Clinical and molecular analysis of arylsulfatase E in patients with brachytelephalangic chondrodysplasia punctata

Abstract

X-linked Recessive Chondrodysplasia Punctata (CDPX1) is due to a defect in arylsulfatase E (ARSE), located on Xp22.3. Neither the substrate nor function of the encoded warfarin-sensitive arylsulfatase has been identified and molecular analysis remains the only confirmatory diagnostic test. Nevertheless, the majority of patients evaluated have not had identifiable mutations in ARSE, and thus far 23 patients have been reported. The major clinical features in these patients are also present in a group now recognized as phenocopies, due to vitamin K deficiency in early gestation or maternal autoimmune disease. We evaluated the ARSE gene in 11 patients who met clinical criteria for CDPX1. We amplified all exons and intronic flanking sequence from each patient, and investigated suspected deletions or rearrangements by southern analysis. We identified mutations in seven individuals. Of the remainder, three had maternal conditions that further expand the phenocopy group. Thus, this group might represent a proportion of the mutation-negative patients in previous studies. We extracted clinical information from all prior reports over the past decade and show that there are few distinguishing features on examination between these two groups of patients. This study supports heterogeneity for CDPX1-like phenotypes and sorting these out will help to define the biological pathway and genetic contributors.

A prospective study of brachytelephalangic chondrodysplasia punctata: identification of arylsulfatase E mutations, functional analysis of novel missense alleles, and determination of potential phenocopies

“…Most children have normal intellect and life span, but comorbidities can be present, including compression of the cervical spinal cord associated with cervical vertebral abnormalities or stenosis of the upper and lower airways that result from extensive calcifications within the tracheal and bronchial cartilage. 3,4 Intrafamilial differences in disease severity have also been documented. 3 The only known genetic cause of CDPX1 is defects in arylsulfatase E (ARSE).…”

“…302950), originally recognized by Sheffield et al, 1 is a panethnic congenital rare disorder that affects males. The most characteristic clinical features are as follows: 2,3 (i) Chondrodysplasia punctata, or stippled epiphyses, observed on X-ray. These minimally involve the ankle and distal phalanges but can also include long bones, vertebrae, hips, costochondral junctions, hyoid bone, and tracheal and bronchial cartilage.…”

“…Only 67 male probands had undergone ARSE mutation analysis, with mutations identified in 31. 3 Functional analysis was performed in 8 of 15 reported missense alleles (Supplementary Table S1 online) by expressing the mutant ARSE complementary DNA in mammalian COS1 cells and measuring ARSE activity using 4MU sulfate. 5 In these experiments, all missense alleles had negligible activity.…”

“…16 In those cases in which ARSE mutations were evaluated in their affected offspring, none were found. 3,13 Another group of children with BCP are born to mothers with autoimmune diseases. [17][18][19] It was proposed that maternal autoantibodies might perturb fetal vitamin K metabolism, 20 thereby reducing the etiology of all phenocopies to disturbances in vitamin K metabolism at a critical fetal time period.…”

“…3,4 Intrafamilial differences in disease severity have also been documented. 3 The only known genetic cause of CDPX1 is defects in arylsulfatase E (ARSE). The ARSE gene is located at Xp22.3, within a cluster of contiguous arylsulfatase genes that share high sequence homology, escape X inactivation, and have pseudogenes on the Y chromosome.…”