| #600121 | ||||||||||||||||||
| RHIZOMELIC CHONDRODYSPLASIA PUNCTATA, TYPE 3; RCDP3 | ||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||
| ALKYLDIHYDROXYACETONEPHOSPHATE SYNTHASE DEFICIENCY ALKYLGLYCERONE-PHOSPHATE SYNTHASE DEFICIENCY AGPS DEFICIENCY | ||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||
| TEXT | ||||||||||||||||||
| A number sign (#) is used with this entry because type 3 rhizomelic chondrodysplasia punctata (RCDP3) is caused by mutations in the alkyldihydroxyacetonephosphate synthase (alkyl-DHAP synthase) gene (AGPS; 603051). Type 1 RCDP (215100) results from a defect in the PEX7 gene (601757). In type 2 RCDP (RCDP2; 222765), there is an isolated deficiency of DHAP acyltransferase (602744). | ||||||||||||||||||
| Clinical Features | ||||||||||||||||||
| The rhizomelic form of chondrodysplasia punctata (RCDP; 215100) is a peroxisomal disorder. Four peroxisomal abnormalities have been identified in the classic form of RCDP: deficiency of dihydroxyacetonephosphate acyltransferase (DHAPAT) and alkyl-DHAP synthase (EC 2.5.1.26), deficient phytanic acid alpha-oxidation, and an abnormal molecular form of peroxisomal thiolase. Wanders et al. (1994) identified a patient showing all the clinical features of RCDP, including the typical radiologic abnormalities, but lacking the tetrad of biochemical abnormalities found in classic RCDP patients. Instead, an isolated deficiency of alkyl-DHAP synthase was found. The gender of the index patient was not given, no information concerning parental consanguinity was provided, and enzyme levels in the parents were apparently not measured. Wanders et al. (1994) considered the disorder most likely autosomal recessive but, with the lack of information, X-linked recessive inheritance was not excluded. Plasmalogen levels are reduced in type 2 and 3 patients with RCDP, while phytanic acid levels and the processing of 3-ketothiolase are normal. The observation that type 2 and 3 patients may display the classic phenotype suggested that the pathogenesis of RCDP may be due solely to a deficiency of plasmalogens (Heymans and Wanders, 1996). | ||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||
| De Vet et al. (1998) identified a missense mutation in the alkyl-DHAP synthase gene of the patient with isolated alkyl-DHAP synthase deficiency described by Wanders et al. (1994) (603051.0001). De Vet et al. (1998) concluded that the resulting arg419-to-his substitution is responsible for the inactivity of the enzyme in this patient. Using fluorescence-activated cytotoxicity selection followed by colony autoradiographic screening of the surviving population, Nagan et al. (1997) isolated a unique plasmalogen-deficient Chinese hamster ovary cell line. The mutant showed a 90% reduction in the rate of biosynthesis and levels of plasmalogens. Further studies showed that the mutant is defective in a single step in the biosynthetic pathway for plasmalogens, namely the step catalyzed by DHAP synthase. Unlike previously described plasmalogen-deficient mutants, this mutant contained peroxisomes, as confirmed by immunofluorescence microscopy and catalase release by digitonin. Peroxisomal functions, including the breakdown of very long-chain fatty acids, phytanic acid oxidation, and the acylation of DHAP, were normal. Cell fusion studies revealed that the mutation is recessive and belongs to a new complementation group. While all 3 RCDP genotypes are associated most commonly with the classic phenotype, milder phenotypes have been described. These include patients in whom the limbs were normal in length and early psychomotor development was normal; these patients were shown to have the type 1 genotype (Motley et al., 1996), i.e., defects in PEX7. | ||||||||||||||||||
| Diagnosis | ||||||||||||||||||
| Brookhyser et al. (1999) reviewed practices in prenatal diagnosis of RCDP. They presented a family with 1 daughter affected with RCDP due to deficiency of DHAPAT synthase, and 3 subsequent pregnancies. Postmortem tests of 1 fetus of a terminated pregnancy showed that radiologic examination could not make the diagnosis of RCDP. They concluded that biochemical or molecular testing is necessary to diagnose accurately type 3 RCDP prenatally. | ||||||||||||||||||
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