Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency.
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 6 months of life in six out of seven patients. Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts as well as increased lactate (five out of six) and glycine concentration (seven out of seven). Our study contributes to a better definition of the phenotypic spectrum associated with NFU1 mutations and to the diagnostic workup of future patients.
Institute of Human Genetics, Technische Universität München Munich, Germany.
Uwe
U
Ahting
Department of Pediatrics, Paracelsus Medical University of Salzburg Salzburg, Austria.
Johannes A
JA
Mayr
Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital Ghent, Belgium.
Arnaud V
AV
Vanlander
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University Medical School Newcastle upon Tyne, UK.
Steven A
SA
Hardy
Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital Birmingham, UK.
Saikat
S
Santra
Department of Pediatrics, Technische Universität München Munich, Germany.
Christine
C
Makowski
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University Medical School Newcastle upon Tyne, UK.
Charlotte L
CL
Alston
Department of Pediatrics, Paracelsus Medical University of Salzburg Salzburg, Austria.
Franz A
FA
Zimmermann
Division of Child Neurology, Children's Research Center, Kinderspital Zürich Zürich, Switzerland.
Lucia
L
Abela
Division of Child Neurology, Children's Research Center, Kinderspital Zürich Zürich, Switzerland.
Barbara
B
Plecko
Division of Metabolism, Children's Research Center, Kinderspital Zürich Zürich, Switzerland.
Marianne
M
Rohrbach
Praxis für Humangenetik Bremen, Germany.
Stephanie
S
Spranger
Research Group Reproduction and Genetics, Center for Medical Genetics, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel Brussels, Belgium.
Sara
S
Seneca
Elblab Zentrum für LaborMedizin, Elblandkliniken Riesa, Germany.
Boris
B
Rolinski
Department of Pediatrics, Klinikum Bremen-Mitte Bremen, Germany.
Angela
A
Hagendorff
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf Hamburg, Germany.
Maja
M
Hempel
Department of Pediatrics, Paracelsus Medical University of Salzburg Salzburg, Austria.
Wolfgang
W
Sperl
Institute of Human Genetics, Technische Universität München Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München Neuherberg, Germany.
Thomas
T
Meitinger
Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital Ghent, Belgium.
Joél
J
Smet
Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University Medical School Newcastle upon Tyne, UK.
Robert W
RW
Taylor
Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital Ghent, Belgium.
Rudy
R
Van Coster
Department of Pediatrics, Klinikum Reutlingen Reutlingen, Germany.
Peter
P
Freisinger
Institute of Human Genetics, Technische Universität München Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München Neuherberg, Germany.
Holger
H
Prokisch
Institute of Human Genetics, Technische Universität München Munich, Germany ; Institute of Human Genetics, Helmholtz Zentrum München Neuherberg, Germany.
Tobias B
TB
Haack
NFU1; iron–sulfur cluster; lipoic acid; mitochondrial respiratory chain; pulmonary hypertension