Última actualización:
June 16, 2015
Años publicados: 2012, 2015
NORD gratefully acknowledges Abhimanyu Garg, MD, Professor of Internal Medicine, Chief, Division of Nutrition and Metabolic Diseases, Distinguished Chair in Human Nutrition Research, UT Southwestern Medical Center at Dallas, for assistance in the preparation of this report.
Summary
Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by selective, progressive loss of body fat (adipose tissue) from various areas of the body. Individuals with FPL often have reduced subcutaneous fat in the arms and legs and the head and trunk regions may or may not have loss of fat. Conversely, affected individuals may also have excess subcutaneous fat accumulation in other areas of the body, especially the neck, face and intra-abdominal regions. Subcutaneous fat is the fatty or adipose tissue layer that lies directly beneath the skin. In most cases, adipose tissue loss begins during puberty. FPL can be associated with a variety of metabolic abnormalities. The extent of adipose tissue loss usually determines the severity of the associated metabolic complications. These complications can include an inability to properly breakdown a simple sugar known as glucose (glucose intolerance), elevated levels of triglycerides (fat) in the blood (hypertriglyceridemia), and diabetes. Additional findings can occur in some cases. Six different subtypes of FPL have been identified. Each subtype is caused by a mutation in a different gene. Four forms of FPL are inherited as autosomal dominant traits; one form is inherited as an autosomal recessive trait. The mode of inheritance of FPL, Kobberling variety is unknown.
Introduction
Lipodystrophy is a general term for a group of disorders that are characterized by complete (generalized) or partial loss of adipose tissue. In addition to FPL, there are other inherited forms of lipodystrophy. Some forms of lipodystrophy are acquired at some point during life. The degree of severity and the specific areas of the body affected can vary greatly among the lipodystrophies. Some individuals may only develop cosmetic problems; other can develop life-threatening complications. The loss of adipose tissue that characterizes these disorders is sometimes referred to as lipoatrophy rather than lipodystrophy by some physicians. FPL was first described in the medical literature in 1970s independently by three groups of physicians, including Doctors Ozer, Kobberling and Dunnigan.
FPL encompasses several subtypes differentiated by the underlying genetic mutation. The specific symptoms present, severity, and prognosis can vary greatly depending upon the specific type of FPL and the presence and extent of associated symptoms. The specific symptoms and severity can also vary among individuals with the same subtype and even among members of the same family. In addition, some subtypes of FPL have only been reported in a handful of individuals, which prevents physicians from developing an accurate picture of associated symptoms, severity, and prognosis. Therefore, it is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis.
Common symptoms of FPL include selective, progressive loss of subcutaneous fat in the arms and legs and chest and trunk regions, abnormal accumulation of subcutaneous fat in other areas, and a variety of metabolic complications. Generally, women are more severely affected than men by the metabolic complications of FPL. Additional symptoms including those affecting the liver or heart may also occur.
FPL Type 2, Dunnigan Variety (FPL2)
This is the most common form of FPL. Affected individuals usually have normal fat distribution during early childhood. However, around the time of puberty, fat in the arms and legs and trunk is gradually lost. In women, the loss of fat may be most striking in the buttocks and hips. At this time, fat may accumulate in other areas of the body including the face, causing a double chin, and the neck and upper back between the shoulder blades, causing a hump. Affected individuals may have a round face similar to individuals with Cushing’s syndrome. This characteristic distribution of fat and the overall muscular appearance makes the disorder more easily recognizable in women than men.
Insulin resistance is common and may be associated with a condition called acanthosis nigricans, a skin condition characterized by abnormally increased coloration (hyperpigmentation) and «velvety» thickening (hyperkeratosis) of the skin, particularly of skin fold regions, such as of the neck and groin and under the arms (axillae). An enlarged liver (hepatomegaly) is also common. Hepatomegaly is caused by the accumulation of fat in the liver (fatty liver or steatosis). Progressive accumulation of fat in the liver can cause scarring and damage to the liver (cirrhosis) and, eventually, liver dysfunction.
Other complications of insulin resistance may occur including glucose intolerance, hypertriglyceridemia, and diabetes. These symptoms are often very difficult to control and diabetes is often severe. Affected women are at a greater risk of developing diabetes than affected men and often experience more severe metabolic complications. Some individuals may experience extreme hypertriglyceridemia, resulting in episodes of acute inflammation of the pancreas (pancreatitis). Pancreatitis can be associated with abdominal pain, chills, jaundice, weakness, sweating, vomiting, and weight loss.
After puberty, some women with FPL may develop polycystic ovary syndrome (PCOS), a complex of symptoms that are not always present in every case. PCOS is often characterized by an imbalance of sex hormones as affected women may have too much androgen, a male hormone, in the body. PCOS can result in irregular menstrual periods or a lack of menstruation, oily skin that is prone to acne, cysts on the ovaries, failure of the ovary to release eggs, and mild hirsutism (a male pattern of hair growth). Hair may develop on the upper lip, chin and other parts of the body.
