ELOVL4 – Congenital Ichthyosis-Intellectual Disability-Spastic Quadriplegia Syndrome

ELOVL4 encodes a fatty acid elongase critical for biosynthesis of very-long-chain fatty acids in skin and brain. Biallelic loss-of-function variants in ELOVL4 underlie autosomal recessive congenital ichthyosis-intellectual disability-spastic quadriplegia syndrome (ISQMR), characterized by early-onset ichthyosis, severe neurodevelopmental impairment, spasticity, and seizures. ISQMR is catalogued as MONDO:0013760 and ELOVL4 as HGNC:14415.

Clinical Validity

Genetic association between ELOVL4 and ISQMR is classified as Moderate. This is supported by 11 affected individuals with biallelic variants identified in four unrelated families with segregation consistent with autosomal recessive inheritance (PMID:37592902).

Genetic Evidence

The disorder follows an autosomal recessive inheritance mode. Eleven probands from four consanguineous families exhibited homozygous ELOVL4 variants, including an exonic deletion suggesting a tribal founder event and two distinct missense substitutions causing predicted loss of elongase function (PMID:37592902). Segregation of variants with disease was observed in all families. Variant spectrum includes presumed loss-of-function alleles and missense changes clustering in catalytic domains. Population data indicate these variants are absent or extremely rare in control databases.

Functional Evidence

No specific experimental studies have assessed these variants in neuronal or skin models. However, prior functional characterization of ELOVL4 demonstrates its essential role in very-long-chain fatty acid synthesis in skin barrier formation and neural membranes, consistent with the clinical phenotype of ISQMR.

Conflicting Evidence

No publications to date dispute the association of biallelic ELOVL4 variants with the neuro-ichthyosis-spastic quadriplegia phenotype.

Integrated Conclusion

Biallelic inactivation of ELOVL4 causes a distinct neuro-ichthyotic syndrome marked by ichthyosis, intellectual disability, spastic quadriplegia, hypotonia, seizures, and neuroimaging findings of delayed myelination, corpus callosum hypoplasia, and cerebral atrophy. Genetic evidence is supported by multiple unrelated families with homozygous variants, though functional assays in disease-relevant tissues remain to be conducted. This association provides clinically actionable information for molecular diagnosis, genetic counseling, and potential future therapeutic targeting of fatty acid elongation pathways. Key take-home: ELOVL4 should be included in diagnostic gene panels for syndromic ichthyosis with neurodevelopmental impairment.

References

• Molecular Genetics & Genomic Medicine • 2023 • Expanding the allelic spectrum of ELOVL4-related autosomal recessive neuro-ichthyosis. PMID:37592902

Evidence Based Scoring (AI generated)