ClinVar

Glycogen Storage Disease IV

In a Jewish female infant with the nonprogressive hepatic form of glycogen storage disease IV (GSD4; 232500), Bao et al. (1996) found 2 missense mutations on separate alleles of the GBE1 gene: leu224-to-pro (L224P; 607839.0003) and tyr329-to-ser (Y329S). The L224P mutation resulted in complete loss of GBE1 activity, whereas the Y329S mutation resulted in loss of approximately 50% of GBE1 activity. Bao et al. (1996) detected the Y329S allele in another patient with the nonprogressive form of GSD IV but not in 35 unrelated controls or in patients with the more severe forms of GSD IV. The Y329S substitution resulted from an A-to-C transversion at nucleotide 1076. The second patient with the Y329S allele was 20 years old at the time of report and had normal liver function.

Adult Polyglucosan Body Neuropathy

In 7 Jewish patients with adult polyglucosan body neuropathy (APBN; 263570), Lossos et al. (1998) identified homozygosity for the Y329S mutation. The authors concluded that despite the very different phenotypes of APBN and GSD IV, they are allelic disorders.

Mochel et al. (2012) identified the Y329S mutation in 35 (76%) of 50 patients with APBN, all of whom were of Ashkenazi Jewish origin. Thirteen of the patients carried the Y329S mutation in heterozygous state, but the gene was not exhaustively studied for other possible variants. Akman et al. (2015) performed follow-up of some of the heterozygous patients reported by Mochel et al. (2012). In a cohort of 16 patients of Ashkenazi Jewish descent who were initially found to be heterozygous for the Y329S mutation, Akman et al. (2015) found that 3 were compound heterozygous for Y329S, caused by a c.986A-C transversion in exon 7, and a c.671T-C transition, resulting in a leu224-to-pro (L224P; 607839.0003) substitution. The remaining 16 heterozygous patients carried a complex deep intronic del/ins mutation in intron 15 (607839.0020) that resulted in a truncated protein. Haplotype analysis suggested a founder effect for the deep intronic mutation. The mean GBE activity in compound heterozygotes was 8% of normal compared to 18% of normal in Y329S homozygotes.