Alternative titles; symbols
SNOMEDCT: 1003858007; ORPHA: 177, 309803; DO: 0110853;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q31.2 | Rhizomelic chondrodysplasia punctata, type 3 | 600121 | Autosomal recessive | 3 | AGPS | 603051 |
A number sign (#) is used with this entry because rhizomelic chondrodysplasia punctata type 3 (RCDP3) is caused by homozygous or compound heterozygous mutation in the gene encoding alkyldihydroxyacetonephosphate synthase (alkyl-DHAP synthase) (AGPS; 603051) on chromosome 2q31.
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 is the most frequent form of RCDP (summary by Wanders and Waterham, 2005). Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP3 is classified as a single peroxisome enzyme deficiency (Waterham and Ebberink, 2012).
For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see 215100.
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. Wanders et al. (1994) thought that the disorder was most likely autosomal recessive. Van Laer (2013) stated that the patient studied by Wanders et al. (1994) was male, that there was no history of consanguinity in the family, and that the parents had declined any further diagnostic tests.
Plasmalogen levels are reduced in patients with RCDP type 2 (RCDP2; 222765) and type 3, whereas phytanic acid levels and the processing of 3-ketothiolase are normal. The observation that patients with type 2 and type 3 may display the classic phenotype suggested that the pathogenesis of RCDP may be due solely to a deficiency of plasmalogens (Heymans and Wanders, 1996).
The transmission pattern of RCDP3 in the family reported by Brookhyser et al. (1999) was consistent with autosomal recessive inheritance.
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.
In the patient with RCDP and isolated alkyl-DHAP synthase deficiency described by Wanders et al. (1994), de Vet et al. (1998) identified a homozygous missense mutation in the AGPS gene (R419H; 603051.0001).
Whereas 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.
Itzkovitz et al. (2012) studied 6 patients with RCDP, 3 with RCDP2 and 3 with RCDP3, and identified homozygosity or compound heterozygosity for mutations in the GNPAT gene (see, e.g., 603744.0007-603744.0009) or AGPS gene (see, e.g., 603051.0004). 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.
Brookhyser, K. M., Lipson, M. H., Moser, A. B., Moser, H. W., Lachman, R. S., Rimoin, D. L. Prenatal diagnosis of rhizomelic chondrodysplasia punctata due to isolated alkyldihydroacetonephosphate acyltransferase synthase deficiency. Prenatal Diag. 19: 383-385, 1999. [PubMed: 10327148] [Full Text: https://doi.org/10.1002/(sici)1097-0223(199904)19:4<383::aid-pd544>3.0.co;2-s]
de Vet, E. C. J. M., IJlst, L., Oostheim, W., Wanders, R. J. A., van den Bosch, H. Alkyl-dihydroxyacetonephosphate synthase: fate in peroxisome biogenesis disorders and identification of the point mutation underlying a single enzyme deficiency. J. Biol. Chem. 273: 10296-10301, 1998. [PubMed: 9553082] [Full Text: https://doi.org/10.1074/jbc.273.17.10296]
Heymans, H. S., Wanders, R. J. A. Rhizomelic chondrodysplasia punctata. In: Moser, H. W. (ed.): Handbook of Clinical Neurology: Neurodystrophies and Neurolipidoses. Amsterdam: Elsevier Science B.V. 1996. Pp. 525-533.
Itzkovitz, B., Jiralerspong, S., Nimmo, G., Loscalzo, M., Horovitz, D. D. G., Snowden, A., Moser, A., Steinberg, S., Braverman, N. Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3. Hum. Mutat. 33: 189-197, 2012. [PubMed: 21990100] [Full Text: https://doi.org/10.1002/humu.21623]
Motley, A. M., Tabak, H. F., Smeitink, J. A. M., Poll-The, B. T., Barth, P. G., Wanders, R. J. A. Non-rhizomelic and rhizomelic chondrodysplasia punctata within a single complementation group. Biochim. Biophys. Acta 1315: 153-158, 1996. [PubMed: 8611652] [Full Text: https://doi.org/10.1016/0925-4439(95)00114-x]
Van Laer, P. Personal Communication. Bruges, Belgium 8/23/2013.
Wanders, R. J. A., Dekker, C., Hovarth, V. A. P., Schutgens, R. B. H., Tager, J. M., Van Laer, P., Lecoutere, D. Human alkyldihydroxyacetonephosphate synthase deficiency: a new peroxisomal disorder. J. Inherit. Metab. Dis. 17: 315-318, 1994. [PubMed: 7807941] [Full Text: https://doi.org/10.1007/BF00711817]
Wanders, R. J. A., Waterham, H. R. Peroxisomal disorders I: biochemistry and genetics of peroxisome biogenesis disorders. Clin. Genet. 67: 107-133, 2005. [PubMed: 15679822] [Full Text: https://doi.org/10.1111/j.1399-0004.2004.00329.x]
Waterham, H. R., Ebberink, M. S. Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim. Biophys. Acta 1822: 1430-1441, 2012. [PubMed: 22871920] [Full Text: https://doi.org/10.1016/j.bbadis.2012.04.006]