title: 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.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Aldahmesh
authors.forename: Jawahir Y
authors.initials: JY
authors.lastname: Mohamed
authors.forename: Hisham S
authors.initials: HS
authors.lastname: Alkuraya
authors.forename: Ishwar C
authors.initials: IC
authors.lastname: Verma
authors.forename: Ratna D
authors.initials: RD
authors.lastname: Puri
authors.forename: Ayodele A
authors.initials: AA
authors.lastname: Alaiya
authors.forename: William B
authors.initials: WB
authors.lastname: Rizzo
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D001483:Base Sequence; D002675:Child, Preschool; D003241:Consanguinity; D002658:Developmental Disabilities / Q000235:genetics; D059472:Exome; D005136:Eye Proteins / Q000235:genetics*; D017809:Fatal Outcome; D005227:Fatty Acids / Q000378:metabolism; D005808:Genes, Recessive; D056726:Genetic Association Studies; D006801:Humans; D007057:Ichthyosis / Q000175:diagnosis / Q000235:genetics*; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D011782:Quadriplegia / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C418975:ELOVL4 protein, human; D005136:Eye Proteins; D005227:Fatty Acids; D008565:Membrane Proteins
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