Congenital generalized lipodystrophy: Difference between revisions
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==Mechanism== |
==Mechanism== |
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===Type 1=== |
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In individuals with Type 1 CGL, the disorder is caused by a mutation at the [[AGPAT2]] gene encoding [[1-acylglycerol-3-phosphate O-acyltransferase|1-acylglycerol-3-phosphate O-acyltransferase 2]] and located at 9q34.3. This enzyme catalyzes the [[acylation]] of [[lysophosphatidic acid]] to form [[phosphatidic acid]], which is important in the [[biosynthesis]] of [[fats]]. This enzyme is highly expressed in [[adipose tissue]], so it can be concluded that when the enzyme is defective in CGL, lipids cannot be stored in the adipose tissue. <ref name=" AGPAT2">{{cite journal | url=http://www.nature.com/ng/journal/v31/n1/pdf/ng880.pdf | title=AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34 | author=Agarwal AK, Arioglu E, de Almeida S, Akkoc N, Taylor SI, Bowcock AM, Barnes RI, Garg A | journal=Nature | year=2002 | month=May | volume=31 | pages=21-23 | doi=10.1038/ng880}}</ref> |
In individuals with Type 1 CGL, the disorder is caused by a mutation at the [[AGPAT2]] gene encoding [[1-acylglycerol-3-phosphate O-acyltransferase|1-acylglycerol-3-phosphate O-acyltransferase 2]] and located at 9q34.3. This enzyme catalyzes the [[acylation]] of [[lysophosphatidic acid]] to form [[phosphatidic acid]], which is important in the [[biosynthesis]] of [[fats]]. This enzyme is highly expressed in [[adipose tissue]], so it can be concluded that when the enzyme is defective in CGL, lipids cannot be stored in the adipose tissue. <ref name=" AGPAT2">{{cite journal | url=http://www.nature.com/ng/journal/v31/n1/pdf/ng880.pdf | title=AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34 | author=Agarwal AK, Arioglu E, de Almeida S, Akkoc N, Taylor SI, Bowcock AM, Barnes RI, Garg A | journal=Nature | year=2002 | month=May | volume=31 | pages=21-23 | doi=10.1038/ng880}}</ref> |
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===Type 2=== |
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In those who have Type 2 CGL, a mutation in the [[BSCL2]] gene encoding the Seipin protein and located at 11q13. This gene encodes a protein, Seipin, whose function is unknown. <!-- If possible research to see if function has been discovered. --> Expression of mRNA for the seipin protein is high in the brain, yet low in [[adipose tissue|adipose tissues]]. Additionally, patients which have mutations in this protein have a higher incidence of [[mental retardation]] and lack mechanically active adipose tissue, which is present in those with [[AGPAT2]] mutations.<ref name="NEJM"></ref> |
In those who have Type 2 CGL, a mutation in the [[BSCL2]] gene encoding the Seipin protein and located at 11q13. This gene encodes a protein, Seipin, whose function is unknown. <!-- If possible research to see if function has been discovered. --> Expression of mRNA for the seipin protein is high in the brain, yet low in [[adipose tissue|adipose tissues]]. Additionally, patients which have mutations in this protein have a higher incidence of [[mental retardation]] and lack mechanically active adipose tissue, which is present in those with [[AGPAT2]] mutations.<ref name="NEJM"></ref> |
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===Type 3=== |
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Type 3 CGL involves a mutation is caused by a mutation in the [[Caveolin 1|CAV1]] gene. This gene codes for the [[Caveolin]] protein, which is a scaffolding membrane protein. This protein plays a role in lipid regulation. High levels of Cav1 are normally expressed in [[adipocytes]]. Thus, when the CAV1 gene mutates the adipocytes do not have Cav1 and are unable to properly regulate lipid levels. <ref name="seven">Parton, R.G. and K. Simons, The multiple faces of caveolae. Nat Rev Mol Cell Biol, 2007. 8(3): p. 185-94.</ref> |
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==Management== |
==Management== |
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===Diet=== |
===Diet=== |
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Revision as of 15:18, 30 October 2012
| Congenital generalized lipodystrophy | |
|---|---|
| Specialty | Endocrinology  |
Congenital generalized lipodystrophy (also known as Berardinelli–Seip syndrome) is a very rare autosomal recessive skin condition, characterized by an extreme scarcity of fat in the subcutaneous tissues.[1] Only 250 cases of the condition have been reported, and it is estimated that it occurs in 1 in 10 million people worldwide. [2]
Presentation