Individuals with FPL, Dunnigan variety are predisposed to coronary artery disease and other types of atherosclerotic vascular disease. In rare cases, in which individuals have a specific mutation of the lamin A/C (LMNA) gene, they are at an increased risk of developing disease of the heart muscles (cardiomyopathy), which can result in congestive heart failure and irregular heartbeats (cardiac arrhythmias) such as heart block or atrial fibrillation. Some individuals also develop muscular dystrophies (diseases of muscles causing loss of strength and joint contractures).
FPL Type 1, Kobberling Variety (FPL1)
This form of FPL has only been reported in a handful of individuals. The symptoms are similar to those seen in FPL2, Dunnigan variety. However, fat loss is generally confined to the arms and legs. Fat loss is usually more prominent on the lower (distal) portions of the arms and legs. Affected individuals have normal or slightly increased fat distribution on the face, neck, and trunk. In addition, some affected individuals may develop excess belly fat (central obesity). Metabolic abnormalities including insulin resistance, high blood pressure (hypertension), and severe hypertriglyceridemia have also been reported. This form of FPL has only been reported in women.
FPL Type 3, due to PPARG Mutations (FPL3)
This form of FPL has only been reported in approximately 30 individuals. It is generally milder than the FPL2, Dunnigan variety. Consequently, it is believed that many cases may go undiagnosed. Fat loss is more prominent in the calves and forearms than in the upper arms and thighs. Diabetes, hypertriglyceridemia, hypertension, fatty liver, pancreatitis, and hirsutism have also been reported. Metabolic abnormalities are more prominent than the lipodystrophy in this form of the disorder.
FPL4, due to PLIN1 Mutations (FPL4)
This form of FPL has only been reported in a handful of individuals. Lipodystrophy is most prominent in the lower limbs and buttocks. Muscular hypertrophy may be prominent in the calves. Insulin resistance, severe hypertriglyceridemia, and diabetes were also reported.
FPL5, due to AKT2 Mutations (FPL5)
This form of FPL has been reported in four members of one family who had hypertension, severe insulin resistance, and diabetes mellitus. Insulin resistance appears around the ages of 20 to 30. Lipodystrophy most prominently affects the arms and legs.
Autosomal Recessive FPL (Type 6 due to CIDEC mutation)
This form of FPL has only been reported in one individual in the medical literature. The reported symptoms include partial lipodystrophy, severe insulin resistance, fatty liver, acanthosis nigricans, and diabetes.
FPL is caused by mutations of specific genes. So far, mutations in five genes that cause FPL have been identified including the LMNA gene, which causes FPL2, Dunnigan variety; the PPARG gene, which causes FPL3; the PLIN1 gene, which causes FPL4; the AKT2 gene, which cases FPL5; and the CIDEC gene, which causes autosomal recessive FPL. The gene that causes FPL1, Kobberling variety has not been identified. Some individuals with FPL do not have mutations in any of these genes, suggesting that additional, as yet unidentified genes can cause the disorder.
Four types of FPL for which the genes have been identified are inherited as autosomal dominant traits. Another type with mutation in the CIDEC gene is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes, one received from the father and one received from the mother. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated «p» and a long arm designated «q». Chromosomes are further sub-divided into many bands that are numbered. For example, «chromosome 1q21-22» refers to bands 21-22 on the long arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that the LMNA gene is located on the long arm (q) of chromosome 1 (1q21-q22). The LMNA gene contains instructions for creating (encoding) the proteins lamin A and lamin C. These proteins are active in the nuclear lamina, a structure found within many types of cells. Mutations of this gene lead to disruption of the normal functions of lamins A and C. Researchers believe that this gene mutation ultimately results in premature cell death of fat cells (adipocytes) in individuals with FPL2, Dunnigan variety.
Mutations of the LMNA gene have also been shown to cause a variety of other disorders (allelic disorders) including a form of mandibuloacral dysplasia, a couple forms of Emery-Dreifuss muscular dystrophy, a form of limb-girdle muscular dystrophy, a form of hereditary spastic paraplegia, a form of Charcot-Marie-Tooth disease, a form of dilated cardiomyopathy, Malouf syndrome, and Hutchinson-Gilford progeria syndrome. Individuals whose symptoms overlap among these disorders have been reported in the medical literature. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
The PPARG gene is located on the short arm of chromosome 3 (3p25) and encodes for a type of protein that acts as a transcription factor known as PPAR gamma. This protein is essential for proper adipocyte cell differentiation. Cell differentiation is the process by which a less specialized or generic cell becomes a more specialized or specific cell type. FPL due to PPARG mutations results from improper adipocyte cell differentiation.
The PLIN1 gene is located on the long arm of chromosome 15 (15q26) and encodes for a protein known as perilipin. Perilipin is the most abundant protein coating the surface of lipid droplets where the fat is stored within the adipose cells. Researchers believe that perilipin is essential for the storage of triglycerides and for the release of fatty acids from lipid droplets. Lipid droplets are organelles, specialized subunits found within cells (such as fat cells) that have specific functions. One function of lipid droplets is the storage of lipids. Perilipin is also believed to be essential for the proper formation and development of lipid droplets.
