Abstract (199)
FAR1-related phenotypes caused by FAR1 gene encodes the
peroxisomal protein, fatty acyl-CoA reductase 1 (FAR1), which is
required to reduce fatty acids to fatty alcohols used to form
ether-linked alkyl bonds. Biallelic loss of function variants have been
associated with severe psychomotor developmental delayed, seizures,
cataracts, growth retardation with microcephaly, and spasticity.
However, Heterozygote variants in FAR1 have been recently linked
to a rare genetic disorder called cataracts, spastic paraparesis, and
speech delay (CSPSD) disorder. Here, we present the first middle eastern
patient with a de novo pathogenic variant in FAR1 identified by
exome sequencing (ES) analysis, and a detailed overview of the reported
clinical phenotypes and genotypes. Our patient represents the milder end
of the clinical spectrum, including medication-free seizures by the
first year of life, proper speech and fine motor development, and
absence of other previously reported features such as learning
difficulties, axial hypotonia, and joint contracture. In addition, she
has developmental dysplasia of the hip (DDH) that failed medical
management and faltering growth. Our patient adds to the small number of
patients recognized so far, and expanding the clinical spectrum to
provide better clinical delineation, improve diagnosis, and development
of precision medicine approaches for this disorder
Introduction : (212)
Recently two disorders with overlapping features and opposite
biochemical phenotypes were identified to be related to FAR1 gene
(Buchert et al. 2014, Ferdinandusse et al. 2021). The causative
gene encodes fatty acyl-CoA reductase 1 (FAR1) the enzyme responsible to
reduce fatty acids to fatty alcohols which is essential for wax
monoesters and ether lipids synthesis (Cheng et al. 2004). The stability
of FAR1 is dependent on cellular plasmalogen levels [Honsho et al.
2010, Honsho et al 2013). Biallelic loss of function variants causingFAR1 deficiency (also known as RCDP type 4, MIM 616154
(https://omim.org/)) characterized by intellectual disability,
cataracts, growth retardation, and seizure disorders without rhizomelia
or the skeletal changes (Buchert et al. 2014). Heterozygous variants inFAR1 cause the loss of feedback regulation leading to plasmalogen
accumulation and increase FAR1 protein level causing clinical symptoms
similar to FAR1 deficiency, including spasticity, early onset seizures,
and cataracts (MIM 619338
(https://omim.org/)) (Ferdinandusse et
al. 2021). Here we report an additional case, with de novo pathogenic
variant in FAR1, expanding the clinical spectrum of CSPSD. In
particular, our patient seems to represent the milder end of the
clinical spectrum, with resolved epilepsy since the age of one-year,
appropriate speech and fine motor development. She has no features of
learning difficulties, hypotonia, or joint contracture.