A child presents with bilateral congenital cataracts, severe global developmental delay, spastic paraparesis, and seizures. Plasma plasmalogens are reduced and dihydroxyacetone phosphate acyltransferase (DHAP-AT) activity in fibroblasts is normal, pointing away from RCDP and toward an isolated downstream block.
FAR1 encodes fatty acyl-CoA reductase 1, a peroxisomal membrane enzyme that reduces fatty acyl-CoAs to fatty alcohols, the rate-limiting step in plasmalogen (ether phospholipid) biosynthesis.
Two clinically and mechanistically distinct disease groups:
| Mechanism | Inheritance | Variant location | Plasmalogen levels | Phenotype |
|---|---|---|---|---|
| Loss-of-function | AR (biallelic) | Throughout the gene; nonsense/frameshift/splice/missense | Decreased | Severe; overlaps rhizomelic chondrodysplasia punctata (RCDP) phenotype but without rhizomelia |
| Gain-of-function | AD (heterozygous) | Specific missense in the C-terminal sterol regulatory domain that disrupts feedback inhibition by plasmalogen | Increased | Distinct cataract + spastic paraparesis + ID phenotype |
Mechanistic note: in healthy cells, FAR1 activity is feedback-inhibited by plasmalogens binding the C-terminal regulatory domain. AD variants in that domain abolish feedback → constitutive plasmalogen overproduction. AR LOF abolishes the enzyme → plasmalogen deficiency. Different ends of the same lever, both causing disease.
AR (loss-of-function) form:
- Severe early-onset intellectual disability
- Bilateral congenital cataracts
- Seizures, spastic quadriparesis
- Growth failure
- Dysmorphic features overlapping RCDP (without the characteristic rhizomelic limb shortening)
- Plasma plasmalogens markedly reduced
- VLCFA (very long chain fatty acids) typically normal; distinguishes from generalized peroxisomal biogenesis disorders (Zellweger spectrum)
AD (gain-of-function) form:
- Bilateral cataracts (often congenital or early childhood)
- Intellectual disability (mild to moderate)
- Progressive spastic paraparesis
- Plasma plasmalogens elevated
- Plasma plasmalogen quantitation (ethanolamine plasmalogens; usually as the C16/C18 ratio in red cells)
- VLCFA screening to exclude Zellweger spectrum
- Molecular: FAR1 sequencing; interpret variants in light of plasmalogen direction:
- Reduced plasmalogens + biallelic LOF → AR FAR1 deficiency
- Elevated plasmalogens + heterozygous regulatory-domain missense → AD FAR1 gain-of-function
- Rhizomelic chondrodysplasia punctata (RCDP) types 1-5: peroxisomal plasmalogen biosynthesis disorders (PEX7, GNPAT, AGPS, FAR1 AR, PEX5) all share decreased plasmalogens and cataracts. RCDP1 (PEX7) is the prototype with rhizomelic shortening; isolated FAR1 LOF lacks rhizomelia
- Zellweger spectrum disorders: global peroxisomal failure with elevated VLCFA + decreased plasmalogens; FAR1 has normal VLCFA
- Hereditary spastic paraplegia: for the AD GOF presentation
- Supportive: developmental therapies, anti-spasticity, cataract surgery, seizure management
- No disease-modifying therapy currently available
- Plasmalogen replacement is investigational