In 2 unrelated Polish boys (patients 1 and 2) with ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facial features (IKSHD; 618527), Kutkowska-Kazmierczak et al. (2018) identified heterozygosity for a c.494C-T transition (c.494C-T, NM_001256399.1) in the ELOVL1 gene, resulting in a ser165-to-phe (S165F) substitution at a highly conserved residue. The mutation arose de novo in patient 2; the father and relatives of patient 1 could not be tested. Calculation of kinship coefficient indicated no relationship between the 2 families, and the patients did not share any ultra-rare variants other than ELOVL1 S165F, which was not found in an in-house database of more than 500 Polish exomes, or the ExAC or gnomAD databases. Studies in transfected HEK293 cells as well as analysis of patient 2 fibroblasts demonstrated a decrease in the concentration of fatty acids with the longest chains (C24:0, C28:0, and C:26.1) and increased levels of those with shorter chains (C20:0 and C22:0). In patient serum, the C24:0/C22:0 ratio was consistently low, suggesting that a lowered C24:0/C22:0 ratio might be a biomarker for the disease.
Independently, Mueller et al. (2019) studied the same 2 Polish boys with IKSHD reported by Kutkowska-Kazmierczak et al. (2018), and also identified heterozygosity for the S165F mutation (c.494C-T, NM_001256399) in the ELOV1 gene, predicted to be located at the border between the endoplasmic reticulum lumen and transmembrane helix 5. Segregation analysis demonstrated that the mutation arose de novo in both patients; haplotype analysis excluded a common ancestral origin of the mutation. In fatty acid elongation assays in vitro, mutant ELOVL1 did not exhibit any enzymatic activity. Lipid analyses of patient fibroblasts and skin samples showed reduced C26 ceramides and sphingomyelins, with an increase in C20 and C22 sphingomyelins. Reduced C24:0/C22:0 and C26:0/C22:0 ratios of ceramide and sphingomyelin were observed in skin keratinocytes and fibroblasts. Transcriptome analysis revealed upregulation of genes involved in epidermal development and keratinization, and downregulation of genes for neurodevelopment, myelination, and synaptogenesis.
