Glycerol Kinase Deficiency

A number sign (#) is used with this entry because glycerol kinase deficiency (GKD) is caused by mutation in the GK gene (300474) on chromosome Xp21.

Description

Francke et al. (1987) noted that there are 3 clinically distinct forms of glycerol kinase deficiency: infantile, juvenile, and adult. The infantile form is associated with severe developmental delay, and those with the adult form have no symptoms and are often detected fortuitously.

The infantile form of GK deficiency, or the 'GK complex,' results from the Xp21 contiguous gene deletion syndrome (300679) with congenital adrenal hypoplasia (300200) and/or Duchenne muscular dystrophy (DMD; 310200), whereas the juvenile and adult forms have isolated GK deficiency (Walker et al., 1996).

Clinical Features

In a 70-year-old mildly diabetic man, Rose and Haines (1978) found an elevated level of serum-free glycerol (about 75 mg per dl) and excretion of free glycerol in the urine (about 13 gm per 25 hr). Homogenates of the patient's leukocytes contained negligible activity of ATP:glycerol phosphotransferase. A brother and the son of a daughter of the proband also showed hyperglycerolemia.

In a 76-year-old man, Goussault et al. (1982) found 'false hypertriglyceridemia' due to a 40-fold increased glycerolemia. Deficiency of glycerol kinase (11% of normal) was found in the leukocytes of the proband, and values of 48% and 100%, respectively, were found in a daughter and sister. Patients with the adult form of glycerol kinase deficiency are usually identified through hyperlipidemia testing. They have pseudotriglyceridemia because the large amount of glycerol in their serum is falsely identified as triglyceride. These adults have no apparent clinical problems. The pedigrees in all reported cases are consistent with X-linked inheritance.

Eriksson et al. (1983) reported a 10-year-old boy who had been admitted on several occasions with severe gastroenteritis and metabolic acidosis. He had increased glycerol in the urine and serum. His glycerol kinase activity in leukocytes and cultured fibroblasts was less than 1% of normal.

Ginns et al. (1984) reported 2 boys with juvenile GKD who initially at 4 years of age had episodic vomiting, metabolic acidosis, stupor, and coma. No further episodes of coma occurred in 1 of them after he began a low-fat diet.

Grier et al. (1989) described biochemical, clinical, and molecular genetic studies in a patient with isolated glycerol kinase deficiency. A low-fat diet resulted in dramatic clinical and developmental improvement. Molecular genetic studies with conventional Southern blot and PCR analyses showed no evidence of deletion.

Sjarif et al. (1998) studied 8 males from 3 families with isolated glycerol kinase deficiency. All except 1 had onset in the neonatal period or in early childhood. Four patients from 2 families were free of symptoms, 3 patients had gastrointestinal symptoms with ketoacidosis or hypoglycemia or both, and 1 patient had recurrent convulsions as the only acute sign, without evidence that it was correlated with a catabolic state.

Sjarif et al. (2000) reviewed isolated and contiguous glycerol kinase gene disorders. Thirty-eight patients from 24 families with isolated GKD had been reported. At least 7 of these patients had a metabolic crisis during a catabolic condition. Approximately 100 patients from 78 families had a complex GKD disorder involving either GKD and adrenal hypoplasia congenita or Duchenne muscular dystrophy or both. Sjarif et al. (2000) presented a diagnostic algorithm for GKD.

Mapping

Hammond et al. (1985) suggested that the locus for glycerol kinase and that for X-linked adrenal hypoplasia are in the segment Xp21-p11.2. The suggestion was based on the finding of an interstitial Xp deletion with breakpoints at p11.2 and p21 in the phenotypically normal mother of a male infant who died at 36 hrs of cytomegalic adrenal hypoplasia with glyceroluria. The infant had a liver deficiency of ornithine carbamoyltransferase (OTC; 300461) as well as hypoglycemia, hyperammonemia, and gross orotic aciduria. The mother showed excessive orotic acid excretion after an orotic-acid-free protein load. Cytogenetic studies in the baby were technically unsatisfactory. Linkage of primary adrenal hypoplasia and glycerol kinase deficiency is supported by description of coincidence of the 2 disorders (McCabe et al., 1977; Guggenheim et al., 1980; Bartley et al., 1982; McCabe, 1983).

Molecular Genetics

In 4 patients with isolated glycerol kinase deficiency, Walker et al. (1996) identified 3 different mutations in the GK gene (300474.0001-300474.0003). The authors noted widely differing phenotypes and suggested ascertainment bias; metabolic or environmental stress as a precipitating factor in revealing GK-related changes, as had previously been described in juvenile GK deficiency; and interactions with functional polymorphisms in other genes that alter the effect of GK deficiency on normal development.

In affected members of a family of French Canadian descent, Gaudet et al. (2000) identified a mutation in the GK gene (N288D; 307030.0008). Although patients with the N288D mutation suffered from severe hyperglycerolemia, they were apparently otherwise healthy. Phenotypic analysis of the family members, however, showed that glycerol levels correlated with impaired glucose metabolism and body fat distribution. They subsequently noted a substantial variation in glycerolemia in subjects of the initial cohort with normal plasma glycerol levels and demonstrated that this variance showed significant family resemblance. These results suggested a potentially important genetic connection between fasting glycerolemia and glucose homeostasis, not only in this X-linked deficiency but, potentially, in individuals within the 'normal' range of plasma glycerol concentrations.

Because the relationship between glycerol and the risk of impaired glucose tolerance was poorly understood, Gaudet et al. (2000) undertook a study of fasting plasma glycerol levels in a cohort of 1,056 unrelated men and women of French Canadian descent. Family screening in the initial cohort identified 18 men from 5 families with severe hyperglycerolemia (values above 2.0 mmol/l) and demonstrated an X-linked pattern of inheritance. Linkage analysis of the data from 12 microsatellite markers surrounding the Xp21.3 GK gene resulted in a peak lod score of 3.46, centered around marker DXS8039. In addition, since all of the families originated in a population with a proven founder effect (the Saguenay-Lac-Saint-Jean region of Quebec), a common disease haplotype was sought. Indeed, a 6-marker haplotype extending over a region of 5.5 cM was observed in all families.

Animal Model

Using microarray analysis, Rahib et al. (2007) examined global gene expression profiles of GK-null and wildtype mice and detected 668 differentially expressed genes, including genes involved in lipid metabolism, carbohydrate metabolism, insulin signaling, and insulin resistance. The authors suggested that glycerol kinase deficiency may play a role in insulin resistance and type 2 diabetes mellitus (125853).

History

Investigations of glycerol kinase deficiency by Seltzer et al. (1985) suggested that primary adrenal hypoplasia seen in association with glycerol kinase deficiency in cases of Xp deletion is not due to loss of a separate (closely linked) locus but rather is a pleiotropic effect of the glycerol kinase deficiency. In the infantile form of GK deficiency, adrenocortical hypoplasia with insufficiency was a consistent feature (in 12 patients in 6 families). Seltzer et al. (1985) proposed that deficiency of outer mitochondrial membrane-bound GK restricts glycerophospholipid synthesis and hence the activation of steroidogenesis.