8. Genetic basis of Mabry’s syndrome

Abstract

We review the discovery of two genes disrupted in Mabry syndrome (hyperphosphatasia with developmental disability; OMIM#239300): a syndrome notable for characteristic facial dysmorphology (hypertelorism, a broad nasal bridge and a tented mouth); subtle hand bone abnormalities (variable shortening of middle and distal phalanges) and nerve abnormalities (plaques disrupting Schwann cells) and persistently elevated serum alkaline phosphatase (ALP). In approximately two thirds of cases, the biochemical abnormalities present in Mabry syndrome result from disruption of the phosphoinositol glycan (GPI) anchor as a result of mutations in the phosphoglycan-inositol biosynthesis type V ( PIGV ) and type O ( PIGO ) genes. The remaining one third of cases have no known mutation in the GPI anchor pathway. These idiopathic cases are reported to accumulate lysosomal storage material that has been putatively identified as a glycolipid material. As twenty genes are integral to GPI anchor synthesis, we hypothesize that idiopathic cases of Mabry syndrome may result from disruptions in other genes encoding GPI anchor biosynthesis enzymes. We are using exome sequencing and candidate gene approaches to identify the gene(s) responsible for idiopathic Mabry syndrome. This work will assist in elucidating the inborn errors of metabolism that underlie the seizures associated with Mabry syndrome.