Familial multiple sclerosis in patients with Von Hippel-Lindau disease

Von Hippel-Lindau disease (VHLD) is an autosomal dominant disease characterized by progressive development of a variety of cysts and tumors. These include hemangioblastomas of the CNS and retina, endolymphatic sac tumors, renal cell carcinoma, pheochromocytoma, and pancreatic neuroendocrine tumors, as well as cysts in the kidney, pancreas, and genital tract [1]. Patients are classified as VHLD type 1, typically without pheochromocytoma, and type 2, predominantly with pheochromocytoma [2]. The incidence of VHLD is approximately 1 in 36,000 live births [3, 4], with a penetrance of over 90% by 65 years of age [3], and an average age of onset in the second decade of life [5].

VHLD is caused by deletions or mutations in the VHL gene which encodes for a protein responsible for substrate specificity that is ultimately ubiquitinated [6]. Once ubiquitinated, substrates are bound by the 26S proteasome for degradation [7]. The most well-established targets of the VHL E3 complex are hypoxia-inducible transcription factors (HIF1a and HIF2a) which initiate transcription of many well studied targets, including vascular endothelial growth factor, platelet-derived growth factor B, and erythropoietin. Under normoxic conditions, HIF1a is hydroxylated by prolyl containing hydroxylases, leading to recognition by VBC and subsequent ubiquitination and destruction by the 26S proteasome [8]. However, under hypoxic conditions oxygen is not available for HIF1a hydroxylation, and the HIF1a protein is able to translocate from the cytosol to the nucleus, form a dimer with HIF1B, and initiate transcription of a number of genes involved in growth factor signaling and mitigation of oxidative stress [9].

Deletions or mutations in the VHL gene lead to inability or impaired ability to properly ubiquitinate and subsequently degrade HIF1a. Consequently, increased transcription of HIF1a targets occurs, resulting in increased predilection for development of the various tumors and cysts of VHDL [9]. To our knowledge no other neurological diseases have been associated with VHLD. Multiple sclerosis, on the other hand, is an autoimmune demyelinating disease of the central nervous system with potential genetic predisposition. In this report, we present for the first time a case of superimposed multiple sclerosis in both a mother and daughter with VHLD and highlight the possible connection between the VHL signaling pathway and multiple sclerosis pathophysiology as an exciting area for further study.

The mother and daughter cases presented in this study were the first to show concomitant multiple sclerosis in patients with VHLD. Though pure coincidence is possible, it is also possible that mutation of the VHL gene contributed to the development of multiple sclerosis in these cases.

Though the exact pathophysiology of MS is not well characterized, it is thought that a combination of genetic susceptibility and environmental exposure play a role [10]. Many mutations have been identified in histocompatibility antigen (HLA) class I and class II loci which confer increased risk of multiple sclerosis [11‐14]. As the HLA system is a fundamental component of antigen presentation and T cell activation, the effect of these alleles is likely increased risk of autoantigen presentation. Several genome wide association studies (GWAS) have identified additional loci which increased susceptibility to multiple sclerosis. Notably, a recent study involving 47,429 multiple sclerosis patients and 68,374 control subjects identified about 200 non-major histocompatibility complex candidate genes [15]. This evidence clearly favors a role for genetic risks in the pathogenesis of the disease.

The presence of multiple sclerosis in a mother and daughter with VHLD is particularly interesting in light of a recent report of adult oligodendrocyte specific conditional knockout of VHL which showed impaired oligodendrocyte maturation and remyelination in an LPC-induced demyelination mouse model [16]. This direct association between VHL gene deletion and impairment of remyelination may be particularly relevant to pathophysiology of multiple sclerosis subtypes which show oligodendrocyte dystrophy [17]. In addition to this direct association between VHL gene deletion and impairment of remyelination, the downstream targets of VHL have also been implicated in multiple sclerosis pathology. HIF1a, one of the most well-established VHL targets, was recently found to be one of five potential transcriptional regulators of proinflammatory astrocytes in experimental allergic encephalomyelitis mouse models by single cell sequencing [18]. Downstream of the VHL-Hif1a axis, many genes which regulate oxidative stress are expressed. These genes show significant overlap with those of Nrf2, a known therapeutic target in multiple sclerosis (Fig. 4) [19]. Indeed, work from our group has demonstrated that dimethyl fumarate-mediated induction of Nrf2-ERK1/2 MAPK pathway protects neural stem and progenitor stem cells from oxidative stress, leading to decreased stress-induced apoptosis in vitro [20]. Given the overlapping function of Nrf2 and HIF1a in mitigating reactive oxidative species, this represents another mechanism by which the VHL mutation could confer increased susceptibility to multiple sclerosis. These cases provide support for research into determining whether VHL and its related pathway genes represent genetic links to MS and could be potential therapeutic targets in both MS and VHL.