ELOVL1 – Cerebral Palsy

ELOVL1 is a fatty acid elongase essential for the synthesis of very long‐chain fatty acids that are critical for neural myelination and skin homeostasis. Recent case reports have identified a compelling association between biallelic ELOVL1 disruption and cerebral palsy, manifesting with spasticity, central nervous system hypomyelination, and dysmorphic facial features (PMID:35379526). The studies describe affected siblings from a consanguineous family, underscoring an autosomal recessive inheritance pattern and highlighting the importance of comprehensive genetic evaluation in ultra‐rare neurological disorders.

Detailed genetic analysis in the cited study revealed a homozygous splice site mutation, c.376-2A>G, that leads to exon skipping and consequent loss of normal protein function. In this family, two probands were identified, with one additional affected relative showing segregating pathology (PMID:35379526). The genetic evidence is further supported by robust case‐level data and segregation analysis from multi‐patient studies, reinforcing the gene–disease link.

Biochemical investigations performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) demonstrated significant alterations in acylceramide profiles in patient samples. These functional assays not only validate the deleterious impact of the splice variant on ELOVL1 enzymatic activity but also corroborate the observed clinical phenotype of cerebral palsy (PMID:35379526). Such concordant findings between molecular defects and altered lipid profiles provide a powerful argument for the pathogenicity of the variant.

Despite the strong evidence for an autosomal recessive mechanism in cerebral palsy, some studies have reported dominant mutations in ELOVL1 associated with overlapping neurocutaneous phenotypes, including ichthyosis, spastic paraplegia, and optic atrophy (PMID:29496980, PMID:30487246). This allelic heterogeneity highlights the diverse impact of ELOVL1 mutations and underscores the need for careful clinical correlation when evaluating patients with complex neurocutaneous presentations.

Integrating the genetic and functional evidence, the association between biallelic ELOVL1 mutations and cerebral palsy is strongly supported. The identified homozygous splice site mutation (c.376-2A>G) causes exon skipping, thereby disrupting the biochemical pathways essential for myelination. Although additional reports indicate a potential dominant mechanism for distinct phenotypes, the current evidence in the context of cerebral palsy is compelling for a recessive mode of inheritance. Clinicians and diagnostic laboratories should consider ELOVL1 disruption as a causative factor in patients with cerebral palsy and related neurological manifestations.

Key Take‑home: The robust genetic and functional data firmly establish biallelic ELOVL1 disruption as a significant contributor to cerebral palsy, warranting its integration into diagnostic pipelines for neurodevelopmental disorders.

References

• Brain & development • 2022 • Hypomyelinating spastic dyskinesia and ichthyosis caused by a homozygous splice site mutation leading to exon skipping in ELOVL1 PMID:35379526
• Journal of medical genetics • 2018 • Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features PMID:29496980
• FASEB bioAdvances • 2019 • Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1 PMID:32123819
• Journal of medical genetics • 2019 • De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy PMID:30487246

Evidence Based Scoring (AI generated)