Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
BMC Neurol. 2022 Mar 8;22(1):80. doi: 10.1186/s12883-022-02604-6.
Multiple sclerosis (MS) is a progressive autoimmune demyelinating disorder. Recent studies suggest that a combination of genetic susceptibility and environmental insult contributes to its pathogenesis. Many candidate genes have been discovered to modulate susceptibility for developing MS by genome wide association studies (GWAS); these include major histocompatibility complex (MHC) genes and non-MHC genes. MS cases in the context of genetic diseases may provide different approaches and clues towards identifying novel genes and pathways involved in MS pathogenesis. Here, we present a case series of two related patients with concomitant Von Hippel-Lindau disease (VHLD) and MS.
We present two patients, a mother (case 1) and daughter (case 2), who developed superimposed relapsing-remitting multiple sclerosis in the background of the autosomal dominant genetic disorder VHLD. Several tumors characteristic of VHLD developed in both cases with pancreatic and renal neoplasms and cerebellar hemangioblastomas. In addition, both patients developed clinical symptoms consistent with multiple sclerosis, supported by radiologic lesions disseminating in time and space.
Though non-MHC susceptibility genes remain elusive in MS, we present the striking finding of superimposed multiple sclerosis in a mother and daughter with VHLD. The VHL gene is known to be the primary regulator of Nrf2, the well-established target of the FDA-approved therapeutic dimethyl fumarate. These cases provide support for further studies to determine whether VHLD pathway related genes represent a novel genetic link in multiple sclerosis.
多发性硬化症（MS）是一种进行性自身免疫脱髓鞘疾病。最近的研究表明，遗传易感性和环境损伤的结合导致了其发病机制。通过全基因组关联研究（GWAS）发现了许多候选基因，这些基因可以调节发生 MS 的易感性；其中包括主要组织相容性复合体（MHC）基因和非 MHC 基因。在遗传疾病的背景下，MS 病例可能为鉴定参与 MS 发病机制的新基因和途径提供了不同的方法和线索。在这里，我们报告了两例同时患有 von Hippel-Lindau 病（VHLD）和 MS 的相关病例。
我们报告了两例患者，一位母亲（病例 1）和女儿（病例 2），她们在常染色体显性遗传疾病 VHLD 的背景下出现了重叠性复发缓解型多发性硬化症。在这两种情况下，均出现了几种特征性的 VHLD 肿瘤，包括胰腺和肾脏肿瘤以及小脑血管母细胞瘤。此外，这两位患者均出现了符合多发性硬化症的临床症状，影像学病变也呈时间和空间上的弥散性。
尽管非 MHC 易感性基因在 MS 中仍然难以捉摸，但我们发现了一个引人注目的现象，即在患有 VHLD 的母亲和女儿中出现了重叠性多发性硬化症。VHL 基因是 Nrf2 的主要调节剂，而 Nrf2 是 FDA 批准的治疗药物二甲基富马酸的明确靶点。这些病例为进一步研究提供了支持，以确定 VHLD 相关基因是否代表多发性硬化症的新遗传联系。
