Clinical Information

Peroxisomes are organelles that carry out essential metabolic functions, including beta-oxidation of very long-chain fatty acids (VLCFA), alpha-oxidation of phytanic acid, and biosynthesis of plasmalogen and bile acids. Peroxisomal disorders include disorders of peroxisomal biogenesis with defective assembly of the entire organelle, and disorders of peroxisome function with single peroxisomal enzyme/transporter defects where the organelle is intact but a specific function is disrupted.

Biochemical abnormalities in peroxisomal biogenesis disorders can include accumulations of VLCFA, phytanic acid, pristanic acid, pipecolic acid, bile acids, and reduced plasmalogens. The differential diagnosis of these disorders is based on recognition of clinical phenotypes combined with a series of biochemical tests to assess peroxisomal function and structure. These include measurements and ratios of VLCFA, phytanic acid, and its metabolite pristanic acid (POX / Fatty Acid Profile, Peroxisomal [C22-C26], Serum or POXP / Fatty Acid Profile, Peroxisomal [C22-C26], Plasma), pipecolic acid (PIPA / Pipecolic Acid, Serum or PIPU / Pipecolic Acid, Random, Urine), bile acids (BAIPD / Bile Acids for Peroxisomal Disorders, Serum), and plasmalogens.

Peroxisomal biogenesis disorders include Zellweger syndrome spectrum disorders, which are clinically diverse and range in severity from neonatal lethal (Zellweger syndrome) to more variable clinical courses in neonatal adrenoleukodystrophy and infantile Refsum disease. Affected children typically have hypotonia, poor feeding, distinctive facial features, seizures, and liver dysfunction. Other features can include retinal dystrophy, hearing loss, developmental delays, and bleeding episodes.

Rhizomelic chondrodysplasia punctata (RCDP) is a malformation disorder characterized by rhizomelic shortening, chondrodysplasia punctata, cataracts, intellectual disability, and seizures, although it can have a milder phenotype with only cataracts and chondrodysplasia punctata. Currently, there are 5 clinical types of rhizomelic chondrodysplasia punctata: RCDP 1, 2, 3, 4 (also known as FAR1 deficiency) and 5. RCDP 1 is the classical form that presents in infancy with skeletal manifestations including rhizomelic shortening, cataracts, and severe to profound postnatal growth deficiency. Infants with RCDP 1 have developmental delay, and later, intellectually disability. The majority of children with RCDP 1 do not survive beyond the first decade of life. RCDP 1 is an autosomal recessive disorder caused by disease-causing variants in the PEX7 gene. RCDP 2 and 3 have clinical phenotypes similar to RCDP 1 and may be distinguished by plasmalogen deficiency. RCDP 2 and 3 are autosomal recessive conditions caused by disease-causing variants in GNPAT and AGPS genes, respectively. Individuals with RCDP 5 have a milder phenotype when compared to classic RCDP 1, with most individuals able to achieve self-feeding, independent ambulation, and development of limited language skills. RCDP5 results in less pronounced reduction in plasmalogens compared to RCDP 1. This newly recognized subtype of RCDP is an autosomal recessive disorder caused by disease-causing variants in the PEX5 gene.

The typical biochemical profile for RCDP shows reduced plasmalogens, elevated phytanic acid, and normal VLCFA. Confirmatory testing via molecular analysis for all types of RCDP is available (PDGP / Peroxisomal Disorder Gene Panel, Varies).

Fatty acyl-CoA reductase 1 (FAR1) deficiency, also known as RCDP type 4, is an autosomal recessive peroxisomal disorder caused by disease-causing variants in the FAR1 gene that result in early-onset epilepsy, microcephaly, cataracts, postnatal growth deficiency, and intellectual disability. Unlike RCDP, however, infants with FAR1 deficiency have no skeletal abnormalities. The biochemical profile for FAR1 deficiency includes reduced plasmalogens, normal to elevated phytanic acid, and normal VLCFA.