Glycerol kinase deficiency (GKD), a rare X-linked recessive disorder, is classified into two types: isolated and complex. Complex GKD is an Xp21 contiguous gene deletion involving the glycerol kinase locus together with the adrenal hypoplasia congenita (AHC) or Duchenne muscular dystrophy (DMD) loci or both. Its clinical features depend on the involved loci. GKD can be confirmed by an elevated urinary glycerol concentration tested by gas chromatography mass spectrometry (GC/MS). The three cases reported here were all male, presenting symptoms from neonatal period. The predominant clinical profile was characterized by hypoadrenocorticism, glyceroluria and Duchenne muscular dystrophy. After receiving a low fat diet and glucocorticoid replacement, they improved with relieved symptoms of hypoadrenocorticism. But they had significant developmental delays and myasthenia. In the follow-up two of them died of adrenal crisis.
Adrenal Insufficiency ; diagnosis ; Diagnosis, Differential ; Genetic Diseases, X-Linked ; diagnosis ; therapy ; Glycerol ; urine ; Glycerol Kinase ; deficiency ; Humans ; Infant ; Male

Agenesis of Corpus Callosum ; Chromosomes, Human, X ; Gene Deletion ; Glycerol Kinase ; genetics ; Humans ; Infant ; Male ; Syndrome

On chromosome Xp21 region, several genes such as glycerol kinase (GK) gene, adrenal hypoplasia congenita gene and Duchenne muscular dystrophy gene are located contiguously. Xp21 contiguous gene deletion syndrome involves the glycerol kinase gene deletion together with the adrenal hypoplasia congenita and/or Duchenne muscular dystrophy gene. The clinical features of a patient with a Xp21 contiguous gene deletion syndrome are sum of each disease,psychomotor retardation and lethargy for glycerol kinase deficiency, hyperpigmentation and salt wasting dehydration for congenital adrenal hypoplasia and muscular weakness and hypotonia for Duchenne muscular dystrophy. We experienced and reviewed two cases of Xp21 contiguous gene deletion syndrome with literatures.
Dehydration ; Gene Deletion* ; Glycerol Kinase ; Humans ; Hyperpigmentation ; Lethargy ; Muscle Hypotonia ; Muscle Weakness ; Muscular Dystrophy, Duchenne

On Xp21 region several genes such as adrenal hypoplasia congenita(AHC) gene, glycerol kinase (GK) gene and Duchenne muscular dystrophy(DMD) gene are located contiguously. If there is a long deletion in that region, various combination of genetic defect can be occurred from one kind of genetic defect to all three kinds of genetic defect simultaneously. In case of more than two genetic defects simultaneously, we call it contiguous gene deletion syndrome. The major clinical manifestations of the Xp21 contiguous gene deletion syndrome are sum of each diseases, electrolyte imbalance and hyperpigmentation for adrenal hypoplasia congenita, psychomotor retardation, letharginess and convulsion for glycerol kinase deficiency and muscle weakness and hypotonia for Duchenne muscular dystrophy. Goals of the treatment are control of each disorders, glucocorticoid and mineralocorticoid for adrenal hypoplasia congenita, low fat diet and prevention of fasting and hypercatabolic status for glycerol kinase deficiency and physiotherapy for Duchenne muscular dystrophy. In case of hyponatremia and hyperkalemia combined with hyperpigmentation, adrenal hypoplasia congenita could be suspected. In glycerol kinase deficiency, markedly elevated glycerol excretion can be detected on urine organic acid analysis by gaschromatography with mass spectrometry. On Duchenne muscular dystrophy, creatinine kinase is markedly elevated on chemistry. We report here first Korean case of Xp21 contiguous gene deletion syndrome of adrenal hypoplasia congenita, glycerol kinase deficiency and Duchenne muscular dystrophy.
Chemistry ; Creatinine ; Diet ; Fasting ; Gene Deletion* ; Glycerol ; Glycerol Kinase ; Hyperkalemia ; Hyperpigmentation ; Hyponatremia ; Mass Spectrometry ; Muscle Hypotonia ; Muscle Weakness ; Muscular Dystrophy, Duchenne* ; Phosphotransferases ; Seizures

