Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA)

Michael C. Kruer, Coro Paisán-Ruiz, Nathalie Boddaert, Moon Y. Yoon, Hiroko Hama, Allison Gregory, Alessandro Malandrini, Randall (Randy) Woltjer, Arnold Munnich, Stephanie Gobin, Brenda J. Polster, Silvia Palmeri, Simon Edvardson, John Hardy, Henry Houlden, Susan Hayflick

Research output: Contribution to journalArticle

157 Citations (Scopus)

Abstract

Objective Neurodegeneration with brain iron accumulation (NBIA) represents a distinctive phenotype of neurodegenerative disease for which several causative genes have been identified. The spectrum of neurologic disease associated with mutations in NBIA genes is broad, with phenotypes that range from infantile neurodegeneration and death in childhood to adult-onset parkinsonism-dystonia. Here we report the discovery of a novel gene that leads to a distinct form of NBIA. Methods Using autozygosity mapping and candidate gene sequencing, we identified mutations in the fatty acid hydroxylase gene FA2H, newly implicating abnormalities of ceramide metabolism in the pathogenesis of NBIA. Results Neuroimaging demonstrated T2 hypointensity in the globus pallidus, confluent T2 white matter hyperintensities, and profound pontocerebellar atrophy in affected members of two families. Phenotypically, affected family members exhibited spastic quadriparesis, ataxia, and dystonia with onset in childhood and episodic neurological decline. Analogous to what has been reported previously for PLA2G6, the phenotypic spectrum of FA2H mutations is diverse based on our findings and those of prior investigators, because FA2H mutations have been identified in both a form of hereditary spastic paraplegia (SPG35) and a progressive familial leukodystrophy. Interpretation These findings link white matter degeneration and NBIA for the first time and implicate new signaling pathways in the genesis of NBIA.

Original languageEnglish (US)
Pages (from-to)611-618
Number of pages8
JournalAnnals of Neurology
Volume68
Issue number5
DOIs
StatePublished - Nov 2010

Fingerprint

Mutation
Genes
Hereditary Spastic Paraplegia
Phenotype
Quadriplegia
Globus Pallidus
Dystonia
Ceramides
Chromosome Mapping
Mixed Function Oxygenases
Nervous System Diseases
Neuroimaging
Neurodegenerative Diseases
Atrophy
Neurodegeneration with brain iron accumulation (NBIA)
Fatty Acids
Research Personnel
White Matter
Adult-Onset Dystonia-Parkinsonism
Spastic Ataxia

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). / Kruer, Michael C.; Paisán-Ruiz, Coro; Boddaert, Nathalie; Yoon, Moon Y.; Hama, Hiroko; Gregory, Allison; Malandrini, Alessandro; Woltjer, Randall (Randy); Munnich, Arnold; Gobin, Stephanie; Polster, Brenda J.; Palmeri, Silvia; Edvardson, Simon; Hardy, John; Houlden, Henry; Hayflick, Susan.

In: Annals of Neurology, Vol. 68, No. 5, 11.2010, p. 611-618.

Research output: Contribution to journalArticle

Kruer, MC, Paisán-Ruiz, C, Boddaert, N, Yoon, MY, Hama, H, Gregory, A, Malandrini, A, Woltjer, RR, Munnich, A, Gobin, S, Polster, BJ, Palmeri, S, Edvardson, S, Hardy, J, Houlden, H & Hayflick, S 2010, 'Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA)', Annals of Neurology, vol. 68, no. 5, pp. 611-618. https://doi.org/10.1002/ana.22122
Kruer, Michael C. ; Paisán-Ruiz, Coro ; Boddaert, Nathalie ; Yoon, Moon Y. ; Hama, Hiroko ; Gregory, Allison ; Malandrini, Alessandro ; Woltjer, Randall (Randy) ; Munnich, Arnold ; Gobin, Stephanie ; Polster, Brenda J. ; Palmeri, Silvia ; Edvardson, Simon ; Hardy, John ; Houlden, Henry ; Hayflick, Susan. / Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). In: Annals of Neurology. 2010 ; Vol. 68, No. 5. pp. 611-618.
@article{23a7aebd47dc44f38860e32efe6c737e,
title = "Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA)",
abstract = "Objective Neurodegeneration with brain iron accumulation (NBIA) represents a distinctive phenotype of neurodegenerative disease for which several causative genes have been identified. The spectrum of neurologic disease associated with mutations in NBIA genes is broad, with phenotypes that range from infantile neurodegeneration and death in childhood to adult-onset parkinsonism-dystonia. Here we report the discovery of a novel gene that leads to a distinct form of NBIA. Methods Using autozygosity mapping and candidate gene sequencing, we identified mutations in the fatty acid hydroxylase gene FA2H, newly implicating abnormalities of ceramide metabolism in the pathogenesis of NBIA. Results Neuroimaging demonstrated T2 hypointensity in the globus pallidus, confluent T2 white matter hyperintensities, and profound pontocerebellar atrophy in affected members of two families. Phenotypically, affected family members exhibited spastic quadriparesis, ataxia, and dystonia with onset in childhood and episodic neurological decline. Analogous to what has been reported previously for PLA2G6, the phenotypic spectrum of FA2H mutations is diverse based on our findings and those of prior investigators, because FA2H mutations have been identified in both a form of hereditary spastic paraplegia (SPG35) and a progressive familial leukodystrophy. Interpretation These findings link white matter degeneration and NBIA for the first time and implicate new signaling pathways in the genesis of NBIA.",
author = "Kruer, {Michael C.} and Coro Pais{\'a}n-Ruiz and Nathalie Boddaert and Yoon, {Moon Y.} and Hiroko Hama and Allison Gregory and Alessandro Malandrini and Woltjer, {Randall (Randy)} and Arnold Munnich and Stephanie Gobin and Polster, {Brenda J.} and Silvia Palmeri and Simon Edvardson and John Hardy and Henry Houlden and Susan Hayflick",
year = "2010",
month = "11",
doi = "10.1002/ana.22122",
language = "English (US)",
volume = "68",
pages = "611--618",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "5",

