Phenotypic variability in hyperphosphatasia with seizures and neurologic deficit (Mabry syndrome)

Hyperphosphatasia with neurologic deficit (Mabry syndrome)was first described in a single family (OMIM#239300) by Mabryet al. [1970]. Although considered rare at the time, more than 20individuals with the triad of developmental disability, seizures,and hyperphosphatasia have been identified world-wide. The 1-6mannosyltransferase 2, phosphatidylinositol glycan V (PIGV)gene has been found to be disrupted in some patients with theadditional feature of brachytelephalangy. In the present reportwe identify three patients compound homozygous for PIGVmutations. Two siblings were found to be compound heterozygotesfor c.467G>A and c.494C>A in exon 3 of PIGV (thec.494C>A PIGV variant is novel). A third patient with similarphenotype, was a compound heterozygote for the knownc.1022C>A/c.1022C>T (p.Ala341Glu/p.Ala341Val) mutation.This patient was also noted to have lysosomal storage in culturedfibroblasts. In contrast, the fourth patient who had no apparenthand abnormality, was found to be heterozygous for a previouslyunclassified c.1369C>T mutation in exon 4 of the PIGV gene,resulting in a p.Leu457Phe substitution in the catalytic domainof the enzyme. Unless this variant has a dominant negative effect,however, it seems likely that another GPI biosynthesis genevariant may contribute to the disorder, possibly through digenicinheritance. Since slightly fewer than half of the nine casespresented in this report and our previous report [Thompsonet al., 2010] have PIGV mutations, we suggest that other genes critical to GPI anchor biosynthesis are likely to be disrupted insome patients