Genetics and Inheritance
NFU1 deficiency is a genetic disease inherited as an autosomal recessive manner. This means that a child has to inherit two altered copies of the NFU1 gene—one from each parent—to develop the disease. Individuals who carry just one altered copy do not have symptoms. There is one mutation c.622G>T (p.Gly208Cys), that is particularly common in European ancestry population. It is speculated that such variants may have been generated many generations ago in a single ancestor in the Basque region. This is known as a founder effect. Another variant that is also seen is c.565G>A (p.Gly189Arg). Both of these pathogenic genetic changes (mutations) affect the function of the NFU1 protein that has an important physiological role
Pathophysiology
The NFU1 protein operates inside the mitochondria that are the part of our cells and act as their power plants. The particular function of NFU1 is to help making iron-sulfur (Fe-S) clusters, which are essential components that many cell processes depend on. The NFU1 protein specifically receives Fe-S clusters from earlier part of the ISC machinery and delivers them to important target proteins in mitochondria, including respiratory chain complexes I and II, which are essential for producing energy, and lipoic acid synthase, an enzyme needed to make lipoic acid, which helps other mitochondrial enzymes to work properly. When NFU1 function is hampered, these processes break down causing multiple problems in the cell’s power plants and lipoic acid production, which explains why patients have serious symptoms affecting the brain, muscles, and other organs.
Diagnosis
Diagnosing NFU1 deficiency usually starts with suspecting the disease based on symptoms, and then by confirming it with biochemical and genetic tests (DNA sequencing). Getting a comprehensive picture of the patient’s symptoms and biochemical results are important because these analyses help to interpret the genetic findings and to confirm that the NFU1 gene variants are causing the disease. Most patients show high levels of lactate and glycine in their blood or other body fluids. Other useful tests are the analyses of mitochondrial respiratory chain activities and the evaluation of lipoic acid levels. Taken together, this combined multi-disciplinary strategy is a good approach to reach the final diagnosis.
NFU1