Recessive mutations in ELOVL4 cause ichthyosis, intellectual disability, and spastic quadriplegia

Abstract

Very-long-chain fatty acids (VLCFAs) play important roles in membrane structure and cellular signaling, and their contribution to human health is increasingly recognized. Fatty acid elongases catalyze the first and rate-limiting step in VLCFA synthesis. Heterozygous mutations in ELOVL4, the gene encoding one of the elongases, are known to cause macular degeneration in humans and retinal abnormalities in mice. However, biallelic ELOVL4 mutations have not been observed in humans, and murine models with homozygous mutations die within hours of birth as a result of a defective epidermal water barrier. Here, we report on two human individuals with recessive ELOVL4 mutations revealed by a combination of autozygome analysis and exome sequencing. These individuals exhibit clinical features of ichthyosis, seizures, mental retardation, and spasticity-a constellation that resembles Sjögren-Larsson syndrome (SLS) but presents a more severe neurologic phenotype. Our findings identify recessive mutations in ELOVL4 as the cause of a neuro-ichthyotic disease and emphasize the importance of VLCFA synthesis in brain and cutaneous development.

Figure 1

Clinical Images of Two Individuals with ELOVL4-Related Pseudo-SLS (A) A photograph of person 2 shows the hypertonic posture and ichthyotic skin. (B) A close-up image of the skin demonstrates the erythematous ichthyosis and a well-demarcated but less-affected region on the upper chest. (C and D) A brain MRI of person 1 (sagittal and coronal views, respectively) shows delayed myelination and evidence of brain atrophy.

Figure 2

Autozygome Analysis of Person 1 Blue bars indicate ROH. The locations of ALDH3A2 and ELOVL4 are indicated by red and blue triangles, respectively.

Figure 3

Filtering Strategy Used for Identification of a Causative Recessive Mutation in a Simplex Case with Pseudo-SLS

Figure 4

Cartoon of ELOVL4 Five transmembrane (TM) domains are indicated by boxes 1–5. The diiron-oxo binding motif (His158-His162) is circled, and Carboxy-terminal dilysine is columned. The previously reported mutations are shown on top of the cartoon, and the two mutations in this work with the DNA chromatogram are shown below the cartoon in the TM-4 domain.