Last Updated: September 15, 2022
Introduction to Infantile Refsum Disease
Infantile Refsum disease (IRD) is an autosomal recessive disorder that is a member of a family of disorders that result from defects in the biogenesis and/or functioning of the peroxisomes and are referred to as peroxisome biogenesis disorders, PBD. The PBD are caused either by peroxisomal assembly defects or by deficiencies of single peroxisomal proteins.
IRD belongs to the Zellweger spectrum PBDs which includes Zellweger syndrome and neonatal adrenoleukodystrophy (NALD). Zellweger syndrome represents the extreme of the clinical manifestation of peroxisome biogenesis dysfunction with patients rarely surviving their first year of life. Zellweger syndrome is associated with either severe, moderate or mild defects in all peroxisome functions. An additional phenotypic spectrum in PBDs is represented by rhizomelic chondrodysplasia punctata, RCDP. RCDP is distinguished from the Zellweger spectrum PBDs by manifesting with more severe skeletal involvement as well as specific biochemical characteristics.
Molecular Biology of Infantile Refsum Disease
Infantile Refsum disease can result from mutations in at least three genes involved in peroxisome biogenesis (PEX genes). These include the PEX1 gene, the PEX2 gene, and the PEX26 gene.
The PEX1 gene is located on chromosome 7q21.2 and is composed of 24 exons that generate three alternatively spliced mRNAs, each of which encode a distinct protein isoform. The PEX1 gene encodes a protein that is a member of the AAA-type ATPases (AAA: ATPases Associated with diverse cellular Activities).
The PEX2 gene is located on chromosome 8q21.13 and is composed of 5 exons that generate four alternatively spliced mRNAs, all of which encode the same 305 amino acid protein. The PEX2 gene is also known as the peroxisomal membrane protein 3 (PXMP3 or PMP35).
The PEX26 gene is located on chromosome 22q11.21 and is composed of 5 exons that generate three alternatively spliced mRNAs that collectively encode two distinct protein isoforms. The PEX26 encoded protein interacts with the PEX6 encoded protein and may have catalase activity.
Overview of Peroxisomal Biogenesis
The peroxisomes are a single membrane organelle, similar to lysosomes, present in virtually all eukaryotic cells. The peroxisome is a specialized enzyme “factory” that contains in excess of 50 different enzymes involved in a variety of metabolic processes including β-oxidation of very long chain fatty acids, α-oxidation of fatty acids and synthesis of ether-lipids. Proteins that are involved in and necessary for correct peroxisome biogenesis are called peroxins (PEX). At least 15 PEX genes have been identified in humans.
Enzymes that are targeted to the peroxisomes contain either of two amino acid consensus elements called peroxisome targeting sequences (PTS). The PTS1 is a C-terminal consensus sequence of –[S/A/C][K/R/H][L/M] referred to as the SKL motif. This sequence element is recognized by a cytosolic PTS1 receptor encoded by the PEX5 gene. There are two isoforms of PEX5 encoded proteins in humans identified as Pex5pS and Pex5pL (for short and long forms, respectively). The Pex5pL protein has an internal 37 amino acid insertion, hence the “long” designation.
The PTS2 is an N-terminal consensus sequence of –[R/K][L/V/I/Q]XX[L/V/I/H/Q][L/S/G/A/K]X[H/Q][L/A/F]–, (where X represents any amino acid). The PTS2 receptor is encoded by the PEX7 gene and the encoded protein is referred to as Pex7p. Proteins that are targeted to the membrane of the peroxisome (called peroxisome membrane proteins, PMPs) contain a consensus sequence identified as the PEX19 binding site (PEX19BS) and this site is recognized by the membrane protein receptor encoded by the PEX19 gene.
Pex5pS, Pex5L, and Pex7p interact with newly synthesized target proteins in the cytosol and direct them to the peroxisome. On the membrane of the peroxisome is a component of the protein import machinery encoded by the PEX14 gene called Pex14p. Following interaction of Pex5pS or Pex5pL, bound to a protein containing a PTS1 sequence, with Pex14p, the PTS1 containing protein is transferred into the peroxisome. The activity of Pex7p in peroxisome protein import actually requires Pex5pL as well. PTS2 containing proteins interact with Pex7p and then, in conjunction with Pex5pL, the complex interacts with Pex14p and the PTS2 containing protein is transferred into the peroxisome. Very few proteins contain a PTS2 sequence but one enzyme of note is phytanoyl-CoA hydroxylase (PHYH) which is defective in classic Refsum disease.
Clinical Features of Infantile Refsum Disease
Infantile Refsum disease is so called because patients manifest a form of phytanic acid storage disease that is both clinically and biochemically distinct from patients with the classic form of Refsum disease. The clinical manifestations of IRD include early onset, intellectual impairment, minor facial dysmorphism, retinitis pigmentosa, sensorineural hearing deficit, hepatomegaly, osteoporosis, failure to thrive, and hypocholesterolemia.
The biochemical abnormalities are not restricted to phytanic acid but also include accumulation of very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid. The retinitis pigmentosa, elevated phytanic acid, and sensorineural hearing loss are symptoms seen in classic Refsum disease, but the dysmorphia observed in IRD is unique to the latter disorder. Most patients with IRD will learn to walk but with a gait that is ataxic and wide. Cognitive impairment in IRD is in the severe retarded range.