Rhizomelic Chondrodysplasia Punctata, Type 2

A number sign (#) is used with this entry because rhizomelic chondrodysplasia punctata type 2 (RCDP2) is caused by homozygous or compound heterozygous mutation in the DHAPAT gene (GNPAT; 602744), which encodes acyl-CoA:dihydroxyacetonephosphate acyltransferase, on chromosome 1q42.

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. RCDP1 (215100) is the most frequent form of RCDP (summary by Wanders and Waterham, 2005). Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 is classified as a single peroxisome enzyme deficiency (Waterham and Ebberink, 2012).

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

Clinical Features

Wanders et al. (1992) described a patient showing all the clinical features of rhizomelic chondrodysplasia punctata but lacking the classic tetrad of biochemical abnormalities: impairment of plasmalogen biosynthesis, elevated phytanic acid, deficiency of alkyl-dihydroxyacetonephosphate synthase, and an abnormal molecular form of peroxisomal thiolase. Instead the patient was found to have an isolated deficiency of dihydroxyacetonephosphate acyltransferase (DHAPAT). The patient (sex not stated) had a low/broad nasal bridge and anteverted nostrils, cataracts, and pronounced rhizomelic shortening, especially of the arms. The patient died at 6 months after a course complicated by frequent infections.

Barr et al. (1993) described rhizomelic chondrodysplasia punctata with isolated deficiency of DHAPAT in a male Saudi infant.

In 1 patient with atypically mild RCDP, Moser et al. (1995) demonstrated DHAPAT deficiency. The patient, who resembled the one reported by Clayton et al. (1994), was found to be small and hypotonic with microcataracts when first seen at the age of 11 months because of poor feeding. Epiphyseal stippling was present. The limbs were not shortened, however, and there were no dysmorphic features. At 4 years of age her tone had improved and she had made developmental progress, although she had moderate delay. Biochemical studies showed moderate reduction of plasmalogen levels in plasma and of plasmalogen synthesis in cultured skin fibroblasts. Complementation assay and enzyme assay showed that she had a deficiency of DHAPAT.

Elias et al. (1998) described a 6.5-year-old girl with DHAPAT deficiency and a distinctive phenotype. The clinical findings were less severe than those seen in classic rhizomelic chondrodysplasia punctata and were notable for short stature, microcataracts, normal limbs, mild hypotonia, and severe mental retardation. Epiphyseal stippling was present. The family was of French Canadian descent. Several relatives were illiterate or learning impaired in school. Normal facial features of an attractive little girl were featured. The enzyme activity of DHAPAT was 1.6% of control activity in cultured fibroblasts. Lower limb contractures, particularly of hips and knees, developed at sites of early epiphyseal stippling. Cataracts did not progress.

Clinical Management

To aid in the clinical management of children with RCDP, Duker et al. (2017) presented detailed growth curves for length, weight, and head circumference for individuals from infancy to 12 years of age, derived from retrospective data from 23 individuals with RCDP types 1 and 2 confirmed by molecular and/or biochemical studies. The growth curves were stratified by age as well as by plasmalogen level, with those with higher plasmalogen levels grouped as 'non-classic.'

Molecular Genetics

Ofman et al. (1998) identified homozygosity for 5 different mutations in the GNPAT gene (602744.0001-602744.0005) in 8 patients with RCDP2, including 3 sibs (602744.0001), 1 of whom was originally reported by Clayton et al. (1994), and the patient previously reported by Wanders et al. (1992) (602744.0003).

Thai et al. (2001) identified mutations in the GNPAT gene in 3 DHAPAT-deficient RCDP patients: compound heterozygous missense mutations (602744.0001 and 602744.0006) in 2 brothers, and a homozygous splice site mutation (602744.0007) in an unrelated girl who was originally described by Elias et al. (1998).

Nimmo et al. (2010) reported a patient with classic RCDP2 who had an apparent homozygous 1-bp deletion in the GNPAT gene, but the mutation was not identified in the mother. Further analysis determined that the patient had paternal isodisomy of chromosome 1, which likely occurred by rescue of a nullisomic gamete. The patient had no additional features, indicating that chromosome 1 is not involved in imprinting disorders. Importantly, the recurrence risk for these parents was well below the 25% risk for autosomal recessive inheritance.

Itzkovitz et al. (2012) studied 6 patients with RCDP, 3 with RCDP2 and 3 with RCDP3 (600121), and identified homozygosity or compound heterozygosity for mutations in the GNPAT (see, e.g., 603744.0007-603744.0009) or AGPS (see, e.g., 603051.0004) genes, respectively. Comparison of phenotypic severity and GNPAT and AGPS protein levels in patients with RCDP of type 1, 2, or 3 indicated that milder RCDP phenotypes are likely to be associated with residual protein function.

Animal Model

Rodemer et al. (2003) generated a mouse model for RCDP by a targeted disruption of the Dhapat gene. The mutant mice revealed multiple abnormalities, such as male infertility, defects in eye development, cataract, and optic nerve hypoplasia, some of which are also observed in RCDP. Mass spectroscopic analysis demonstrated the presence of highly unsaturated fatty acids including docosahexaenoic acid (DHA) in brain plasmalogens and the occurrence of plasmalogens in lipid raft microdomains (LRMs) isolated from brain myelin. In mutants, plasmalogens were completely absent and the concentration of brain DHA was reduced. The marker proteins flotillin-1 (FLOT1; 606998) and contactin (CNTN1; 600016) were found in brain LRMs in reduced concentrations. In addition, the gap junctional protein connexin-43 (GJA1; 121014), known to be recruited to LRMs and essential for lens development and spermatogenesis, was downregulated in embryonic fibroblasts of the ether lipid-deficient mice. In these fibroblasts, free cholesterol, an important constituent of LRMs, was found to be accumulated in a perinuclear compartment. Rodemer et al. (2003) concluded that plasmalogens may be required for the correct assembly and function of LRMs.

Teigler et al. (2009) characterized a mouse model carrying a targeted deletion of Dhapat gene that results in the complete lack of ether lipids (ELs). The cerebellum of these mice demonstrated defects in foliation patterning and delay in precursor granule cell migration and defects in myelination and concomitant reduction in the level of myelin basic protein. Further studies showed disturbances in paranode organization by extending Caspr (CNTNAP1; 602346) distribution and disrupting axoglial septate-like junctions, impaired innervation of Purkinje cells by both parallel fibers and climbing fibers, and formation of axon swellings by the accumulation of inositol-trisphosphate receptor-1 (ITPR1; 147265) containing smooth ER-like tubuli. Functionally, conduction velocity of myelinated axons in the corpus callosum was significantly reduced.