Rhizomelic Chondrodysplasia Punctata, Type 5

A number sign (#) is used with this entry because of evidence that rhizomelic chondrodysplasia punctata type 5 (RCDP5) is caused by homozygous mutation in the PEX5 gene (600414) on chromosome 12p13.

Description

Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life (summary by Wanders and Waterham, 2005).

For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see 215100.

Clinical Features

Baroy et al. (2015) described 3 Pakistani sibs and an unrelated Pakistani patient, all born of consanguineous parents, with RCDP5. The patients had a mild reduction in tissue plasmalogen level. Their clinical phenotype was analogous to other RCDP patients with mild biochemical defects who often have less pronounced skeletal abnormalities, later onset of epilepsy, and less profound growth delay and intellectual disability. The patients described by Baroy et al. (2015) reached more developmental milestones, such as self-feeding, independent ambulation, and limited receptive and expressive language skills, than do most patients with severely reduced plasmalogen levels. All 4 patients presented with congenital cataracts. Clinical and neurophysiologic studies in the 3 affected sibs indicated that they had demyelination peripheral neuropathy, which had not been reported in RCDP patients but is an important sign of adult Refsum disease (266500).

Molecular Genetics

In 3 sibs, born to consanguineous Pakistani parents, with RCDP, Baroy et al. (2015) identified a homozygous frameshift mutation in exon 9 (coding exon 7) of the long isoform of PEX5 (c.722dupA; 600414.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The same mutation was identified in an unrelated Pakistani girl, born to consanguineous Pakistani parents, with RCDP. Studies of peroxisomal parameters in cultured fibroblasts of this patient had indicated a PTS2 protein import defect; no mutation was identified in PEX7 (601757). Baroy et al. (2015) showed that, similar to mutations in PEX7, loss of the PEX5-long isoform results in a peroxisomal dysfunction due to selective defect in the import of PTS2-tagged proteins only, causing RCDP instead of a peroxisome biogenesis disorder (see 214110). Baroy et al. (2015) demonstrated that expression of the PEX5-long isoform restored the import of PTS2-tagged proteins in patient fibroblasts.