A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency

(A–D) MRI of individual II-1. Axial T2-weighted images obtained at 9 years of age (A) and again at 15 years of age (B) show increased signal intensity diffusely but more prominently in the posterior periventricular and peritrigonal regions bilaterally. There is subtle evidence of progression of these white-matter changes over time. (C) A coronal MP-RAGE-weighted image at 15 years of age shows prominence of the cerebellar folia consistent with mild to moderate cerebellar atrophy. (D) A sagittal T1-weighted image at 9 years of age shows mild atrophy of the cerebellum and no evidence of cervical spinal stenosis.

Buchert R, Tawamie H, Smith C, Uebe S, Innes AM, Hallak BA, Ekici AB, Sticht H, Schwarze B, Lamont RE, Parboosingh JS, Bernier FP, and Jamra RA. (2014) A peroxisomal disorder of severe intellectual disability, epilepsy, and cataracts due to fatty acyl-CoA reductase 1 deficiency. The American Journal of Human Genetics, 95

Plasmalogens are a class of lipids that contain a vinyl-ether bond at sn-1 causing unique characteristics which aid in protection from reactive oxygen species, membrane structure, and vesicular fusion. When genetic mutations lead to defective plasmalogen biosynthetic enzymes it causes the ultra-rare disorder called rhizomelic chondrodysplasia punctata (RCDP). Depending on the mutation causing RCDP, patients are categorized into different RCDP types. RCDP presents with congenital cataracts, rhizomelia, chondrodysplasia punctata, recurrent respiratory tract infections, and delayed cognitive development and is considered “Classic RCDP” (further information about RCDP can be found here). One of the first enzymes in the plasmalogen biosynthesis pathway is the fatty acyl-CoA reductase 1 (FAR1). This study provides a description of FAR1 mutations in two families, including clinical manifestations of RCDP. FAR1 reduces fatty acyl-CoAs to fatty alcohols, a critical reaction required for plasmalogen synthesis. This work by Buchert et al is the first to describe mutations in the human FAR1 gene and the discovery of RCDP type 4.

The RCDP presentation of three individuals from two different families (V-1 and V-2 from Family A and II-1 from Family B) was described. The three patients developed seizures between 10 months and 3.5 years of age, that were able to be controlled by medication. One individual from each of the two families was diagnosed with congenital cataracts and microencephaly, while all three were small for their ages and had intellectual disabilities. II-1 from Family B was 19 at the date of publication and had begun regressing, losing the ability to sit and use communication devices. The individuals studied by Buchert et al were not diagnosed with rhizomelia or chondrodysplasia punctata, two of the hallmark symptoms of RCDP, and II-1 had developed the ability to sit and communicate, demonstrating a non-classic presentation of RCDP.

Genetic and metabolic investigations came back normal in these individuals, indicating that what was causing this phenotype in the patients was likely novel. After genotyping with a non-targeted genome-wide array in Family A, four FAR1 candidate regions were found to be homozygous in both children. Mapping analyses allowed the group to narrow down to one FAR1 variant that segregated individuals with severe intellectual disability, but was absent in 280 ethnically matched controls. For Family B, whole exome sequencing of II-1 and his parents allowed the investigation of the sporadic intellectual disability. Biallelic variants in FAR1 were found and inherited from each of the parents. Neither had been reported previously, so their effect in the FAR1 sequence was modelled and found that the mutations would result in a protein conformation predicted to impair the enzymatic activity. The three mutations were used for site-directed mutagenesis in human embryonic kidney 293 (HEK293) cells to confirm the impaired enzymatic activity of each through quantifying the levels of hexadecanol and octadecanol (the products of reducing palmitic acid and stearic acid, respectively). The cells transfected with plasmids encoding FAR1 containing any of the three mutations did not produce significant levels of hexadecanol or octadecanol, suggesting that these mutations resulted in a total loss of FAR1 activity.

Through investigating these mutations, Buchert et al found that the FAR1 mutations produce an autosomal-recessive peroxisomal disorder that result in intellectual disability, congenital cataracts, growth defects, and epilepsy. Although these symptoms are present in classic rhizomelic chondrodysplasia punctata, these individuals did not display the rhizomelia or skeletal abnormalities typically present. Commonly in RCDP the defective enzymes are earlier in the biosynthetic pathway, such as glyceronephosphate O-acyltransferase (GNPAT) or alkylglycerone phosphate synthase (AGPS). The role of FAR1 is to supply the biosynthetic pathway with fatty alcohols to be incorporated into ether and vinyl ethers. It is interesting that the outcome of mutations in GNPAT, AGPS, and FAR1 leads to a plasmalogen deficit, and although most symptoms are similar, there is an absence of rhizomelia. As well, children with RCDP typically do not live to 10 years of age, therefore it is surprising that II-1 was at least 19 years old at time of diagnosis. Buchert et al suspect that there may be a compensation mechanism to make up for the loss of FAR1 activity or that fatty alcohols are supplied from β-oxidation. Since many of these symptoms do not match “Classic RCDP”, it is possible that this novel form of RCDP is more prevalent than currently appreciated and there are other individuals undiagnosed or misdiagnosed. Further work into the consequences of FAR1 mutations may help to identify and diagnose individuals with RCDP 4.