| #222765 | ||||||||||||||||||||||||
| RHIZOMELIC CHONDRODYSPLASIA PUNCTATA, TYPE 2; RCDP2 | ||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||
| DIHYDROXYACETONEPHOSPHATE ACYLTRANSFERASE DEFICIENCY DHAPAT DEFICIENCY GLYCERONEPHOSPHATE O-ACYLTRANSFERASE DEFICIENCY GNPAT DEFICIENCY PEROXISOMAL DIHYDROXYACETONEPHOSPHATE ACYLTRANSFERASE DEFICIENCY CHONDRODYSPLASIA PUNCTATA, RHIZOMELIC, DUE TO DIHYDROXYACETONEPHOSPHATE ACYLTRANSFERASE DEFICIENCY | ||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||
| TEXT | ||||||||||||||||||||||||
| A number sign (#) is used with this entry because type 2 rhizomelic chondrodysplasia punctata (RCDP2) is caused by homozygous mutation in the gene encoding acyl-CoA:dihydroxyacetonephosphate acyltransferase (GNPAT; 602744). | ||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||
| Wanders et al. (1992) described a patient showing all the clinical features of rhizomelic chondrodysplasia punctata (see RCDP1; 215100) 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 this enzyme in a male Saudi infant. In 1 patient with a typically 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. | ||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||
| In the patient reported by Clayton et al. (1994), Ofman et al. (1998) demonstrated a homozygous mutation in the GNPAT gene (R211H; 602744.0001). Ofman et al. (1998) found that all RCDP type 2 patients analyzed had homozygous mutations in the GNPAT gene. 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. | ||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||
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