In order to establish an efficient and low-cost production procedure of recombinant glycerol kinase (r-GK), we expressed the r-GK gene at high level in E. coli by induction with lactose on a large-scale fermentation of 300L. The results showed that the biomass concentration reached OD600 of 42 and the expression of r-GK in E. coli accounted for about 30% of total soluble protein. The cell-free extract was processed by selective thermo-denaturation and then purified with Ni sepharose FF column chromatography. Finally, highly purified r-GK was obtained and its purity reached 97% by using analysis on sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), polyacrylamide gel electrophoresis (PAGE) and gradient polyacrylamide gel electrophoresis (Gradient PAGE). Further identification study showed that the molecular weight of r-GK was 120kDa with two subunit of 58kDa. Contaminants of NADH oxidase and catalase were not detected in the sample pool of r-GK. The purified r-GK was able to retain about 85% of its initial activity at 4 degrees C for 30 days. After lyophilized, it can retain 93% of its initial activity at 4 degrees C for one year.
Escherichia coli ; genetics ; metabolism ; Fermentation ; Glycerol Kinase ; biosynthesis ; genetics ; isolation & purification ; Recombinant Proteins ; biosynthesis ; genetics ; isolation & purification

Adrenal Insufficiency ; genetics ; Child, Preschool ; Chromosome Deletion ; Chromosomes, Human, X ; genetics ; Gene Deletion ; Glycerol Kinase ; deficiency ; genetics ; Humans ; Male ; Muscular Dystrophy, Duchenne ; genetics ; Sex Chromosome Aberrations

OBJECTIVETo construct a lentiviral vector for RNA interference (RNAi) of human glycerol kinase (GK) gene to stably down-regulate GK expression in human hepatocytes.

METHODSThe sequence of siRNA for GK interference were cloned into the pSicoR vector. Following packaging in 293T cells, the lentivirus was titrated using fluorescence activated cell sorting. Human hepatocyte L02 cells was infected with the lentivirus and the expression of GK was analyzed using Western blotting.

RESULTSThe lentiviral particle pSicoR-GK was successfully packaged with a virus titer reaching 3×10(7) pfu/ml. The expression level of GK protein was down-regulated to 20% of the control level in L02 cells infected with the lentivirus.

CONCLUSIONThe lentiviral vector for RNAi of human GK gene has been successfully constructed, which can significantly down-regulate GK expression in human hepatocytes.

Cell Line ; Gene Expression Regulation ; Genetic Vectors ; Glycerol Kinase ; genetics ; Hepatocytes ; enzymology ; Humans ; Lentivirus ; genetics ; Plasmids ; RNA Interference ; RNA, Small Interfering ; genetics ; Transfection

X-linked adrenal hypoplasia congenita is caused by the mutation of DAX-1 gene (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), and can occur as part of a contiguous gene deletion syndrome in association with glycerol kinase (GK) deficiency, Duchenne muscular dystrophy and X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) gene deficiency. It is usually associated with hypogonadotropic hypogonadism, although in rare cases, it has been reported to occur in normal puberty or even central precocious puberty. This study addresses a case in which central precocious puberty developed in a boy with X-linked adrenal hypoplasia congenita who had complete deletion of the genes DAX-1, GK and IL1RAPL1 (Xp21 contiguous gene deletion syndrome). Initially he was admitted for the management of adrenal crisis at the age of 2 months, and managed with hydrocortisone and florinef. At 45 months of age, his each testicular volumes of 4 mL and a penile length of 5 cm were noted, with pubic hair of Tanner stage 2. His bone age was advanced and a gonadotropin-releasing hormone (GnRH) stimulation test showed a luteinizing hormone peak of 8.26 IU/L, confirming central precocious puberty. He was then treated with a GnRH agonist, as well as steroid replacement therapy. In Korea, this is the first case of central precocious puberty developed in a male patient with X-linked adrenal hypoplasia congenita.
Adrenal Hyperplasia, Congenital ; Adrenal Insufficiency ; DAX-1 Orphan Nuclear Receptor ; Fludrocortisone ; Gene Deletion ; Genetic Diseases, X-Linked ; Glycerol Kinase ; Gonadotropin-Releasing Hormone ; Hair ; Humans ; Hydrocortisone ; Hypogonadism ; Interleukin-1 ; Korea ; Luteinizing Hormone ; Male ; Muscular Dystrophy, Duchenne ; Puberty ; Puberty, Precocious

