Isolated and contiguous glycerol kinase gene disorders: A review

Abstract

Glycerol kinase deficiency (GKD) is an X-linked recessive disorder. There are two types. an isolated form and a complex form. We review the clinical, biochemical and molecular genetic features of GKD. The clinical and biochemical phenotype of isolated GKD may vary from a life-threatening childhood metabolic crisis to asymptomatic adult 'pseudohypertriglyceridaemia', resulting from hyperglycerolaemia. To date 38 patients from 24 families with isolated GKD have been reported. At least 7 of these patients had a metabolic crisis during a catabolic condition. The complex GKD is an Xp21 contiguous gene syndrome involving the glycerol kinase locus together with the adrenal hypoplasia congenita (AHC) or Duchenne muscular dystrophy (DMD) loci or both. Clinical features of a patient with complex GKD depend on the loci that are involved. Approximately 100 patients from 78 families with a complex GKD have been reported. Seventeen patients with complex GKD (AHC-GKD-DMD or AHC-GKD) died in the neonatal period or early childhood because of unrecognized or inappropriate management of adrenal dysfunction. Since the outcome of the crisis in GKD is highly dependent on the physicians' knowledge of the disease, we devised an algorithmic approach to the diagnosis. From molecular genetic investigations of isolated GKD, 7 missense mutations, 2 splice site mutations, I nonsense mutation, 1 Alu Sx insertion and 2 small deletions were reported for isolated GKD in 13 unrelated families. In 4 families consisting of more than one patient with the same biochemical and genetic defect, the phenotypic variability of the isolated GKD was remarkable. The clinical variability in isolated GKD cannot be explained by biochemical or by molecular heterogeneity. Isolated GKD patients showed a tendency towards hypoglycaemia with hyperketonaemia; whether the clinical symptoms of GKD are caused by dysfunction of gluconeogenesis and/or ketolysis needs to be investigated further.

Glycerol Hypersensitivity in a Drosophila Model for Glycerol Kinase Deficiency Is Affected by Mutations in Eye Pigmentation Genes

“…Glycerol 3-phosphate can be directed towards gluconeogenesis or lipid metabolism and alteration of GK activity also has a substantial effect on metabolic flux through other metabolic pathways such as the pentose phosphate pathway [2]. In humans, GKD patients can have severe metabolic and CNS abnormalities, while others possess hyperglycerolemia and glyceroluria with no other apparent phenotype [3], [4]. Extensive studies incorporating patient data, mutation analysis and protein tertiary structure reveal no obvious phenotype-genotype correlations [4]–[6].…”

Multiplex Ligation-Dependent Probe Amplification Analysis of the <i>NR0B1</i><i>(DAX1)</i> Locus Enables Explanation of Phenotypic Differences in Patients with X-Linked Congenital Adrenal Hypoplasia

“…It is of note that while GKD and DMD can also be ruled out by measuring glycerol, triglycerides and creatine kinase, respectively, no markers for MR are available, making the detection of IL1RAPL1 deletions in very young patients of significant help for the prognosis of the patient. However, it is important to remember that a severe adrenal crisis due to AHC can lead to brain damage and consequent MR, as well as that GKD can lead to psychomotor impairment as a consequence of hypoglycemic episodes [8]. These two latter causes of MR can be prevented with optimal medical management.…”

“…GKD, even in the isolated form, presents with variable phenotypes, and even within the same family, these range from asymptomatic hyperglycerolemia to severe and life-threatening metabolic crisis and/or psychomotor retardation [8,9]. DMD, together with Becker muscular dystrophy, is a neuromuscular disease characterized by progressive muscular weakness and degeneration of skeletal muscle and is caused by mutations of the DMD gene; at least 20% of the patients also show mental impairment [10].…”

Identification of Novel Mutations of the <i>DAX-1</i> Gene in Patients with X-Linked Adrenal Hypoplasia Congenita

“…GK deficiency is an X-linked recessive disorder characterized by psychomotor retardation, Reye-like syndrome, pseudohypertriglyceridemia, and hyperglyceroluria resulting from hyperglycerolemia [20, 21]. Patient 3 manifested typical clinical features of Duchenne muscular dystrophy, GK deficiency, AHC, and mental retardation while lacking the clinical features of OTC deficiency, such as hyperammonemia.…”