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Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency

Lookup NU author(s): Dr Steven Hardy, Professor Robert Taylor


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© 2015 Ahting, Mayr, Vanlander, Hardy, Santra, Makowski, Alston, Zimmermann, Abela, Plecko, Rohrbach, Spranger, Seneka, Rolinski, Hagendorff, Hempel, Sperl, Meitinger, Smet, Taylor, Van-coster, Freisinger, Prokisch and Haack. Disorders of the mitochondrial energy metabolism are clinically and genetically heterogeneous. An increasingly recognized subgroup is caused by defective mitochondrial iron-sulfur (Fe-S) cluster biosynthesis, with defects in 13 genes being linked to human disease to date. Mutations in three of them, NFU1, BOLA3, and IBA57, affect the assembly of mitochondrial [4Fe-4S] proteins leading to an impairment of diverse mitochondrial metabolic pathways and ATP production. Patients with defects in these three genes present with lactic acidosis, hyperglycinemia, and reduced activities of respiratory chain complexes I and II, the four lipoic acid-dependent 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). To date, five different NFU1 pathogenic variants have been reported in 15 patients from 12 families. We report on seven new patients from five families carrying compound heterozygous or homozygous pathogenic NFU1 mutations identified by candidate gene screening and exome sequencing. Six out of eight different disease alleles were novel and functional studies were performed to support the pathogenicity of five of them. Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first six months of life in six out of seven patients. Laboratory investigations revealed combined defects of PDHc (5 out of 5) and respiratory chain complexes I and II+III (4 out of 5) in skeletal muscle and/or cultured skin fibroblasts as well as increased lactate (5 out of 6) and glycine concentration (7 out of 7). Our study contributes to a better definition of the phenotypic spectrum associated with NFU1 mutations and to the diagnostic workup of future patients.

Publication metadata

Author(s): Ahting U, Mayr JA, Vanlander AV, Hardy SA, Santra S, Makowski C, Alston CL, Zimmermann FA, Abela L, Plecko B, Rohrbach M, Spranger S, Seneca S, Rolinski B, Hagendorff A, Hempel M, Sperl W, Meitinger T, Smet J, Taylor RW, Van Coster R, Freisinger P, Prokisch H, Haack TB

Publication type: Article

Publication status: Published

Journal: Frontiers in Genetics

Year: 2015

Volume: 6

Issue: MAR

Online publication date: 13/04/2015

Acceptance date: 16/03/2015

ISSN (electronic): 1664-8021

Publisher: Frontiers Research Foundation


DOI: 10.3389/fgene.2015.00123


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