Professionals

Summary of the disease
NFU1 deficiency is an ultrarare autosomal recessive disease, with just over 50 reported cases worldwide. The NFU1 protein acts in a late step of the mitochondria-localized iron–sulfur cluster assembly (ISC) pathway, where it receives [4Fe–4S] clusters for delivery to target apoproteins. These include components of the mitochondrial respiratory chain (complexes I and II) and lipoic acid synthase (LIAS), the enzyme required for lipoic acid (LA) biosynthesis. Clinically, the most frequent presentation is a severe, early-onset encephalopathy with neurological regression and pulmonary hypertension. Death usually occurs before 2 years of age. Brain MRI typically shows leukoencephalopathy or leukodystrophy, often accompanied by cavitation.

However, later-onset cases with longer survival have also been described. This milder phenotype is mainly characterized by spastic paraplegia and varying degrees of neurodevelopmental delay. Notably, none of the later-presenting individuals have exhibited pulmonary hypertension. The diagnostic evaluation begins with clinical and biochemical analyses and culminates in molecular confirmation. With few exceptions, elevated lactate and glycine levels in physiological fluids are common findings. Additionally, measurement of lipoic acid levels also provides valuable insights to identify NFU1as a disease-related gene, in addition to other genes directly involved in lipoylation. Unfortunately, no disease-specific treatment currently exists, and management remains purely supportive.