ALDH3A2 – Sjögren-Larsson syndrome

Sjögren-Larsson syndrome (SLS) is a rare autosomal recessive neurocutaneous disorder characterized by congenital ichthyosis, spastic diplegia or paraplegia, and intellectual disability, caused by deficient activity of fatty aldehyde dehydrogenase (FALDH) encoded by ALDH3A2 (PMID:20142464).

Multiple case reports describe biallelic ALDH3A2 variants in affected siblings and extended families: a homozygous nonsense variant c.1320T>A (p.Tyr440Ter) in five consanguineous relatives (PMID:32930514), compound heterozygous c.1291_1292del (p.Lys431fs) and c.798+1del in adolescent-onset neurodegeneration (PMID:30157790).

In an MRI/MRS cohort of 11 FALDH-deficient patients, all exhibited the characteristic ichthyosis and retinal glistening dots, while variable dysmyelination and lipid accumulation correlated with neurologic severity (PMID:10227616).

A mutation screen of 63 kindreds identified 49 unique ALDH3A2 defects, including 22 missense, 10 deletions, 3 nonsense, 9 splice-site, and 3 complex alleles; recurrent founder mutation C943T (p.Pro315Ser) accounts for ~24% of alleles in Northern European families (PMID:10577908, PMID:9204959).

Functional assays demonstrate that missense and nonsense substitutions abolish FALDH catalytic activity, splice-site variants lead to aberrant transcripts, and alternative splicing yields peroxisomal versus ER isoforms, confirming loss-of-function as the pathogenic mechanism (PMID:9204959, PMID:17510064).

Collectively, these data provide definitive evidence that biallelic ALDH3A2 mutations cause Sjögren-Larsson syndrome with consistent genotype–phenotype correlations. Key take-home: targeted sequencing of ALDH3A2 in patients with ichthyosis, spastic diplegia, and intellectual disability enables accurate diagnosis, genetic counseling, and early intervention.

References

• Journal of child neurology • 2010 • A very rare neurocutaneous disorder in 2 siblings: Sjögren-Larsson syndrome PMID:20142464
• Molecular genetics & genomic medicine • 2020 • Sjogren-Larsson Syndrome: A case series of five members from an extended family with a novel mutation PMID:32930514
• BMC medical genetics • 2018 • Neurodegeneration in an adolescent with Sjogren-Larsson syndrome: a decade-long follow-up case report PMID:30157790
• Neurology • 1999 • Sjögren-Larsson syndrome: clinical and MRI/MRS findings in FALDH-deficient patients PMID:10227616
• American journal of human genetics • 1999 • The molecular basis of Sjögren-Larsson syndrome: mutation analysis of the fatty aldehyde dehydrogenase gene PMID:10577908
• The Journal of investigative dermatology • 1997 • Sjögren-Larsson syndrome is caused by a common mutation in northern European and Swedish patients PMID:9204959
• The Journal of biological chemistry • 2007 • Dual subcellular localization in the endoplasmic reticulum and peroxisomes and a vital role in protecting against oxidative stress of fatty aldehyde dehydrogenase are achieved by alternative splicing PMID:17510064

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