X-linked adrenal hypoplasia congenita is caused by the mutation of DAX-1 gene (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1), and can occur as part of a contiguous gene deletion syndrome in association with glycerol kinase (GK) deficiency, Duchenne muscular dystrophy and X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1) gene deficiency. It is usually associated with hypogonadotropic hypogonadism, although in rare cases, it has been reported to occur in normal puberty or even central precocious puberty. This study addresses a case in which central precocious puberty developed in a boy with X-linked adrenal hypoplasia congenita who had complete deletion of the genes DAX-1, GK and IL1RAPL1 (Xp21 contiguous gene deletion syndrome). Initially he was admitted for the management of adrenal crisis at the age of 2 months, and managed with hydrocortisone and florinef. At 45 months of age, his each testicular volumes of 4 mL and a penile length of 5 cm were noted, with pubic hair of Tanner stage 2. His bone age was advanced and a gonadotropin-releasing hormone (GnRH) stimulation test showed a luteinizing hormone peak of 8.26 IU/L, confirming central precocious puberty. He was then treated with a GnRH agonist, as well as steroid replacement therapy. In Korea, this is the first case of central precocious puberty developed in a male patient with X-linked adrenal hypoplasia congenita.
Adrenal Hyperplasia, Congenital ; Adrenal Insufficiency ; DAX-1 Orphan Nuclear Receptor ; Fludrocortisone ; Gene Deletion ; Genetic Diseases, X-Linked ; Glycerol Kinase ; Gonadotropin-Releasing Hormone ; Hair ; Humans ; Hydrocortisone ; Hypogonadism ; Interleukin-1 ; Korea ; Luteinizing Hormone ; Male ; Muscular Dystrophy, Duchenne ; Puberty ; Puberty, Precocious

Patients with type 2 diabetes mellitus are associated with insulin resistance and/or impaired insulin secretion. Previous observations indicate that patients with type 2 diabetes tend to have an impaired insulin response after a glycemic load. Recently it has been reported that hyperglycemia after a glucose load is itself a risk factor for the development of cardiovascular complications in the absence of elevated fasting plasma glucose. There are several points to be addressed for the application of new pathogenesis to diabetes treatment. One of them is the association between postprandial hyperglycemia and mortality from cardiovascular diseases. For the management of postprandial hyperglycemia inhibitors ofglucosidase and rapidacting insulin secretagogues have beneficial effects. Alphaglucosidase inhibitors in combination with diet therapy ameliorate insulin resistance and reduce the blood sugar level. A rapidly acting insulin secretagogue, such as repaglinide, lowers postprandial glucose levels without asignificant gain of body weight. These drugs may protect pancreaticcells from postprandial glucose toxicity and prevent the progression of diabetes. Both metformin and thiazolidinedione derivative (TZDs) improve insulin resistance, the major pathogenetic background of type 2 diabetes, and decrease blood glucose levels without stimulating, insulin secretion. Metformin inhibits glucose output from the liver, while TZDs increase glucose utilization in the peripheral tissues. In addition, it has been indicated that these agents ameliorate the metabolic syndrome beyond lowering the glucose level. Molecular targets for these agents have recentl been revealed ; AMPactivated protein kinase for metfOrnin and adiponectin, while PPAR for TZDs that induce gene expression of adipocyte glycerol kinase and adiponectin. Insulin-sensitizing agents are clinically useful for obese diabetic patients with insulin resistance. However, periodical examinations are necessary to avoid serious adverse effects such as lactic acidosis, although rare, by metformin and liver injury by TZDs. The advantage of insulin therapy for type 2 diabetic patients is still controversial. However, in many intervention studies, the intensive insulin therapy provided promising effects on preventing cardiovascular diseases. Moreover, insulin has been shown to stimulate nitric oxide production by cultured endothelial cells and to suppress the expression of intercellular adhesion molecule1 at least in vitro. In view of this antiinflammatory effect, longterm insulin therapy may potentially have an antiatherogenic effect.
Acidosis, Lactic ; Adipocytes ; Adiponectin ; Blood Glucose ; Body Weight ; Cardiovascular Diseases ; Clinical Trial ; Diabetes Mellitus ; Diabetes Mellitus, Type 2 ; Diet Therapy ; Endothelial Cells ; Fasting ; Gene Expression ; Glucose ; Glycerol Kinase ; Humans ; Hyperglycemia ; Insulin ; Insulin Resistance ; Intervention Studies ; Liver ; Metformin ; Mortality ; Nitric Oxide ; Peroxisome Proliferator-Activated Receptors ; Protein Kinases ; Risk Factors