the glycerol 3-phosphate can then be reduced to dihydroxyacetone phosphate which enters the glycolytic pathway , or be used as the backbone for the formation of glycerolipids ( triglycerides and plasmalogens ) as well as glycerol phospholipids . glycerol kinase deficiency ( gkd : mim : 307030 ) is an x - linked inborn error of metabolism that is due to mutations , deletions or insertions within the gk gene on xp21 . patients with isolated gkd ( igkd ) can be either symptomatic with episodes of metabolic acidosis and central nervous system decompensation or asymptomatic with only pseudo - hypertriglyceridemia . we and others have previously shown that there is no genotype  phenotype correlation in gkd and therefore , we can not predict by the dna mutation or the gkd activity , which patients will be symptomatic and which will be asymptomatic , . this suggests that there is additional complexity in the system and we have hypothesized that this complexity is due in part to other factors that are inherited independently , including modifier genes , flux through related metabolic pathways , post - transcriptional and post - translational modifications , and the cellular network within which gk functions , , . given that gk is at the interface of fat and carbohydrate metabolism , it is interesting to note that gk and gkd have links to both obesity and type 2 diabetes mellitus ( t2 dm ) . reported that 12 out of 18 men carrying a gkd missense mutation ( n288d ) had obesity and met the criteria for impaired glucose tolerance and/or t2 dm . we determined that the lymphoblastoid cell line from a patient with the n288d missense mutation had residual gk enzymatic activity . in addition , the thiazolidinediones , common drugs to treat t2 dm , increase gk expression in adipocytes and treat insulin insensitivity by making a futile cycle involving gk that ultimately reduces free fatty acids , , . gk also plays a role in obesity in mice . in a mouse cross using quantitative traits to identify genes important in abdominal obesity , gk was identified as one of the top ten genes important for the predisposition for abdominal obesity . a gyk ( the mouse ortholog of gk ) knockout ( ko ) mouse was made by gene - targeted deletion using a mouse gyk cdna . the gyk ko male mice are born in the expected numbers and are normal at birth . the ko mice have a >  80 fold increase in plasma glycerol and ~  3 fold increase of free fatty acid . the ultimate cause of death of the mice still remains unclear , but we have shown that it is due in part to extensive metabolic acidosis . additionally , we have previously shown that there are altered expression levels of genes in metabolism and insulin signaling pathway in glycerol kinase ( gyk ) knockout ( ko ) mouse liver , brown fat , and muscle . the altered expression of insulin signaling genes in the gyk ko mice suggested that they have reduced glucose uptake , and consequently reduced insulin sensitivity . after consent using a ucla irb approved protocol , a lymphoblastoid cell line was made from blood isolated from the proband and his mother as previously described . for the proband , his mother and maternal grandmother , we sequenced the 20 exons and intron  exon boundaries of the xp21 gk gene as previously described . the instt mutation was confirmed by restriction fragment polymorphism with the ddei restriction enzyme ( new england biolabs , ipswich , ma ) . the dna was digested for 13  h at 37  c with one unit of ddei enzyme per microgram of dna per manufacturer 's protocol and run on a 1% agarose gel . we determined the gk activity in a lymphoblastoid cell line from the patient and his mother using a radiochemical assay as previously described . after consent using a ucla irb approved protocol , a lymphoblastoid cell line was made from blood isolated from the proband and his mother as previously described . for the proband , his mother and maternal grandmother , we sequenced the 20 exons and intron  exon boundaries of the xp21 gk gene as previously described . the instt mutation was confirmed by restriction fragment polymorphism with the ddei restriction enzyme ( new england biolabs , ipswich , ma ) . the dna was digested for 13  h at 37  c with one unit of ddei enzyme per microgram of dna per manufacturer 's protocol and run on a 1% agarose gel . we determined the gk activity in a lymphoblastoid cell line from the patient and his mother using a radiochemical assay as previously described . urine organic acids revealed glyceroluria and blood analysis showed elevated triglycerides ( pseudo - hypertriglyceridemia ) , which are consistent with the symptomatic form of isolated glycerol kinase deficiency ( gkd ) . he was born at 37  weeks gestational age , and his birth weight was 3785  g , birth length 57  cm and head circumference 36  cm . he was born by induced vaginal delivery and the umbilical cord was wrapped around a leg . otherwise