Congenital Generalized Lipodystrophy (CGL) is a rare autosomal recessive disorder associating insulin resistance, absence of subcutaneous fat and muscular hypertrophy.[3] The condition presents itself in early childhood with accelerated linear growth , quick aging of bones, and a large appetite. As the child grows up, acanthosis nigricans will begin to present itself throughout the body - mainly in the neck, trunk, and groin. [2] The disorder also has characteristic features like hepatomegaly which arises from fatty liver and made lead to cirrhosis, muscle hypertrophy, lack of adipose tissue, splenomegaly, hirsutism and hypertriglyceridemia.[4] Common cardiovascular problems related to this syndrome are cardiac hypertrophy and arterial hypertension.[5] This disorder is also associated with metabolic syndrome. Most with the disorder also have a prominent umbilicus or umbilical hernia. Commonly, patients will also have acromegaly with enlargement of the hands, feet, and jaw. After puberty, additional symptoms can develop. In women, clitoromegaly and the polycystic ovary syndrome can develop. This impairs fertility for the women, and only a few documented cases of successful pregnancies in women with CGL exist. However, the fertility of men with the disorder is unaffected. [2]
There are differences in how Type 1 vs Type 2 patients are affected by the disease. In type 1 patients, they still have mechanical adipose tissue, but type 2 patients do not have any adipose tissue, including mechanical.[6] In type 2 patients, there is a greater likelihood of psychomotor retardation and intellectual impairment. [7]
Diagnosis
Medical diagnosis of CGL can be made after observing the physical symptoms of the disease: lipoatrophy affecting the trunk, limbs, and face; hepatomegaly; acromegaly; insulin resistance; and high serum levels of triglycerides. Genetic testing can also confirm the disease, as mutations in the AGPAT2 gene is indicative of CGL1 and in the BSCL2 gene is indicative of CGL2.[7] Physical diagnosis is easier, as CGL patients are recognizable from birth, due to their extreme muscular appearance, which is caused by the absence of subcutaneous fat. [6]
CGL3 patients have serum creatine kinase concentrations much higher than normal (2.5 to 10 times the normal limit). This can be used to diagnose type 3 patients and differentiate them from CGL 1 and 2 without mapping their genes. CGL3 is caused by a mutation in the CAV1 gene. Additionally, CGL3 patients have low muscle tone when compared with other CGL patients.[8]
Mechanism
Type 1
In individuals with Type 1 CGL, the disorder is caused by a mutation at the AGPAT2 gene encoding 1-acylglycerol-3-phosphate O-acyltransferase 2 and located at 9q34.3. This enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, which is important in the biosynthesis of fats. This enzyme is highly expressed in adipose tissue, so it can be concluded that when the enzyme is defective in CGL, lipids cannot be stored in the adipose tissue. [9]
Type 2
In those who have Type 2 CGL, a mutation in the BSCL2 gene encoding the Seipin protein and located at 11q13. This gene encodes a protein, Seipin, whose function is unknown. Expression of mRNA for the seipin protein is high in the brain, yet low in adipose tissues. Additionally, patients which have mutations in this protein have a higher incidence of mental retardation and lack mechanically active adipose tissue, which is present in those with AGPAT2 mutations.[2]
Type 3
Type 3 CGL involves a mutation is caused by a mutation in the CAV1 gene. This gene codes for the Caveolin protein, which is a scaffolding membrane protein. This protein plays a role in lipid regulation. High levels of Cav1 are normally expressed in adipocytes. Thus, when the CAV1 gene mutates the adipocytes do not have Cav1 and are unable to properly regulate lipid levels. [10]
Management
Diet
CGL patients have to maintain a strict diet for life, as their excess appetite will cause them to overeat. Carbohydrate intake should be restricted in these patients. To avoid chylomicronemia, CGL patients with hypertriglyceridemia need to have a diet very low in fat. CGL patients also need to avoid total proteins, trans fats, and eat high amounts of soluble fiber to avoid getting high levels of cholesterol in the blood. [11]
Treatment
Metformin is the main drug used for treatment, as it is normally used for patients with hyperglycemia. [12] Metformin reduces appetite and improves symptoms of hepatic steatosis and polycystic ovary syndrome. [2] Leptin can also be used to reverse insulin resistance and hepatic steatosis, to cause reduced food intake, and decrease blood glucose levels. [13]
Genetics
| OMIM | Type | Gene Locus |
|---|---|---|
| Template:OMIM2 | CGL1 | AGPAT2 at 9q34.3 |
| Template:OMIM2 | CGL2 | BSCL2 at 11q13 |
| Template:OMIM2 | CGL3 | CAV1 at 7q31.1 |
| Template:OMIM2 | CGL4 | PTRF at 17q21 |
See also
External links
References
- ^ James, William D.; Berger, Timothy G.; et al. (2006). Andrews' Diseases of the Skin: clinical Dermatology. Saunders Elsevier. p. 495. ISBN 0-7216-2921-0.
