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

Abstract

Hyperphosphatasia with neurologic deficit (Mabry syndrome) was first described in a single family (OMIM#239300) by Mabry et al. [1970]. Although considered rare at the time, more than 20 individuals with the triad of developmental disability, seizures, and hyperphosphatasia have been identified world‐wide. The 1‐6 mannosyltransferase 2, phosphatidylinositol glycan V (PIGV) gene has been found to be disrupted in some patients with the additional feature of brachytelephalangy. In the present report we identify three patients compound homozygous for PIGV mutations. Two siblings were found to be compound heterozygotes for c.467G > A and c.494C > A in exon 3 of PIGV (the c.494C > A PIGV variant is novel). A third patient with similar phenotype, was a compound heterozygote for the known c.1022C > A/c.1022C > T (p.Ala341Glu/p.Ala341Val) mutation. This patient was also noted to have lysosomal storage in cultured fibroblasts. In contrast, the fourth patient who had no apparent hand abnormality, was found to be heterozygous for a previously unclassified c.1369C > T mutation in exon 4 of the PIGV gene, resulting in a p.Leu457Phe substitution in the catalytic domain of the enzyme. Unless this variant has a dominant negative effect, however, it seems likely that another GPI biosynthesis gene variant may contribute to the disorder, possibly through digenic inheritance. Since slightly fewer than half of the nine cases presented in this report and our previous report [Thompson et al., 2010] have PIGV mutations, we suggest that other genes critical to GPI anchor biosynthesis are likely to be disrupted in some patients. © 2012 Wiley Periodicals, Inc.

Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis

“…A nonsense mutation in the X-linked PIGA gene, which encodes another subunit of this enzyme, was recently reported to cause a lethal disorder characterized by multiple congenital abnormalities, structural brain malformations, joint contractures and neonatal seizures with a burst-suppression EEG (35). Recessive mutations in other GPI synthesis genes cause clinically heterogeneous syndromes, all of which involve seizures (36–39). Thus, this PIGQ mutation seemed a very plausible candidate for causing OS in Patient 4.…”

Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome

“…Of note, in this patient only one missense variant in PIGV was found, which did not show a functional effect (data not shown). 5 In conclusion, severe developmental delay, the particular facial gestalt, and hyperphosphatasia constitute this distinct syndrome. A variable degree of brachytelephalangy has been observed in all molecularly confirmed cases.…”

“…Of note, another missense mutation, c.1022C4T, at the same position has been identified in three reported cases. 3,5,6 It is striking that all the families of European descent except one carry at least one mutation at this position of the gene. The novel mutations, c. 176T4G, c.53G4A, c.905T4C, and c.1405C4T, were not found in the HapMap or the NCBI dbSNP database.…”

“…2 PIGV mutations as one of the causes of HPMRS have been reported in eight affected families so far. 3,5,6 In two families with HPMRS, PIGO mutations have been identified; in two further families PGAP2 mutations have been found. 2,4 PGAP2 mutations have also been found to be associated with nonspecific autosomal recessive intellectual disabilities in two consanguineous families.…”

Vitamin B-6 Metabolism and Interactions with TNAP

“…Considering the marked elevation of plasma pyridoxal phosphate in hypophosphatasia, one might expect markedly reduced concentrations in hyperphosphatasia resulting from a defect in the biosynthesis of the phosphatidylinositol glycan anchor which attaches the enzyme to the membrane (Thompson et al 2012) (see also Chap. 16).…”