MTI)和弥散张量成像(DTI)序列。患者在确诊后立即开始口服治疗,或间隔长达 2.5 年。如果效果不佳,则升级为静脉注射和鞘内注射。五名患者的病情有所改善,一名无症状患者开始治疗后仍无症状,一名治疗不连贯的患者病情恶化。治疗开始后,CSF 5-甲基四氢叶酸和 MRS 参数立即恢复正常,而髓鞘敏感的 MTI 和 DTI 指标则与临床症状的逐渐改善和治疗中持续的髓鞘化有关。考虑到早期鞘内应用,以足够的剂量尽早开始治疗是取得良好疗效的关键。大多数患者的临床改善与 MTI 参数的相关性最佳,从而可以对髓鞘化的恢复进行个体化监测。无症状治疗似乎能确保正常发育,因此有必要对新生儿进行筛查。此外,用于治疗评估的髓鞘敏感核磁共振成像的定量参数现在也可用于一般的髓鞘功能减退症。
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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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