{{cite book}}: Explicit use of et al. in:|author=(help)CS1 maint: multiple names: authors list (link) - ^ a b c d e Garg, A (2004). "Acquired and inherited lipodystrophies". The New England Journal Of Medicine. 350 (12): 1220–1234.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Friguls B, Coroleu W, del Alcazar R, Hilbert P, Van Maldergem L, Pintos-Morell G (2009). "Severe cardiac phenotype of Berardinelli-Seip congenital lipodystrophy in an infant with homozygous E189X BSCL2 mutation". Eur J Med Genet. 52 (1): 14–6. doi:10.1016/j.ejmg.2008.10.006. PMID 19041432. Retrieved 2009-03-04.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Gürakan F, Koçak N, Yüce A (1995). "Congenital generalized lipodystrophy: Berardinelli syndrome. Report of two siblings". Turk. J. Pediatr. 37 (3): 241–6. PMID 7502362.
{{cite journal}}:|access-date=requires|url=(help)CS1 maint: multiple names: authors list (link) - ^ Viégas RF, Diniz RV, Viégas TM, Lira EB, Almeida DR (2000). "Cardiac involvement in total generalized lipodystrophy (Berardinelli- Seip syndrome)". Arq. Bras. Cardiol. 75 (3): 243–8. PMID 11018810.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b Khandpur, Sujay. "Congenital generalized lipodystrophy of Berardinelli-Seip type: A rare case". Indian Journal Of Dermatology, Venereology And Leprology. p. 402. Retrieved October 16, 2012.
- ^ a b Van Maldergem, Lionel (1993). "Berardinelli-Seip Congenital Lipodystrophy". University of Washington, Seattle. Retrieved September 05, 2012.
{{cite web}}: Check date values in:|accessdate=(help) - ^ C. A. Kim, Marc Delépine ,Emilie Boutet ,Haquima El Mourabit; et al. (2008). "Association of a Homozygous Nonsense Caveolin-1 Mutation with Berardinelli-Seip Congenital Lipodystrophy". Journal of Clinical Endocrinology & Metabolism. 93 (4): 1129. doi:10.1210/jc.2007-1328.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Agarwal AK, Arioglu E, de Almeida S, Akkoc N, Taylor SI, Bowcock AM, Barnes RI, Garg A (2002). "AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34" (PDF). Nature. 31: 21–23. doi:10.1038/ng880.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Parton, R.G. and K. Simons, The multiple faces of caveolae. Nat Rev Mol Cell Biol, 2007. 8(3): p. 185-94.
- ^ Gomes K, Pardini VC, Fernandes AP (2009). "Clinical and molecular aspects of Berardinelli–Seip Congenital Lipodystrophy (BSCL)". Clinica Chimica Acta. 402: 1–6. doi:10.1016/j.cca.2008.12.032.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Victoria, I; Saad, M; Purisch, S; Pardini, V (1997). "Metformin improves metabolic control in subjects with congenital generalized lipoatrophic diabetes". Diabetes. 46: 618.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ Petersen K.F., Oral E.A., Dufour S.; et al. (2002). "Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy". Journal of Clinical Investigation. 109: 1345–1350. doi:10.1172/JCI15001.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link)
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