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. 2010 Nov;68(5):611-8.
doi: 10.1002/ana.22122.

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

Michael C Kruer  1 , Coro Paisán-Ruiz, Nathalie Boddaert, Moon Y Yoon, Hiroko Hama, Allison Gregory, Alessandro Malandrini, Randall L Woltjer, Arnold Munnich, Stephanie Gobin, Brenda J Polster, Silvia Palmeri, Simon Edvardson, John Hardy, Henry Houlden, Susan J Hayflick
Affiliations

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

Michael C Kruer et al. Ann Neurol. 2010 Nov.

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.

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Conflict of interest statement

Potential Conflicts of Interest

Nothing to report.

Figures

FIGURE 1
FIGURE 1
Features of FAHN. (A) Partial pedigree of family 1. (B) MRI features of FAHN. Column 1 depicts MRI images from the index family; Column 2 illustrates findings in the second family identified; Column 3 depicts findings from the case previously published by Edvardson et al; Column 4 features MRI findings from Dick et al. Hypointensity of the globus pallidus, consistent with iron deposition, is seen on coronal and sagittal T2-weighted images (arrowheads). White matter hyperintensity is demonstrable as well (arrows). Profound pontocerebellar atrophy, mild cerebral atrophy, and thinning of the corpus callosum is also evident (long arrows).
FIGURE 2
FIGURE 2
Identification and analysis of a novel FA2H mutation. (A) A shared block of homozygosity nearly 2 Mb in length, common to all three affected members of the index family but absent in the unaffected brother genotyped, was identified. (B) FA2H was selected as a prominent candidate gene given its critical role in lipid metabolism; sequencing identified a c.460C>T homozygous transition in all three affected family members. (C) By aligning homologs across species using ClustalW (http://www.ebi.ac.uk/Tools/clustalw2/index.html), amino acid sequence conservation across species was compared; the mutation identified (R154C) was predicted to alter a highly conserved arginine residue. (D) Comparison of this novel mutation with other identified mutations, (red arrows = Family 1 and 2; black arrows = previously reported mutations; black line indicates extent of splice site mutation predicted to result in skipping of exons 5 and 6).
FIGURE 3
FIGURE 3
Ceramides connect several neurodegenerative disorders. *Some lysosomal storage disorders, such as the gangliosidoses, features significant alterations in brain iron composition.,
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