}

TY - JOUR

T1 - Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA)

AU - Kruer, Michael C.

AU - Paisán-Ruiz, Coro

AU - Boddaert, Nathalie

AU - Yoon, Moon Y.

AU - Hama, Hiroko

AU - Gregory, Allison

AU - Malandrini, Alessandro

AU - Woltjer, Randall (Randy)

AU - Munnich, Arnold

AU - Gobin, Stephanie

AU - Polster, Brenda J.

AU - Palmeri, Silvia

AU - Edvardson, Simon

AU - Hardy, John

AU - Houlden, Henry

AU - Hayflick, Susan

PY - 2010/11

Y1 - 2010/11

N2 - Objective Neurodegeneration with brain iron accumulation (NBIA) represents a distinctive phenotype of neurodegenerative disease for which several causative genes have been identified. The spectrum of neurologic disease associated with mutations in NBIA genes is broad, with phenotypes that range from infantile neurodegeneration and death in childhood to adult-onset parkinsonism-dystonia. Here we report the discovery of a novel gene that leads to a distinct form of NBIA. Methods Using autozygosity mapping and candidate gene sequencing, we identified mutations in the fatty acid hydroxylase gene FA2H, newly implicating abnormalities of ceramide metabolism in the pathogenesis of NBIA. Results Neuroimaging demonstrated T2 hypointensity in the globus pallidus, confluent T2 white matter hyperintensities, and profound pontocerebellar atrophy in affected members of two families. Phenotypically, affected family members exhibited spastic quadriparesis, ataxia, and dystonia with onset in childhood and episodic neurological decline. Analogous to what has been reported previously for PLA2G6, the phenotypic spectrum of FA2H mutations is diverse based on our findings and those of prior investigators, because FA2H mutations have been identified in both a form of hereditary spastic paraplegia (SPG35) and a progressive familial leukodystrophy. Interpretation These findings link white matter degeneration and NBIA for the first time and implicate new signaling pathways in the genesis of NBIA.

AB - Objective Neurodegeneration with brain iron accumulation (NBIA) represents a distinctive phenotype of neurodegenerative disease for which several causative genes have been identified. The spectrum of neurologic disease associated with mutations in NBIA genes is broad, with phenotypes that range from infantile neurodegeneration and death in childhood to adult-onset parkinsonism-dystonia. Here we report the discovery of a novel gene that leads to a distinct form of NBIA. Methods Using autozygosity mapping and candidate gene sequencing, we identified mutations in the fatty acid hydroxylase gene FA2H, newly implicating abnormalities of ceramide metabolism in the pathogenesis of NBIA. Results Neuroimaging demonstrated T2 hypointensity in the globus pallidus, confluent T2 white matter hyperintensities, and profound pontocerebellar atrophy in affected members of two families. Phenotypically, affected family members exhibited spastic quadriparesis, ataxia, and dystonia with onset in childhood and episodic neurological decline. Analogous to what has been reported previously for PLA2G6, the phenotypic spectrum of FA2H mutations is diverse based on our findings and those of prior investigators, because FA2H mutations have been identified in both a form of hereditary spastic paraplegia (SPG35) and a progressive familial leukodystrophy. Interpretation These findings link white matter degeneration and NBIA for the first time and implicate new signaling pathways in the genesis of NBIA.

UR - http://www.scopus.com/inward/record.url?scp=78249252333&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78249252333&partnerID=8YFLogxK

U2 - 10.1002/ana.22122

DO - 10.1002/ana.22122

M3 - Article

C2 - 20853438

AN - SCOPUS:78249252333

VL - 68

SP - 611

EP - 618

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 5

ER -