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Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.

ABSTRACT: Isolated glycerol kinase deficiency (GKD) is an X linked recessive disorder. The clinical and biochemical picture may vary from a childhood metabolic crisis to asymptomatic adult "pseudohypertriglyceridaemia", the result of hyperglycerolaemia. We performed glycerol kinase (GK) gene analysis to study the molecular heterogeneity and genotype-phenotype correlation in eight males from three families with isolated GKD. All patients had hyperglycerolaemia and glyceroluria. Four patients from two families were essentially free of symptoms. Three patients had gastrointestinal symptoms with ketoacidosis or hypoglycaemia or both. One patient had recurrent convulsions as the only acute sign, without evidence that it was correlated with a catabolic state. Fasting tests in two symptomatic patients of family 1 showed hyperketotic states, together with a tendency to hypoglycaemia. The diagnosis was confirmed by a defective 14C-glycerol incorporation into trichloroacetic acid precipitable macromolecules in intact skin fibroblasts. Mutation screening of the GK gene was performed by amplification and direct sequencing of exons using PCR. Three novel mutations were identified: (1) a deletion starting downstream of exon 9, extending to the 3' end of the gene; (2) a nonsense mutation R413X caused by a C1351T transition; and (3) a missense mutation W503R caused by a T1651C transition. In addition, we found differences from the reported sequence: (1) exon 9 actually consists of two exons, which consequently will change the number of GK gene exons from 19 to 20 exons, and (2) nucleotide differences in exon 19. So far, no genotype-phenotype correlation can be established in these GKD families.

SUBMITTER: Sjarif DR

PROVIDER: S-EPMC1051390 | biostudies-other | 1998 Aug

REPOSITORIES: biostudies-other

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Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.

Sjarif D R DR Sinke R J RJ Duran M M Beemer F A FA Kleijer W J WJ Ploos van Amstel J K JK Poll-The B T BT

Journal of medical genetics 19980801 8

Isolated glycerol kinase deficiency (GKD) is an X linked recessive disorder. The clinical and biochemical picture may vary from a childhood metabolic crisis to asymptomatic adult "pseudohypertriglyceridaemia", the result of hyperglycerolaemia. We performed glycerol kinase (GK) gene analysis to study the molecular heterogeneity and genotype-phenotype correlation in eight males from three families with isolated GKD. All patients had hyperglycerolaemia and glyceroluria. Four patients from two famil ...[more]

PMID: 9719371

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Project description:Abstract Background: Hypertriglyceridemia (HTG) is common; however, pseudo-HTG due to high glycerol in glycerol kinase deficiency (GKD, MIM: 307030) is a rare cause of HTG that need to be delineated for appropriate management. GKD is an X-linked recessive disorder characterized by hyperglycerolemia and glyceroluria. Two of three GKD subtypes are known as “isolate” GKD due to a mutation in GK gene alone: (1) symptomatic juvenile form, and (2) benign adult form, associated with an incidental finding of HTG. Since most commercial laboratories determine triglyceride (TG) levels by a glycerol measurement, TG-backbone, patients with GKD are mistakenly labelled as having HTG. Glycerol-blanking is required to reveal the actual TG, but it is costly. Since usual TG-lowering medications are ineffective or even harmful, novel methods to screen for individuals with GKD or pseudo-HTG are necessary. Objective: Through identification of a clinical case of GKD that was diagnosed by glycerol-blanking, we are proposing two potential methods to screen for pseudo-HTG, and presenting their reliability. Methods: The patient was recruited into an IRB-approved study investigating etiologies of dyslipidemia at the University of Pennsylvania. Patient provided consent for medical record review. Results: A 49-year-old man was referred for HTG management. His reported TG levels ranged between 490 and 559 mg/dL without any other adverse lipid levels for several years without a history of pancreatitis or diabetes mellitus. Intriguingly, he reported a family history of HTG. Since TG-lowering medications (fibrates and fish oil) had not reduced his TG levels, specialized lipid analyses were obtained: a non-blanked TG level of 521 mg/dL and a glycerol-blanked TG of 66 mg/dL, consistent with pseudo-HTG or hyperglycerolemia. Repeat glycerol blanked TG levels were 68 and 69 mg/dL, confirming the previous result, and the likely diagnosis of GKD. With two methods, estimated TG levels were calculated, using some of his laboratory values: (1) modified Friedewald equation to solve for TG with a direct LDL (dLDL) value, and (2) the application of a newly developed formula derived from a collection of 17,545 patient samples, to calculate the absolute TG-gap, using apolipoprotein A and B, estimating TG levels (% deltaTG), and determining whether a TG mesurement might be falsely deviated from the “plausible” TG value. Although neither methods showed perfect concordance, the calculated TG-valued derived by the two methods were significantly lower than the non-glycerol blanked TG values. The difference was statistically significant (p<0.05). Conclusion: The patient was clinically diagnosed with GKD, and was taken off of fibrate and the recently added niacin. These two methods can be used quickly to screen for pseudo-HTG or patients with GKD. Currently, it is unknown whether high glycerol levels are associated with high cardiovascular risks.

Dataset Information

Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.

Publications

Clinical heterogeneity and novel mutations in the glycerol kinase gene in three families with isolated glycerol kinase deficiency.

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