Isolated dihydroxyacetonephosphate acyltransferase deficiency presenting with developmental delay

Abstract

A boy aged 21 months who was being investigated for developmental delay and failure to thrive was found to have punctate epiphyseal calcification. He had no evidence of rhizomelic shortening of the limbs or cataracts. Investigation revealed defective plasmalogen synthesis due to isolated deficiency of dihydroxyacetonephosphate acyltransferase (DHAP-AT). The parents were consanguineous and a sister was similarly affected, suggesting autosomal recessive inheritance. Hitherto, recessively inherited isolated DHAP-AT deficiency has only been described in patients with a phenotype similar to that of rhizomelic chondrodysplasia punctata. This report indicates that the same biochemical disorder can be associated with a less severe phenotype.

Abnormal myelin formation in rhizomelic chondrodysplasia punctata type 2 (DHAPAT‐deficiency)

“…The girl's low activity of DHAPAT and deficient de novo plasmalogen synthesis in association with normal alkyl-DHAP synthase activity, phytanic acid concentration, and 3-oxoacyl-CoA thiolase protein are consistent with RCDP type 2 due to isolated DHAPAT deficiency. Only a few cases of chondrodysplasia punctata have been described previously with this isolated enzyme deficiency (Wanders et al 1992, Barr et al 1993, Clayton et al 1994, Hebestreit et al 1996. Those patients showed clinical heterogeneity: both rhizomelic forms with severe outcome and non-rhizomelic variants with a relatively mild clinical course have been described (Wanders et al 1992, Barr et al 1993, Clayton et al 1994, Hebestreit et al 1996.…”

“…Mutation analysis in eight individuals from five families has recently revealed five types of mutations (Ofman et al 1998). Three affected children in another Yemeni family (Clayton et al 1994, Sztriha et al 1997, Ofman et al 1998) had the same mutation as the reported girl. The arginine residue, which has been substituted by a histidine at position 211 (R211H) in these cases, is conserved in several species, suggesting an important role of this residue for the catalytic activity of the enzyme (Ofman et al 1998).…”

“…As the older children had less severe abnormalities in the white matter than the younger children in previously published cases (Sztriha et al 1997), it is very likely that a significant delay in myelination in infancy might be responsible for clinical signs and abnormal white matter signal on MRI. As DHAPAT deficiency may occur without rhizomelia and significant dysmorphic features (Clayton et al 1994), the described pattern of abnormal white matter seen on MRI and the punctate epiphyseal calcification in an infant with delayed development can be highly suggestive of this inborn error of metabolism. The plasmalogen deficiency probably plays a role in the abnormal myelin formation, although the underlying molecular pathophysiology and the cause of selective vulnerability of the white matter are not understood.…”

“…However, a significant biochemical heterogeneity within RCDP has been established recently. Individuals with all the clinical signs and symptoms of RCDP but with an isolated single deficiency of either DHAPAT (RCDP type 2) or alkyl-DHAP synthase (RCDP type 3) have been identified (Wanders et al 1992, Wanders et al 1994, Ofman et al 1998. Clinical heterogeneity has also been observed, even among individuals with isolated DHAPAT deficiency: cases of a milder, variant form of chondrodysplasia punctata have been described in addition to those with the classic clinical manifestations (Wanders et al 1992, Barr et al 1993, Clayton et al 1994, Hebestreit et al 1996.…”

1q42.12q42.2 Deletion in a Child with Midline Defects and Hypoplasia of the Corpus Callosum

“…Our patient has all these features except rhizomelia. A phenotype with GNPAT mutation without rhizomelia and cataracts has previously been described [Clayton et al, 1994]. Six additional patients with RCDP2 and RCDP3 due to GNPAT mutations have been identified [Itzkovitz et al, 2012].…”