Genetics and Inheritance:NFU1 deficiency is an ultrarare autosomal recessive disease with just over 50 reported cases worldwide. It is interesting to note the existence of a prevalent pathogenic variant (c.622G>T, p.Gly208Cys) in the European population, which possibly has a founder effect in the Basque population. Another frequently reported mutation is c.565G>A (p.Gly189Arg). Both mutations affect highly conserved residues.
Pathophysiology:The NFU1 protein is a member of the mitochondria-localized ISC (iron-sulfur cluster assembly) machinery, which is responsible for the biogenesis of cellular iron-sulfur (Fe-S) proteins. Fe-S clusters are among the most ancient, ubiquitous, and versatile metal cofactors in nature. In contrast to their simple structure, the biogenesis of Fe-S clusters is an extraordinarily complex process. It involves a large number of proteins required for assembly, maturation, and delivery of Fe-S to their target proteins. Functionally, NFU1 protein operates in a late step of the mitochondrial ISC pathway, where it can receive [4Fe-4S] clusters to be transferred to target apoproteins, including members of the respiratory chain (complexes I and II) and lipoic acid synthase (LIAS), the enzyme responsible of lipoic acid synthesis. Consistent with this role, patients with pathogenic variants in the NFU1 gene exhibit multiple mitochondrial dysfunctions. This includes impaired lipoylation of, e.g., the E2 subunits of pyruvate and 2-ketoglutarate dehydrogenase complexes, as well as the E2 component of the glycine cleavage system (GCS). In addition, respiratory chain complexes that dependent on [4Fe-4S] clusters, - particularly complexes I and II - are also compromised.
Diagnosis: The diagnostic process goes from clinical suspicion to molecular studies. In this context, accurate clinical and biochemical characterization of patients is crucial for interpreting genetic data and narrowing down potential disease-causing mutations. With few exceptions, high levels of lactate and glycine in physiological fluids are common findings. Additionally, the analysis of protein-bound lipoic acid provides a valuable information to identify NFU1 and other lipoylation defects. This assessment is performed in patient’s tissues using a specific antibody that recognizes the lipoylated forms of the E2 subunits of 2-oxoacid dehydrogenase complexes as well as the lipoylated H-protein of the GCS. The fact that this antibody does not react against non-lipoylated proteins provides an efficient and cost-effective tool to identify lipoylation defects. Taken together, this combined strategy is a useful approach to reach the final diagnosis.
NFU1