ACSL4 – Non-syndromic X-linked Intellectual Disability

ACSL4 encodes long-chain acyl-CoA synthetase 4, a brain-enriched enzyme crucial for fatty acid activation and lipid signaling. Hemizygous loss-of-function alleles in ACSL4 cause non-syndromic X-linked intellectual disability by disrupting neural lipid metabolism. Evidence includes a de novo 1.56 Mb Xq22.3-q23 deletion encompassing ACSL4 in a 10-year-old male with moderate ID and multisystem anomalies ([PMID:23520119]) and a missense variant co-segregating in a multi-generation MRX68 family.

1. Clinical Validity

Inheritance is X-linked recessive with two unrelated hemizygous ACSL4 lesions (one de novo deletion and one c.1001C>T (p.Pro334Leu) point mutation) in male probands. The MRX68 family shows co-segregation of p.Pro334Leu with cognitive impairment in multiple affected males ([PMID:12525535]). Functional concordance across models further supports causality.

Overall classification: Moderate (2 probands, one multi-generation segregation, concordant functional data).

2. Genetic Evidence

Inheritance mode: X-linked recessive.

Segregation: 3 affected male relatives with p.Pro334Leu in MRX68 ([PMID:12525535]).

Case reports: 2 unrelated hemizygous variants in ACSL4.

Variant spectrum: one large deletion and one missense variant.

Recurrent/founder alleles: none reported.

Phenotypic spectrum: moderate intellectual disability often with sensorineural hearing loss, facial dysmorphism, pyloric stenosis, and intestinal obstruction.

3. Functional Evidence

Enzymatic assays of p.Pro334Leu show marked reduction in ACSL activity in patient cells ([PMID:12525535]). Overexpression and inhibition studies in human arterial smooth muscle cells demonstrate ACSL4’s role in arachidonoyl-CoA synthesis and lipid mediator release, indicating haploinsufficiency as the mechanism ([PMID:21242590]).

4. Model Organism Studies

Drosophila dAcsl mutants recapitulate synaptic vesicle transport defects and impaired neurotransmission, fully rescued by human ACSL4, confirming functional conservation ([PMID:21307243]). Acsl mutant larvae exhibit reduced mushroom body neuroblast proliferation and premature differentiation, linking ACSL4 loss to neurodevelopmental failure ([PMID:30594466]).

5. Integration and Conclusion

Genetic and experimental data collectively demonstrate that hemizygous loss of ACSL4 disrupts neural lipid metabolism and synaptic function, leading to X-linked intellectual disability. Although additional case series are pending, current evidence suffices for moderate clinical validity.

Key take-home: ACSL4 sequencing and deletion analysis should be considered in males with unexplained intellectual disability, particularly with sensorineural and gastrointestinal features.

References

• American journal of medical genetics. Part A • 2013 • Xq22.3-q23 deletion including ACSL4 in a patient with intellectual disability. [PMID:23520119]
• Journal of medical genetics • 2003 • A third MRX family (MRX68) is the result of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene: proposal of a rapid enzymatic assay for screening mentally retarded patients. [PMID:12525535]
• The Journal of neuroscience • 2011 • Drosophila Acyl-CoA synthetase long-chain family member 4 regulates axonal transport of synaptic vesicles and is required for synaptic development and transmission. [PMID:21307243]
• Journal of genetics and genomics = Yi chuan xue bao • 2019 • Drosophila homolog of the intellectual disability-related long-chain acyl-CoA synthetase 4 is required for neuroblast proliferation. [PMID:30594466]

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