Isolated and contiguous glycerol kinase gene disorders: A review

Glycerol kinase deficiency (GKD) is an X-linked recessive disorder. There a re two types, an isolated form and a complex form. We review the clinical, biochemical and molecular genetic features of GKD. The clinical and biochem ical phenotype of isolated GKD may vary from a life-threatening childhood m etabolic crisis to asymptomatic adult 'pseudohypertriglyceridaemia', result ing from hyperglycerolaemia. To date 38 patients from 24 families with isol ated GKD have been reported. At least 7 of these patients had a metabolic c risis during a catabolic condition. The complex GKD is an Xp21 contiguous g ene syndrome involving the glycerol kinase locus together with the adrenal hypoplasia congenita (AHC) or Duchenne muscular dystrophy (DMD) loci or bot h. Clinical features of a patient with complex GKD depend on the loci that are involved. Approximately 100 patients from 78 families with a complex GK D have been reported. Seventeen patients with complex GKD (AHC-GKD-DMD or A HC-GKD) died in the neonatal period or early childhood because of unrecogni zed or inappropriate management of adrenal dysfunction. Since the outcome o f the crisis in GKD is highly dependent on the physicians' knowledge of the disease, we devised an algorithmic approach to the diagnosis. From molecul ar genetic investigations of isolated GKD, 7 missense mutations, 2 splice s ite mutations, 1 nonsense mutation, 1 Alu Sx insertion and 2 small deletion s were reported for isolated GKD in 13 unrelated families. In 4 families co nsisting of more than one patient with the same biochemical and genetic def ect, the phenotypic, variability, of, the, isolated GKD was remarkable. The clinical variability, in, isolated, GKD, cannot, be, explained, by, bioche mical, or, by molecular heterogeneity. Isolated GKD patients showed a tende ncy towards hypoglycaemia with hyperketonaemia; whether the clinical sympto ms of GKD are caused by dysfunction of gluconeogenesis and/or ketolysis nee ds to be investigated further.