Hyperglycerolemia

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Hyperglycerolemia
Specialty Medical genetics

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", which means it affects less than 200,000 people in the US population, or less than about 1 in 1500 people.

Contents

Signs and symptoms

The Human Phenotype Ontology provided the following list of symptoms and signs for hyperglycerolemia: [1] 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. [2] If the glycerol kinase gene is deleted then the NROB1 gene is also often deleted, which causes X-linked adrenal hypoplasia congenita. [3]

Cause

Hyperglycerolemia is caused by excess glycerol in the bloodstream. People with more severe cases of glycerol kinase deficiency may have a deletion of the GK gene that is large enough to see by routine cytogenetic evaluation. [4] 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. [5] There is no known prevention for hyperglycerolemia because it is caused by a mutation or deletion of an individual's genetic code.

Mechanism

Hyperglycerolemia or glycerol kinase deficiency, is caused by a rare X-linked recessive genetic disorder caused by a mutation or a deletion in the glycerol kinase gene, located at the locus Xp21.3 of the X chromosome between base pairs 30,653,358 to 30,731,461. [6] Glycerol kinase catalyzes the phosphorylation of glycerol by ATP, yielding ADP and glycerol-3-phosphate. [7] It is more common in males because they only have one X chromosome, whereas females rarely manifest the disease because they have two X chromosomes. If hyperglycerolemia is caused by a mutation in the glycerol kinase gene then it generally causes an isolated glycerol kinase deficiency, resulting in the inability to synthesize triglycerides and glycerophospholipids. If hyperglycerolemia results from a deletion of the glycerol kinase gene then it often is part of a contiguous gene deletion syndrome with associated Duchenne muscular dystrophy and adrenal hypoplasia congenita. [8]

Diagnosis

Glycerol and glycerol kinase activity analyses are usually not offered by routine general medical laboratories. [9] To diagnose hyperglycerolemia, blood and urine can be tested for the amounts of glycerol present. 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 glyceroluria more than 360 mmol/24h. [9] To confirm the diagnosis, genetic testing of the Xp21 gene is definitive. [9] 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. [9] Patients with the juvenile and adult forms often have no symptoms and are diagnosed fortuitously when a medical professional tests 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. [10]

Treatment

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 concentrations. 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 history of this condition, then it may be difficult to know whether the young child has the symptomatic or benign form of the disorder. [1] 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. [9] The Genetic and Rare Diseases Information Center (GARD) does not list any treatments at this time. [1]

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 concentrations of blood triglycerides have 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] Another group treated patients with elevated concentrations of blood triglycerides with little or no effect on reducing the triglycerides. A few laboratories can test for high concentrations of glycerol, and some laboratories can compare a glycerol-blanked triglycerides assay with the routine non-blanked method. [13] Both cases show how the human body may exhibit features suggestive of a medical disorder when in fact it is another medical condition causing the issue.

See also

Related Research Articles

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<span class="mw-page-title-main">Familial hypertriglyceridemia</span> Medical condition

Familial hypertriglyceridemia is a genetic disorder characterized by the liver overproducing very-low-density lipoproteins (VLDL). As a result, an affected individual will have an excessive number of VLDL and triglycerides on a lipid profile. This genetic disorder usually follows an autosomal dominant inheritance pattern. The disorder presents clinically in patients with mild to moderate elevations in triglyceride levels. Familial hypertriglyceridemia is typically associated with other co-morbid conditions such as hypertension, obesity, and hyperglycemia. Individuals with the disorder are mostly heterozygous in an inactivating mutation of the gene encoding for lipoprotein lipase (LPL). This sole mutation can markedly elevate serum triglyceride levels. However, when combined with other medications or pathologies it can further elevate serum triglyceride levels to pathologic levels. Substantial increases in serum triglyceride levels can lead to certain clinical signs and the development of acute pancreatitis.

Glycerol kinase deficiency (GKD) is an X-linked recessive enzyme defect that is heterozygous in nature. Three clinically distinct forms of this deficiency have been proposed, namely infantile, juvenile, and adult. National Institutes of Health and its Office of Rare Diseases Research branch classifies GKD as a rare disease, known to affect fewer than 200,000 individuals in the United States. The responsible gene lies in a region containing genes in which deletions can cause Duchenne muscular dystrophy and adrenal hypoplasia congenita. Combinations of these three genetic defects including GKD are addressed medically as Complex GKD.

<span class="mw-page-title-main">Jordans' anomaly</span> Persistent vacuolation of white blood cells

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References

  1. 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 Archived 2020-09-16 at the Wayback Machine
  2. ↑ 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.
  3. ↑ 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
  4. ↑ 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.
  5. ↑ Rose, C. I., & Haines, D. S. (1978). Familial hyperglycerolemia. Journal of Clinical Investigation, 61(1), 163.
  6. ↑ Genetics Home Reference (n.d.), GK. Retrieved from http://ghr.nlm.nih.gov/gene/GK
  7. ↑ Glycerol Kinase (n.d.). Retrieved from http://omim.org/entry/300474
  8. ↑ 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.
  9. 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.
  10. ↑ 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
  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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