Hyperglycerolemia

Hyperglycerolemia
Classification and external resources
Specialty endocrinology
ICD-10 E74.8
OMIM 307030
DiseasesDB 29827

Hyperglycerolemia, also known as Glycerol kinase deficiency (GKD), is a genetic disorder where the enzyme glycerol kinase is deficient resulting in a build-up of glycerol in the body. Glycerol kinase is responsible for synthesizing triglycerides and glycerophospholipids in the body. Excess amounts of glycerol can be found in the blood and/ or urine. Hyperglycerolmia occurs more frequently in males. Hyperglycerolemia is listed as a “rare disease” by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH), which means it affects less than 200,000 people in the US population (U.S. Department of Health & Human Services).

Mechanism

Hyperglycerolemia or Glycerol kinase deficiency, is caused by a rare X-linked recessive genetic disorder caused by mutations or a deletion in the glycerol kinase gene. The glycerol kinase gene is located on the locus Xp21.3 of the X chromosome between base pairs 30,653,358 to 30,731,461. [1] Glycerol kinase catalyzes the phosphorylation of glycerol by ATP, yielding ADP and glycerol-3-phosphate.[2] It is more common in males because they only have one chromosome where females rarely get the disease because they have two X chromosomes. If Hyperglycerolemia is caused by a mutation in the glycerol kinase gene, it generally causes an isolated enzyme deficiency of the enzyme glycerol kinase. This can result in the human body not being able to synthesize triglycerides and glycerophospholipids. If Hyperglycerolemia results from a deletion of the glycerol kinase gene, it has been shown to be a part of a contiguous gene deletion syndrome with association of Duchenne muscular dystrophy and adrenal hypoplasia congenita.[3]

Signs and symptoms

In general, glycerol and glycerol kinase activity analyses are not included in routine labs. [4] To test for Hyperglycerolemia, blood is tested for the amounts of glycerol present and urine is tested for the amount of glycerol present. High amounts of glycerol in the blood and urine may be symptoms of Hyperglycerolemia. The Human Phenotype Ontology provided the following list of signs and symptoms for Hyperglycerolemia:[5] Abnormality of metabolism/homeostasis, Cognitive Deficit, EMG abnormality, Muscular Hypotonia, Myopathy, Neurological speech impairment, Primary adrenal insufficiency, Short stature, Cryptorchidism, EEG abnormality, Lumbar Hyperlordosis, Reduced bone mineral density, Scoliosis, Seizures, Abnormal facial shape, and Adrenal insufficiency. Adrenal insufficiency is associated with the genetic disease, X-linked adrenal hypoplasia congenita.[6] If the glycerol kinase gene is deleted, it also deletes the NROB1 gene which causes X-linked adrenal hypoplasia congenita.[7]

Diagnosis

There are three clinical forms of GKD: infantile, juvenile, and adult. The infantile form is associated with severe developmental delay and results in a syndrome with Xp21 gene deletion with congenital adrenal hypoplasia and/or Duchenne muscular dystrophy. The infantile diagnosis is made by measuring plasma glycerol and is characterized by glycerol levels between 1.8 and 8.0 mmol/l and gliceroluria 360 mmol/24h.[4] To confirm or determine diagnosis, genetic testing investigating the Xp21 gene is the only definitive way.[4] Children with GKD have severe hypoglycemic episodes and profound metabolic acidosis, or are completely symptom free. Individuals who are unable to form glucose from the glycerol released during triglyceride catabolism also the hypoglycemic episodes often disappear during adolescence.[4] Patients with the juvenile and adult forms often have no symptoms and are diagnosed on accident when a medical professional was testing for another medical condition. The juvenile form is an uncommon form characterized by Reye syndrome-like clinical manifestations including episodic vomiting, acidemia, and disorders of consciousness.[8]

Cause and prevention

Hyperglycerolemia is caused by excess glycerol in the bloodstream. People with more severe cases of glycerol kinase deficiency will have a deletion of the GK gene that may be large enough to be seen by routine cytogenetic evaluation.[9] It has been found an x-linked recessive inheritance pattern of the trait when a study was conducted on a grandfather and grandson. In addition, there is a high prevalence of diabetes mellitus in this family.[10] There is no known prevention for Hyperglycerolemia because it is caused by mutations or a deletion of an individuals genetic code.

