A novel complex neurological phenotype due to a homozygous mutation in FDX2

Juliana Gurgel-Giannetti, David S. Lynch, Anderson Rodrigues Brandão de Paiva, Leandro Tavares Lucato, Guilherme Yamamoto, Christer Thomsen, Somsuvro Basu, Fernando Freua, Alexandre Varella Giannetti, Bruno Della Ripa de Assis, Mara Dell Ospedale Ribeiro, Isabella Barcelos, Katiane Sayão Souza, Fernanda Monti, Uirá Souto Melo, Simone Amorim, Leonardo G. L. Silva, L. cia Inês Macedo-Souza, Angela M. Vianna-Morgante, Michio Hirano & 6 others Marjo S. van der Knaap, Roland Lill, Mariz Vainzof, Anders Oldfors, Henry Houlden, Fernando Kok

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)2289-2298
JournalBrain
Volume141
Issue number8
DOIs
Publication statusPublished - 2018

Cite this

Gurgel-Giannetti, J., Lynch, D. S., Brandão de Paiva, A. R., Lucato, L. T., Yamamoto, G., Thomsen, C., ... Kok, F. (2018). A novel complex neurological phenotype due to a homozygous mutation in FDX2. Brain, 141(8), 2289-2298. https://doi.org/10.1093/brain/awy172
Gurgel-Giannetti, Juliana ; Lynch, David S. ; Brandão de Paiva, Anderson Rodrigues ; Lucato, Leandro Tavares ; Yamamoto, Guilherme ; Thomsen, Christer ; Basu, Somsuvro ; Freua, Fernando ; Giannetti, Alexandre Varella ; Ripa de Assis, Bruno Della ; Ospedale Ribeiro, Mara Dell ; Barcelos, Isabella ; Souza, Katiane Sayão ; Monti, Fernanda ; Melo, Uirá Souto ; Amorim, Simone ; Silva, Leonardo G. L. ; Macedo-Souza, L. cia Inês ; Vianna-Morgante, Angela M. ; Hirano, Michio ; van der Knaap, Marjo S. ; Lill, Roland ; Vainzof, Mariz ; Oldfors, Anders ; Houlden, Henry ; Kok, Fernando. / A novel complex neurological phenotype due to a homozygous mutation in FDX2. In: Brain. 2018 ; Vol. 141, No. 8. pp. 2289-2298.
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title = "A novel complex neurological phenotype due to a homozygous mutation in FDX2",
abstract = "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.",
author = "Juliana Gurgel-Giannetti and Lynch, {David S.} and {Brand{\~a}o de Paiva}, {Anderson Rodrigues} and Lucato, {Leandro Tavares} and Guilherme Yamamoto and Christer Thomsen and Somsuvro Basu and Fernando Freua and Giannetti, {Alexandre Varella} and {Ripa de Assis}, {Bruno Della} and {Ospedale Ribeiro}, {Mara Dell} and Isabella Barcelos and Souza, {Katiane Say{\~a}o} and Fernanda Monti and Melo, {Uir{\'a} Souto} and Simone Amorim and Silva, {Leonardo G. L.} and Macedo-Souza, {L. cia In{\^e}s} and Vianna-Morgante, {Angela M.} and Michio Hirano and {van der Knaap}, {Marjo S.} and Roland Lill and Mariz Vainzof and Anders Oldfors and Henry Houlden and Fernando Kok",
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Gurgel-Giannetti, J, Lynch, DS, Brandão de Paiva, AR, Lucato, LT, Yamamoto, G, Thomsen, C, Basu, S, Freua, F, Giannetti, AV, Ripa de Assis, BD, Ospedale Ribeiro, MD, Barcelos, I, Souza, KS, Monti, F, Melo, US, Amorim, S, Silva, LGL, Macedo-Souza, LCI, Vianna-Morgante, AM, Hirano, M, van der Knaap, MS, Lill, R, Vainzof, M, Oldfors, A, Houlden, H & Kok, F 2018, 'A novel complex neurological phenotype due to a homozygous mutation in FDX2' Brain, vol. 141, no. 8, pp. 2289-2298. https://doi.org/10.1093/brain/awy172

A novel complex neurological phenotype due to a homozygous mutation in FDX2. / Gurgel-Giannetti, Juliana; Lynch, David S.; Brandão de Paiva, Anderson Rodrigues; Lucato, Leandro Tavares; Yamamoto, Guilherme; Thomsen, Christer; Basu, Somsuvro; Freua, Fernando; Giannetti, Alexandre Varella; Ripa de Assis, Bruno Della; Ospedale Ribeiro, Mara Dell; Barcelos, Isabella; Souza, Katiane Sayão; Monti, Fernanda; Melo, Uirá Souto; Amorim, Simone; Silva, Leonardo G. L.; Macedo-Souza, L. cia Inês; Vianna-Morgante, Angela M.; Hirano, Michio; van der Knaap, Marjo S.; Lill, Roland; Vainzof, Mariz; Oldfors, Anders; Houlden, Henry; Kok, Fernando.

In: Brain, Vol. 141, No. 8, 2018, p. 2289-2298.

Research output: Contribution to journalArticleAcademicpeer-review

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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.

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Gurgel-Giannetti J, Lynch DS, Brandão de Paiva AR, Lucato LT, Yamamoto G, Thomsen C et al. A novel complex neurological phenotype due to a homozygous mutation in FDX2. Brain. 2018;141(8):2289-2298. https://doi.org/10.1093/brain/awy172