FV 241. Mutations in NFE2L2 Lead to a Novel Treatable Neurological Disorder with Leukoencephalopathy

Background: We describe four patients with a novel disorder characterized by muscle weakness, dystrophy, immunodeficiency, and leukoencephalopathy. Laboratory investigations showed reduced homocysteine levels and elevated activity of G-6-P-dehydrogenase.

Aim: Analysis of pathophysiology and genetics of this novel disorder and development of therapeutic strategies.

Methods: Exome sequencing, biochemical analyses in fibroblasts.

Results: Exome sequencing revealed heterozygous missense variants in the NEF2L2 gene coding for the transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) in all four patients. NRF2 plays a key role in the cellular defense against various forms of stress especially oxidative stress. In the absence of stress, NRF2 is bound by two molecules of Kelch-like ECH-associated protein 1 (KEAP1) and consecutively degraded by the 26S proteasome. Under oxidative stress, NRF2 translocates into the nucleus where it upregulates the expression of more than 200 genes, among them G6PD and those responsible for the glutathione production from homocysteine. The variants detected in the patients affect the binding site of KEAP1. Experiments in fibroblasts showed that the disturbed bindings lead to high concentration of NRF2 and chronic high expression of the genes regulated by NRF2.

As experiments in various tumors have shown that luteolin, a flavone found in leaves, downregulates NRF2 concentration, we treated the fibroblasts of one of the patients with luteolin. This treatment also resulted in significantly reduced NRF2 levels. We therefore initiated an experimental treatment with luteolin and acetylcysteine on the German patients. Acetylcysteine was given as an alternative substrate for glutathione production to reduce homocysteine degradation. The treatment has led to a normalization of homocysteine levels. Moreover, the parents have reported an increase in muscle strength and reduction in the frequency of infections.

Conclusion: We describe a novel disorder characterized by muscle weakness, dystrophy, immune deficiency, and leukoencephalopathy. Laboratory investigations show reduced homocysteine and elevated activity of G-6-P-dehydrogenase. The disorder is caused by heterozygous variants in NEF2L2 coding for NRF2. Experiments in fibroblasts have led to the development of promising therapeutic strategies.

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