Sjögren-Larsson syndrome is caused by a common mutation in northern European and Swedish patients.

Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. Patients with SLS have deficient activity of fatty aldehyde dehydrogenase (FALDH), an enzyme involved in long-chain fatty alcohol oxidation. The cDNA encoding FALDH has recently been cloned and several different mutations have been found in SLS patients. We have now identified a point mutation (C943 --> T) in 7 of 19 kindreds of European descent, accounting for 24% of the SLS alleles. The C943T mutation was only found in patients of northern European ancestry from Sweden, the Netherlands, Germany, and Belgium. Haplotype analysis suggested that the patients carrying the C943T allele were distantly related. All four Swedish patients were homozygous for C943T, indicating that this mutation is probably the major cause of SLS in the inbred Swedish families. The mutation leads to the substitution of serine for the highly conserved proline 315 in the FALDH protein, and expression studies confirm that it destroys enzymatic activity. The mutation was readily detected with an MnlI restriction enzyme digestion test. The finding that C943T is a common SLS mutation in northern European and Swedish patients affords a rapid simple method for diagnosing SLS by screening patients for this mutation with DNA-based methods.