Phenotypic continuum of NFU1-related disorders

Abstract

Bi-allelic variants in Iron-Sulfur Cluster Scaffold (NFU1) have previously been associated with multiple mitochondrial dysfunctions syndrome 1 (MMDS1) characterized by early-onset rapidly fatal leukoencephalopathy. We report 19 affected individuals from 10 independent families with ultra-rare bi-allelic NFU1 missense variants associated with a spectrum of early-onset pure to complex hereditary spastic paraplegia (HSP) phenotype with a longer survival (16/19) on one end and neurodevelopmental delay with severe hypotonia (3/19) on the other. Reversible or irreversible neurological decompensation after a febrile illness was common in the cohort, and there were invariable white matter abnormalities on neuroimaging. The study suggests that MMDS1 and HSP could be the two ends of the NFU1-related phenotypic continuum.

Figure 1

Clinical features of the individuals reported in this study and NFU1‐associated phenotypic continuum. (A) Ages of the affected individuals at the study recruitment. (B) Clinical features of the present cohort. (C) NFU1‐associated phenotypic continuum. HSP, hereditary spastic paraplegia. (D) Representative brain MRI features of the present cohort. Individual F1‐II:2 (A, D, G, L), individual F4‐II:5 (B), individual F10‐II:1 (C, F, I, M, N), individual F5‐II:2 (E, K), individual F7‐II:1 (H), individual F4‐II:6 (J), and individual F10‐II:2 (O, P, Q, R). T2/FLAIR hyperintense signal involving the bilateral posterior centrum semiovale (Q), corona radiata, and periatrial regions (A‐C). T2 hyperintense signal involving the bilateral thalami and basal ganglia (D‐F), pons, and cerebellum (G‐I). Hypoplastic corpus callosum and mega cisterna magna (J‐L). Bilateral cerebral white matter volume loss (A‐F, Q, R). Areas of restricted diffusion involving the bilateral subcortical white matter and cerebral peduncles (M‐P). Areas of cystic degeneration/leukomalacia in the white matter of the bilateral frontal lobes (Q, R). Vermian hypoplasia (K).

Figure 2

Overview of the genetic and biochemical characteristics of NFU1 variants. (A) Pedigrees and segregation results of the ten families included in this study. (B) NFU1 gene structure with the localization of all previously known mutations (black, above) and mutations reported in this cohort (colored, below). The corresponding amino acid changes is shown in (C) with known protein domains in NFU1 (NifU N‐terminal domain, residue 59 to 155, and NifU C‐terminal domain, residue 162 to 247) depicted in the illustration. The variant, p.(Val241Leu), was the only mutation discovered in this study to have been located outside of the NFU1 protein domains. Regions are not drawn to scales and both illustrations were created from the program. (D) Conservation of the nine mutations reported in the present cohort across 10 species. (E) Western blot analysis of structural subunits from each OXPHOS complex (CI [NDUFB8], CII [SDHB], CIII [UQCRC2], CIV [COXII], and CV [ATP5A]) in fibroblasts from F1‐II:1 (affected individual), F1‐I:1 (mother) and a pediatric control. GAPDH and VDAC1 were used as cell and mitochondrial loading controls, respectively. (F) Protein model of the NifU N‐terminal domain and NifU C‐terminal domain of the NFU1 structure. Positions of amino acids affected by NFU1 missense variants are indicated in orange.