the birth history was unremarkable . the first pregnancy was uneventful and oral glucose tolerance test ( ogtt ) was normal . with the second pregnancy ( when she carried this affected fetus ) she had gestational diabetes . while this is a modest insulin dose , it is striking that she required insulin given that only 10% of pregnancies result in gestational diabetes   and many of these are treated with only diet and exercise . the diabetes resolved after the pregnancy indicating she was not one of the many individuals for whom the diagnosis of gestational diabetes was simply revealing type 2 diabetes that was not yet diagnosed . in the first pregnancy she had gestational diabetes and required insulin therapy starting in the 6th month of gestation . in her second pregnancy , she had trace glucose in the urine but normal blood sugars . in the last two pregnancies sequence analysis of the proband ( iii-2 ) revealed an insertion of two thymidine ( tt ) residues at position 378 of the xp21 gk cdna ( 378379instt ) which was confirmed by allele specific cleavage with the restriction enzyme ddei ( table 1 , fig . his mother ( ii-1 ) was heterozygous for this mutation and therefore a carrier for gkd . the proband 's gk activity in the lymphoblastoid cell line was 0.8% of a normal control . she had gestational diabetes requiring insulin during this pregnancy but not in her previous pregnancy . , gk is at the interface of fat and carbohydrate metabolism and gkd has been shown to increase risk for obesity , insulin resistance and diabetes , , , , , . recent data suggest that glycerol - stimulated proinsulin biosynthesis and insulin secretion in pancreatic islets after adenoviral - mediated expression of gk require the mitochondrial metabolism of glycerol . one mechanism for obesity in gkd may be the need for frequent meals to treat the hypoglycemia . in addition , there is evidence of increased fat storage in liver cells overexpressing gk suggesting that gk has a role in lipid storage . while there are many factors increasing risk of gestational diabetes , it is intriguing to note that the mother of the proband ( ii-1 ) had gestational diabetes when she was pregnant with an affected fetus ( iii-2 ) , but not with her other pregnancy ( iii-1 ) . it is likely that some of the risk for the gestational diabetes was due to the fact that the mother was a carrier for this disorder and has only half the normal activity . this risk was increased due to the fact that she was carrying an affected fetus with less than 1% activity . this would add gkd to a host of other diseases where the maternal and fetal genotypes affect risk for pregnancy related complications . this list includes risk of prenatal complications such as preeclampsia , low birth weight and hla - b maternal  fetal genotype in families with risk for schizophrenia . other inborn errors of metabolism ( iem ) also have been noted to have maternal  fetal genotype effects . in particular pregnancies where the mother is carrying a fetus with an iem ( such as long - chain 3-hydroxyacyl coa dehydrogenase [ lchad ] ) , the mother can present with pre - eclampsia , hellp ( hemolysis , elevated liver enzymes and low platelets ) syndrome or acute fatty liver of pregnancy , ; in addition , the fetus may have non - immune hydrops . given the complexity of gestational diabetes   and the association of gkd with diabetes , , , it may be that the maternal ( gkd carrier status ) and the fetal ( gkd male ) milieu may be only one component in the etiology of this mother 's gestational diabetes . the of the proband had a history of gestational diabetes in one of her four pregnancies and isolated glucosuria in another , but she was not a carrier of the 378379instt mutation . therefore , it is likely that there are other genetic factors predisposing to gestational diabetes in this family and the gk mutation and/or glycerol load in her daughter ( ii-1 ) and her daughter 's fetus ( iii-2 ) contributed to manifest this predisposition in her daughter . in summary , this is a case of symptomatic gkd due to a novel gk mutation ( instt ) that suggests the possibility of a maternal  fetal effect . specifically , there may be an increased risk of gestational diabetes in a mother heterozygous for a gk frameshift mutation when carrying a hemizygous male fetus with that mutation that may result from the maternal  fetal interaction . the observations that gkd is associated with insulin resistance and diabetes ( , , ) , a group of drugs routinely used to treat t2 dm increases gk expression in fat , and gk plays an important role in murine obesity   suggest that the possible maternal  fetal interaction in this maternal  fetal dyad may not be a coincidence . we recommend that other metabolic centers monitor female carriers of gkd for gestational diabetes and see if gestational diabetes occurs more often when a carrier mother has an affected fetus .