Rhizomelic Chondrodysplasia Punctata Type 1 and Adult Refsum Disease via the PEX7 Gene

Mutations in PEX7 can lead to Rhizomelic Chondrodysplasia Punctata (RCDP) type 1 or relatively mild adult Refsum disease (ARD). Rhizomelic Chondrodysplasia Punctata (RCDP) is neonatal onset and characterized by proximal shortening of the long bones (rhizomelia), multiple epiphyseal calcifications and joint contractures, cataracts, dysmorphic facies, profound intellectual disability and growth deficiency. RCDP type 1 is the most common and classic type of RCDP and is clinically indistinguishable from type 2 or 3. Most patients with RCDP type 1 die in the first or second year, few survive beyond the first decade of life (Braverman et al. 2012; Purdue et al. 1997).

Adult Refsum disease (ARD) usually develops in late childhood with the first set of clinical symptoms including anosmia, night blindness, and progressive retinitis pigmentosa. In the following 10-15 years, other symptoms including peripheral neuropathy, nerve deafness, cerebellar ataxia, ichthyosis, skeletal dysplasia, and cardiac arrhythmias may occur. Unexplained remission has been observed in some patients. Most ARD cases are due to deficiency of phytanoyl-CoA hydroxylase, encoded by the PHYH gene. PEX7 defects account for less than 10% of all reported patients (Wanders et al. 2010; Braverman et al. 2002; van den Brink et al. 2003).

RCDP type 1 is inherited in an autosomal recessive manner and caused by PEX7 defects. Reported mutation spectrum includes missense, nonsense, splicing site mutations, and small deletion/insertions. Among studied patients with European ancestry, p.Leu292X was the most common (~50 %) due to a founder effect, followed by three other mutations (c.903+1G>C, p.Gly217Arg, and p.Ala218Val), together accounting for 15-20% of pathogenic alleles (Braverman et al. 2002; Motley et al. 2003).

PEX7-associated ARD is recessively inherited and expected to be very rare since less than 10 patients have been reported to date. Although not completely proven, it is presumed that residual function of the mutant PEX7 protein is correlated with milder phenotype in patients with ARD or RCDP Type 1 (Braverman et al. 2002; van den Brink et al. 2003). RCDP type 2 and type 3 are due to defects in GNPAT or AGPS, respectively, which encode enzymes required for plasmalogen synthesis in peroxisomes.

The PEX7 gene encodes the cytosolic receptor protein that specifically imports the PTS2-containing enzymes into peroxisomes. There are only three peroxisomal PTS2 enzymes (thiolase, PHYH, and AGPS), which play critical roles in α-oxidation of branched-chain lipids (e.g. phytanic acid) and plasmalogen synthesis. Peroxisomal enzymes involved in VLCFAs metabolism are imported by the PTS1 receptor (PEX5). Therefore, metabolic characteristics found in both RCDP type 1 and ARD patients include elevated plasma phytanic acid and deficient plasmalogen synthesis but normal levels of VLCFAs (C24:0 and C26:0) (Braverman et al. 2012; van den Brink et al. 2003)

In two unrelated cohorts, PEX7 mutations were found in > 90% of patients clinically diagnosed with RCDP. The founder mutation p.Leu292X has a high frequency in individuals of Northern European descent (Braverman et al. 2002; Motley et al. 2003).

No gross deletions/duplications have been reported so far in PEX7.

This test provides full coverage of all coding exons of the PEX7 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.