What laboratory or imaging studies are needed to confirm a diagnosis of NFU1‑related multiple mitochondrial dysfunctions syndrome?

definitive diagnosis requires a combination of elevated plasma lactate, characteristic brain MRI findings (e.g., basal ganglia changes), echocardiography showing pulmonary hypertension, and confirmatory genetic sequencing of the NFU1 gene. Muscle biopsy may reveal abnormal mitochondria but is not always necessary.

What hallmark clinical features should prompt evaluation for NFU1‑related mitochondrial disease?

Key red flags include early‑onset pulmonary hypertension, severe developmental regression, seizures, and profound hypotonia. A history of unexplained respiratory distress or failure to thrive in infancy should also raise suspicion.

Is there any treatment that can improve outcomes for children with NFU1 mutations?

There is no curative therapy yet; management focuses on supportive care. Pulmonary hypertension is treated with pulmonary vasodilators (e.g., endothelin receptor antagonists, phosphodiesterase‑5 inhibitors), while seizures are managed with antiepileptic drugs. Early referral to a multidisciplinary mitochondrial disease center can optimize supportive interventions.

How should families prepare for genetic testing of NFU1?

Families should obtain pre‑test counseling to discuss the implications of a positive result, potential carrier status of relatives, and options for future pregnancies. Blood samples are usually collected for sequencing; ensure the laboratory is accredited for mitochondrial disease testing and that the sample is processed promptly.===

NFU1 gene

The NFU1 gene encodes a mitochondrial protein essential for iron‑sulfur cluster assembly, and pathogenic variants cause a fatal form of multiple mitochondrial dysfunctions syndrome. These variants disrupt energy production and lead to severe neurological decline in early childhood.

Overview

Normal Function

The NFU1 gene provides instructions for making a protein that is involved in the formation and transport of molecules called iron-sulfur (Fe‑S) clusters. Certain proteins require Fe‑S clusters to function properly.

The NFU1 protein is found in cellular structures called mitochondria. Mitochondria are the energy‑producing centers of cells. In these structures, several proteins carry out a series of chemical steps called oxidative phosphorylation to convert the energy in food into a form that cells can use. Many of the proteins that play a role in this process require Fe‑S clusters to function. Proteins that contain Fe‑S clusters are involved in many functions in the body including DNA repair and the regulation of gene activity.

Health Conditions Related to Genetic Changes

Multiple mitochondrial dysfunctions syndrome

Genetic changes that cause disease are called pathogenic variants. Pathogenic variants in the NFU1 gene cause multiple mitochondrial dysfunctions syndrome type 1. This condition is characterized by abnormally high blood pressure (hypertension) in the blood vessel that carries blood from the heart to the lungs (the pulmonary artery). People with type 1 have additional health problems that are common to all forms of multiple mitochondrial dysfunctions syndrome, such as severe brain dysfunction (encephalopathy) and a loss of mental abilities and acquired skills (developmental regression). Affected individuals usually do not survive past early childhood.

Pathogenic variants in the NFU1 gene cause cells to produce altered versions of the NFU1 proteins. The most common variant (written as Gly208Cys or G208C) changes a single protein building block (amino acid) in the NFU1 protein. This variant prevents the Fe‑S cluster from attaching to other proteins. Without Fe‑S clusters, certain proteins cannot function normally. This reduces the amount of energy produced by mitochondria and impairs other cellular functions, leading to the severe signs and symptoms of multiple mitochondrial dysfunctions syndrome type 1.

Other Names for This Gene

CGI-33
HIRA-interacting protein 5
HIRIP5
NIFUC

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Tests of NFU1

Scientific Articles on PubMed

PubMed

Catalog of Genes and Diseases from OMIM

NFU1 IRON-SULFUR CLUSTER SCAFFOLD; NFU1

Gene and Variant Databases

NCBI Gene
ClinVar

References

Cameron JM, Janer A, Levandovskiy V, Mackay N, Rouault TA, Tong WH, Ogilvie I, Shoubridge EA, Robinson BH. Mutations in iron-sulfur cluster scaffold genes NFU1 and BOLA3 cause a fatal deficiency of multiple respiratory chain and 2-oxoacid dehydrogenase enzymes. Am J Hum Genet. 2011 Oct 7;89(4):486-95. doi: 10.1016/j.ajhg.2011.08.011. Epub 2011 Sep 22. Citation on PubMed or Free article on PubMed Central
Invernizzi F, Ardissone A, Lamantea E, Garavaglia B, Zeviani M, Farina L, Ghezzi D, Moroni I. Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations. Front Genet. 2014 Nov 20;5:412. doi: 10.3389/fgene.2014.00412. eCollection 2014. Citation on PubMed or Free article on PubMed Central
Mayr JA, Feichtinger RG, Tort F, Ribes A, Sperl W. Lipoic acid biosynthesis defects. J Inherit Metab Dis. 2014 Jul;37(4):553-63. doi: 10.1007/s10545-014-9705-8. Epub 2014 Apr 29. Citation on PubMed
Navarro-Sastre A, Tort F, Stehling O, Uzarska MA, Arranz JA, Del Toro M, Labayru MT, Landa J, Font A, Garcia-Villoria J, Merinero B, Ugarte M, Gutierrez-Solana LG, Campistol J, Garcia-Cazorla A, Vaquerizo J, Riudor E, Briones P, Elpeleg O, Ribes A, Lill R. A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins. Am J Hum Genet. 2011 Nov 11;89(5):656-67. doi: 10.1016/j.ajhg.2011.10.005. Citation on PubMed or Free article on PubMed Central
Rouault TA. Biogenesis of iron-sulfur clusters in mammalian cells: new insights and relevance to human disease. Dis Model Mech. 2012 Mar;5(2):155-64. doi: 10.1242/dmm.009019. Citation on PubMed or Free article on PubMed Central
Wachnowsky C, Wesley NA, Fidai I, Cowan JA. Understanding the Molecular Basis of Multiple Mitochondrial Dysfunctions Syndrome 1 (MMDS1)-Impact of a Disease-Causing Gly208Cys Substitution on Structure and Activity of NFU1 in the Fe/S Cluster Biosynthetic Pathway. J Mol Biol. 2017 Mar 24;429(6):790-807. doi: 10.1016/j.jmb.2017.01.021. Epub 2017 Feb 1. Citation on PubMed

Genomic Location

The NFU1 gene is found on chromosome 2.