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Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive disorder due to the deficiency in ether lipid synthesis. RCDP type 1, the most prominent type, is caused by the dysfunction of the receptor of peroxisome targeting signal type 2, Pex7 (peroxisomal biogenesis factor 7), and the rest of the patients, RCDP types 2 and 3, have defects in peroxisomal enzymes catalyzing the initial two steps of alkyl-phospholipid synthesis, glyceronephosphate O-acyltransferase and alkylglycerone phosphate synthase (Agps). We herein investigated defects of two patients with RCDP type 3. Patient 1 had a novel missense mutation, T1533G, resulting in the I511M substitution in Agps. The plasmalogen level was mildly reduced, whereas the protein level and peroxisomal localization of Agps-I511M in fibroblasts were normal as in the control fibroblasts. Structure prediction analysis suggested that the mutated residue was located in the helix α15 on the surface of V-shaped active site tunnel in Agps, likely accounting for the mild defects of plasmalogen synthesis. These results strongly suggest that an individual with mildly affected level of plasmalogen synthesis develops RCDP. In fibroblasts from patient 2, the expression of AGPS mRNA and Agps protein was severely affected, thereby giving rise to the strong reduction of plasmalogen synthesis.

Cerebellar atrophy, consequent to the postdevelopmental degeneration and loss of Purkinje cells and granular neurons, has been identified in three patients with rhizomelic chondrodysplasia punctata (RCDP). Cerebellar atrophy in our two chronic patients was symmetrical, but the vermis and medial portions of both hemispheres, particularly the dorsal lobules, displayed more severe atrophy than the lateral hemispheres. The distal tips of folia showed the greatest neuronal loss. Residual Purkinje cells showed progressive degenerative changes that appeared to be due, in part, to their topography. The precise mode of death of Purkinje cells in RCDP has not been established, but it does not appear to be mediated by entrance into the cell cycle or by ubiquitination; however, alterations in intracellular calcium levels and mitochondria may be involved. Elevated serum/CSF phytanic acid, decreased levels of tissue plasmalogens and increased chronological age are believed to play synergistic pathogenetic roles in this lesion.

We report on a skeleton dating from the last century with a severe, strictly rhizomelic shortening of all four extremities and a deformed skull. To the best of our knowledge no similar skeletal findings have been described. We suggest that this individual suffered from a hitherto unreported form of skeletal dysplasia.

Rhizomelic chondrodysplasia punctata (RCP), a rare autosomal recessive disease characterized by a disorder of peroxisome metabolism, has been shown to affect multiple organ systems. A neonate presenting with a colonic perforation in the first few hours of life was subsequently diagnosed with RCP. A literature search revealed no previous reports of intestinal perforation associated with RCP. Intestinal perforation should be added to the list of medical complications associated with RCP.

Rhizomelic chondrodysplasia punctata (RCDP) is clinically characterized by symmetrical shortening of the proximal limbs, contractures of joints, a characteristic dysmorphic face, and cataracts. In the classical form an impairment of several peroxisomal functions and enzymes (plasmalogen synthesis, phytanic acid oxidation, 3-oxoacyl-CoA thiolase) has been repeatedly shown. Recently a variant involving only the peroxisomal dihydroxyacetonephosphate acyltransferase (DHAP-AT) has been described. We present a patient with isolated DHAP-AT deficiency and all clinical, radiological and pathological features of classical RCDP. For the first time, microscopy and immunocytochemistry of hepatocytes could be performed. CONCLUSION: In contrast to studies on classical rhizomelic chondrodysplasia punctata which have shown enlarged peroxisomes in numbers varying from hepatocyte to hepatocyte, the peroxisomes in our patient seem to be normal in size, number and shape