Abstract 799
Inborn Errors of Metabolism Platform, Monday, 5/3
Glycerol kinase deficiency (GKD) can occur as part of an Xp21 contiguous gene syndrome or as an isolated glycerol kinase deficiency. Patients with isolated GKD may be asymptomatic (benign isolated GKD) and only come to medical attention because of pseudo-hypertriglyceridemia caused by their hyperglycerolemia, or they may have episodic metabolic and central nervous system (CNS) compromise (symptomatic isolated GKD). In an attempt to understand the relationship between genotype and the distinct clinical phenotypes among patients with isolated GKD, we sequenced the GK gene from affected patients. We identified four missense mutations and one splice site alteration. The three patients with benign isolated GKD who presented as asymptomatic adults had either missense mutations (N288D, Q438R) or a splice site alteration (g.IVS3+1G>A, c.exon3del). By reverse-transcription-polymerase chain reaction (RT-PCR), cells from the individual with the splice site mutation had mRNA with and without exon 3. A missense mutation (R405Q) was observed in the one patient who had episodic hypoglycemia and glyceroluria, which are characteristic features of symptomatic isolated GKD. The fifth patient (M428T), who had a missense mutation, is difficult to classify clinically, since he presented with neonatal asphyxia but had no further problems. In addition to our studies, Walker et al. (Am. J. Hum. Genet. 58:1205, 1996) reported one mentally retarded patient with isolated GKD who had a missense mutation (D440V), and one asymptomatic adult with a splice site alteration (g.IVS6-1G>C,c.553-554delAG) and reduced GK transcription causing benign isolated GKD. All five missense mutations found in symptomatic and asymptomatic patients occurred in conserved regions of the protein near the ADP binding site, and additional detailed structure-function analyses will be required to distinguish the potential metabolic impacts of the different mutations. The two splice site alterations were both associated with maintenance of expression of the normal GK transcript, though presumably in reduced amounts and interestingly, these patients only had benign GKD. We conclude that reduced but continued expression of normal GK transcripts above a threshold level is associated with a benign clinical course. A full understanding of the genotype-phenotype relationships among the missense mutations will require investigation of structural and functional changes in expressed mutant GK proteins.
