Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration

Abstract

Fatty acid hydroxylase-associated neurodegeneration due to fatty acid 2-hydroxylase deficiency presents with a wide range of phenotypes including spastic paraplegia, leukodystrophy, and/or brain iron deposition. All previously described families with this disorder were consanguineous, with homozygous mutations in the probands. We describe a 10-year-old male, from a non-consanguineous family, with progressive spastic paraplegia, dystonia, ataxia, and cognitive decline associated with a sural axonal neuropathy. The use of high-throughput sequencing techniques combined with SNP array analyses revealed a novel paternally derived missense mutation and an overlapping novel maternally derived ~28-kb genomic deletion in FA2H. This patient provides further insight into the consistent features of this disorder and expands our understanding of its phenotypic presentation. The presence of a sural nerve axonal neuropathy had not been previously associated with this disorder and so may extend the phenotype.

Figure 1

Pedigree and FA2H mutations. (a) Family pedigree. The proband is indicated by an arrow. The affected individual is indicated in black. (b) Segregation of the paternally inherited FA2H missense mutation (c.707C>T; p.F236S). Schematic diagram of genomic locus and sequencing chromatogram (star and arrow represent mutation). (c) F236 and R235 are highly conserved residues across species. (d) Fluorescence intensity plot of SNP array showing a ∼28-kb single copy deletion in proband and mother (FA2H exons 3–7). (e) qPCR results for FA2H exon 6 confirming the hemizygous deletion in the mother (I-1) and the proband (II-2).

Figure 2

Brain MRI (3Tesla). (a) Diffuse white matter signal abnormalities consistent with demyelinating leukodystrophy (arrows; axial FLAIR). (b) Thin corpus callosum (black arrow) and mild brainstem/cerebellar atrophy (white arrow; sagittal T1-weighted). (c) Borderline mineralization of the globi pallidi (arrows; axial FLAIR).