TY - JOUR
T1 - A novel complex neurological phenotype due to a homozygous mutation in FDX2
AU - Gurgel-Giannetti, Juliana
AU - Lynch, David S.
AU - Brandão de Paiva, Anderson Rodrigues
AU - Lucato, Leandro Tavares
AU - Yamamoto, Guilherme
AU - Thomsen, Christer
AU - Basu, Somsuvro
AU - Freua, Fernando
AU - Giannetti, Alexandre Varella
AU - Ripa de Assis, Bruno Della
AU - Ospedale Ribeiro, Mara Dell
AU - Barcelos, Isabella
AU - Souza, Katiane Sayão
AU - Monti, Fernanda
AU - Melo, Uirá Souto
AU - Amorim, Simone
AU - Silva, Leonardo G. L.
AU - Macedo-Souza, L. cia Inês
AU - Vianna-Morgante, Angela M.
AU - Hirano, Michio
AU - van der Knaap, Marjo S.
AU - Lill, Roland
AU - Vainzof, Mariz
AU - Oldfors, Anders
AU - Houlden, Henry
AU - Kok, Fernando
PY - 2018
Y1 - 2018
N2 - Defects in iron–sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C 4 T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis.
AB - Defects in iron–sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C 4 T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85055771370&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30010796
U2 - https://doi.org/10.1093/brain/awy172
DO - https://doi.org/10.1093/brain/awy172
M3 - Article
C2 - 30010796
SN - 0006-8950
VL - 141
SP - 2289
EP - 2298
JO - Brain
JF - Brain
IS - 8
ER -