Peroxisomal Fatty Acyl-Coa Reductase 1 Disorder

A number sign (#) is used with this entry because of evidence that peroxisomal fatty acyl-CoA reductase-1 disorder (PFCRD) is caused by homozygous or compound heterozygous mutation in the FAR1 gene (616107) on chromosome 11p15.

Description

Peroxisomal fatty acyl-CoA reductase-1 disorder is an autosomal recessive disorder characterized by onset in infancy of severely delayed psychomotor development, growth retardation with microcephaly, and seizures. Some patients may have congenital cataracts and develop spasticity later in childhood. Biochemical studies tend to show decreased plasmalogen, consistent with a peroxisomal defect. The disorder is reminiscent of rhizomelic chondrodysplasia punctata (see, e.g., RCDP1, 215100), although the characteristic skeletal abnormalities observed in RCDP are absent (Buchert et al., 2014).

Nomenclature

Baroy et al. (2015) considered the disorder described by Buchert et al. (2014) to be a form of rhizomelic chondrodysplasia punctata, which they called type 4 (RCDP4).

Clinical Features

Buchert et al. (2014) reported 3 patients from 2 families with a severe disorder comprising intellectual disability, growth retardation, and early-onset epilepsy. Two sibs, born of consanguineous Syrian parents, showed neonatal hypotonia, delayed psychomotor development, and onset of well-controlled seizures around age 13 months. At ages 5 and 3 years, both had significant microcephaly (-6.6 and -8.7 SD, respectively) and were small for their age. One sib had bilateral cataracts, developed spasticity of the upper and lower extremities, and showed a Dandy-Walker variant on brain imaging. One sib was reported to have mild dysmorphic facial features, including long philtrum, high-arched eyebrows, large ears, and flattened nasal root. The third patient, born of unrelated parents, had a complex medical and neurodevelopmental history. In infancy, he showed significant growth delay with microcephaly (-4 to -5 SD), nuclear cataracts, and generalized and complex seizures that were difficult to control. Dysmorphic facial features included hypertelorism, short nose, long and smooth philtrum, high-arched eyebrows, and thin upper lip. He later developed progressive spastic quadriparesis with contractures, had symmetric short stature, and never achieved independent walking or standing. At age 19 years, he was severely disabled and often drowsy. Brain imaging showed cerebellar atrophy with progressive multiple punctate white matter lesions throughout the cortical and subcortical regions. He had a coarse facial appearance with ptosis. None of the patients had rhizomelia or evidence of bone dysplasia.

Inheritance

The transmission pattern of peroxisomal fatty acyl-CoA reductase-1 disorder in the families reported by Buchert et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated families with peroxisomal fatty acyl-CoA reductase-1 disorder, Buchert et al. (2014) identified biallelic mutations in the FAR1 gene (616107.0001-616107.0003). The mutations, which were found by exome sequencing, segregated with the disorder in the families. In vitro functional expression studies showed that all the mutations resulted in a complete loss of enzyme activity. Red blood cell plasmalogens of 1 patient were significantly decreased compared to controls, consistent with the functional studies.