Novel PHKG2 mutation causing GSD IX with prominent liver disease: report of three cases and review of literature.

Glycogen storage disease type IX (GSD IX) is a common form of glycogenosis due to mutations in PHKA1, PHKA2, or PHKB and PHKG2 genes resulting in the deficiency of phosphorylase kinase. The first two genes are X-linked while the latter two follow an autosomal recessive inheritance. The majority of cases of GSD IX are attributed to defects in PHKA2 which usually cause a mild disease. We report three patients with PHKG2-related GSD IX presenting with significant hepatic involvement, fibrosis, and cirrhosis. Interestingly, the homozygosity mapping resolved a dilemma about an erroneously normal phosphorylase kinase activity in patient 1. The novel mutation found in all the three patients (p.G220E) affects the catalytic subunit of the phosphorylase kinase. Increasing evidence shows that patients with PHKG2 mutations have a severe hepatic phenotype within the heterogeneous GSD IX disorder. Therefore, defect in PHKG2 should be considered in patients with suspected glycogenosis associated with significant liver fibrosis and cirrhosis.

Mutation in MPDZ causes severe congenital hydrocephalus.

BACKGROUND: Congenital hydrocephalus is an important birth defect that is heterogeneous in aetiology and clinical presentation. Although genetics is believed to play an important role in the aetiology of non-syndromic congenital hydrocephalus, the overwhelming majority of cases lack mutations in L1CAM, the only disease gene identified to date. The purpose of this study is to identify a novel genetic cause of congenital hydrocephalus. METHODS: Families with congenital hydrocephalus were phenotyped clinically and, in one family, autoyzogisty mapping and linkage analysis were pursued. Sequencing of the genes within the candidate locus was followed by targeted sequencing of the likely candidate gene in two other families. RESULTS: We have identified a family in which severe congenital hydrocephalus of the communicating type follows an autosomal recessive mode of inheritance. Linkage analysis and autozygosity mapping narrowed the critical interval to 6.9 Mb on 9p24.1-p22.3 spanning just six genes. Direct sequencing of these genes revealed a truncating mutation in MPDZ, encoding a tight junction protein. Remarkably, we have also identified the same founder mutation in a stillbirth with massive congenital hydrocephalus from another family. CONCLUSIONS: Our data strongly support the candidacy of MPDZ as a novel congenital hydrocephalus disease gene.