Treatment and prognosis

In adults, Fibrates and Statins have been prescribed to treat Hyperglycerolemia by lowering blood glycerol levels. Fibrates are a class of drugs that are known as amphipathic carboxylic acids that are often used in combination with Statins. Fibrates work by lowering blood triglyceride levels. When combined with Statins, the combination will lower LDL cholesterol, lower blood triglycerides and increase HDL cholesterol levels.[11] If hyperglycerolemia is found in a young child without any family medical history of it, it may be difficult to know whether the young child has the symptomatic or benign form of the disorder.[5] Common treatments include: a low-fat diet, IV glucose if necessary, monitor for insulin resistance and diabetes, evaluate for Duchenne muscular dystrophy, adrenal insufficiency & developmental delay.[4] The Genetic and Rare Diseases Information Center (GARD) does not list any treatments at this time.[5]

Current research

According to Clinicaltrials.gov, there are no current studies on hyperglycerolemia. Clinicaltrials.gov is a service of the U.S. National Institutes of Health. Recent research shows patients with high levels of blood triglycerides are being diagnosed with an increased risk of coronary heart disease. Normally, a blood glycerol test is not ordered. The research was about a child having elevated levels of triglycerides when in fact the child had glycerol kinase deficiency. This condition is known as pseudo-hypertriglyceridemia, a falsely elevated condition of triglycerides.[12] A second recent case of similar research involved treating patients with elevated levels of blood triglycerides with little or no effect on lowering the levels. The laboratory technician must then redirect and test for high levels of glycerol in the blood resulting from Hyperglycerolemia and make the appropriate reporting to the physician.[13] Both cases show how the human body may exhibit symptoms for one type of medical condition when in fact it is another medical condition causing the issue.

See also

References

  1. ↑ Genetics Home Reference (n.d.), GK. Retrieved from http://ghr.nlm.nih.gov/gene/GK
  2. ↑ Glycerol Kinase (n.d.). Retrieved from http://omim.org/entry/300474
  3. ↑ Huq, A. M., Lovell, R. S., Ou, C. N., Beaudet, A. L., & Craigen, W. J. (1997). X-linked glycerol kinase deficiency in the mouse leads to growth retardation, altered fat metabolism, autonomous glucocorticoid secretion and neonatal death. Human molecular genetics, 6(11), 1803-1809.
  4. 1 2 3 4 5 Arrobas-Velilla, T., Mondéjar-García, R., Gómez-Gerique, J. A., Díaz, I. C., Mengibar, M. C., de Diego, A. O., & Fabiani-Romero, F. (2013). Pseudo-hypertriglyceridaemia or hyperglycerolemia?. Clínica e Investigación en Arteriosclerosis, 25(3), 123-126.
  5. 1 2 3 U.S. Department of Health & Human Services (n.d.), Genetic and Rare Diseases Information Center. Retrieved from https://rarediseases.info.nih.gov/gard/2807/disease/resources/1
  6. ↑ Domenice S, Latronico AC, Brito VN, Arnhold IJ, Kok F, Mendonca BB (September 2001). "Adrenocorticotropin-dependent precocious puberty of testicular origin in a boy with X-linked adrenal hypoplasia congenita due to a novel mutation in the DAX1 gene". J. Clin. Endocrinol. Metab. 86 (9): 4068–71. doi:10.1210/jc.86.9.4068. PMID 11549627.
  7. ↑ Tabarin A, Achermann JC, Recan D, Bex V, Bertagna X, Christin-Maitre S, Ito M, Jameson JL, Bouchard P (February 2000). "A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism". J. Clin. Invest. 105 (3): 321–8. doi:10.1172/JCI7212. PMC 377437. PMID 10675358
  8. ↑ Orphanet (n.d.),The Portal for Rare Diseases and Orphan Drugs. Retrieved from http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=284411
  9. ↑ Blau, N., Duran, M., Blaskovics, K.M., & Gibson, K.M. (2012). Physician's guide to the laboratory diagnosis of metabolic diseases. New York, NY: Springer.
  10. ↑ Rose, C. I., & Haines, D. S. (1978). Familial hyperglycerolemia. Journal of Clinical Investigation, 61(1), 163.
  11. ↑ Medicinenet.com (n.d.), Retrieved from http://www.medicinenet.com/fibrates/article.htm,
  12. ↑ Fabiani, R. F., Bermúdez, D. L. V. J., González, M. C., Gentil, G. J., Oribe, A., & Cruz, C. (2009, July). [Hyperglycerolemia, a pseudo-hypertriglyceridemia: a case report]. In Anales de pediatria (Barcelona, Spain: 2003) (Vol. 71, No. 1, pp. 68-71)
  13. ↑ Backes, J. M., Dayspring, T., Mieras, T., & Moriarty, P. M. (2012). Pseudohypertriglyceridemia: Two cases of probable glycerol kinase deficiency. Journal of clinical lipidology, 6(5), 469-473.
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