An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Abstract

In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu). METHODS: Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics. RESULTS: All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogendependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production. CONCLUSION: Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.

Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

“…Due to the rapid rate of progress of HSP research, new genes are being identified on a regular basis. Examples of recently identified HSP genes include UCHL1 (SPG79), UBAP1 (SPG80), SELENOI (SPG81), PCYT2 (SPG82), HPDL (SPG83), and those not yet assigned a locus (RNF170 and FAR1) [7][8][9][10][11][12][13][14][15][16]. Some genes are much rarer than others, and it cannot be excluded that certain mutations may be 'private' to individual families.…”

Discovery of over 200 new and expanded genetic conditions using GeneMatcher

“…In general, our participation in GeneMatcher has been a very positive Ferdinandusse et al, 2021). In all, we gathered twelve individuals (eight tested at GeneDx) with heterozygous de novo missense variants at the same residue.…”

Inherited disorders of complex lipid metabolism: A clinical review

“…Though patients with FAR1 deficiency have not exhibited the skeletal phenotype of RCDP, they present with developmental delay, microcephaly, seizures, growth retardation, cataracts, and spasticity reminiscent of the extra‐skeletal manifestations of plasmalogen synthesis defects 135 leading some to consider this disorder as RCDP type 4 137 . FAR1 overactivity was recently associated with a syndrome of spastic paraparesis, cataracts, and developmental delay 138 . Deficiency of alkylglycerol monooxygenase, the enzyme necessary for cleavage of ether linked FAs during recycling of ether lipids, can cause a disorder characterized by microcephaly, developmental delay, and short stature 139 .…”

“…137 FAR1 overactivity was recently associated with a syndrome of spastic paraparesis, cataracts, and developmental delay. 138 Deficiency of alkylglycerol monooxygenase, the enzyme necessary for cleavage of ether linked FAs during recycling of ether lipids, can cause a disorder characterized by microcephaly, developmental delay, and short stature. 139 RCDP and other phenotypes associated with skeletal, ophthalmological, and nervous system abnormalities can also be seen in other genetic disorders associated with peroxisome biogenesis outside the scope of this review but have been described in detail in other works.…”