The AKT2 gene is located on the long arm of chromosome 19 (19q13.2) and encodes for protein kinase B beta. The exact role of this protein in the body is not fully understood, although it is believed that this protein plays a role in post receptor insulin signaling and may be involved in regulating the expression of PPAR gamma (see above). The loss of adipose tissue in individuals with a mutation of the AKT2 gene may be due to reduced adipocyte differentiation due to improper regulation of PPAR gamma or to dysfunctional post receptor signaling.
The CIDEC gene is located on the short arm of chromosome 3 (3p25.3) and encodes for the CIDEC protein. CIDEC is expressed in the lipid droplets and plays a role in storage of fat within these structures. Mutation of the CIDEC gene resulted in low levels of functional CIDEC protein, resulting in lack of ability of lipid droplets to store fat.
Researchers believe that various genes and gene products associated with FPL are involved with the proper creation, function, and/or health of adipocytes. Adipocytes are fat cells. Each adipocyte has a lipid droplet that accounts for approximately 90% of its cell volume. An adipocyte stores fats (triglycerides) within its lipid droplet. Mutations in the abovementioned genes ultimately lead to a loss of adipocytes and an inability to store fat. Consequently, fat is stored in other tissues of the body such as the liver and skeletal muscle causing symptoms such as liver disease and insulin resistance. The cause of other symptoms sometimes associated with FPL such as cardiomyopathy is not fully understood. More research is necessary to understand the exact, underlying mechanisms that ultimately cause FPL and its associated symptoms.
FPL is a rare disorder that has been reported in women more often than in men. This may be due to ascertainment bias because women are more severely affected and more easily recognized. The prevalence of FPL is estimated to be 1 in 1,000,000 people in the general population. However, many cases may go misdiagnosed or undiagnosed, making it difficult to determine the true frequency of the disorder in the general population. The majority of individuals reported in the medical literature have been of European descent. The disorder has also been reported individuals of African and Asian Indian descent.
A diagnosis of FPL is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. A diagnosis of FPL should be suspected in individuals who lose subcutaneous fat around puberty and gain a muscular appearance. Lipodystrophy, in general, should be suspected in individuals who are lean or «non-obese» and who present with early diabetes, severe hypertriglyceridemia, hepatic steatosis, hepatosplenomegaly, acanthosis nigricans and/or polycystic ovarian syndrome.
Clinical Testing and Workup
Although the diagnosis of lipodystrophy is primarily clinical, a variety of tests can be used to aid in the diagnosis and/or rule out other conditions. A blood chemical profile may be conducted to assess the levels of glucose, lipids, liver enzymes, and uric acid.
The characteristic pattern of fat loss in the arms and legs and trunk, but fat gain in muscular fasciae can be noted on magnetic resonance imaging (MRI).
Molecular genetic testing can confirm a diagnosis of FPL in most cases. Molecular genetic testing can detect mutations in specific genes that cause FPL, but is only available on a clinical basis for only few genes such as LMNA.
Individuals with FPL may undergo tests to detect and/or evaluate the presence of potential complications including heart abnormalities. Holter monitoring, echocardiography, and a stress test are conducted for individuals suspected of have cardiomyopathy or coronary heart disease. A Holter monitor is a portable device that continually monitors the heart’s rhythms. An echocardiography uses reflected sound waves to create a picture of the heart. A stress test measures the heart’s ability to respond to external stress in a controlled environment.
Individuals with FPL may be evaluated to determine their leptin levels. Leptin is a hormone found in adipocytes. Some affected individuals have low levels of leptin.
Treatment
The treatment of FPL is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, plastic surgeons, cardiologists, endocrinologists, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
Individuals with FPL and their families are encouraged to seek counseling after a diagnosis because the diagnosis can cause anxiety, stress, and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected individuals and their families. Genetic counseling may be of benefit for affected individuals and their families as well.
Despite the lack of clinical trial evaluation, individuals with FPL are encouraged to follow a high carbohydrate, low-fat diet. Such a diet can improve chylomicronemia associated with acute pancreatitis. Chylomicronemia is a condition characterized by the accumulation of fatty droplets called chylomicrons in the plasma. However, such diets may also raise very low density lipoprotein triglyceride concentration.
Because individuals with FPL have an increased risk of coronary heart disease, they should limit the intake of saturated and trans-unsaturated fats and dietary cholesterol. It is unknown whether such measures will be beneficial over the long term to reduce fatty liver or serum triglycerides levels, or whether they can improve glycemic control.
Regular exercise and maintaining a healthy weight are also encouraged as a way to decrease the chances of developing diabetes. In individuals with FPL, exercise and reducing energy intake can is also necessary to avoid excess fat deposition and accumulation in non-lipodystrophic areas such as the face, neck, and intra-abdominal region.
Individuals with extreme hypertriglyceridemia may be treated with fibric acid derivatives, statins, or n-3 polyunsaturated fatty acids.
The characteristic loss of adipose tissue in individuals with FPL cannot be reversed. Consequently, cosmetic surgery may be beneficial in improving appearance and management metabolic complications. Procedures such as liposuction can be performed to remove excess, unwanted fat in areas where fat accumulates (e.g. chin).
In some cases, liver disease associated with FPL can ultimately require a liver transplantation.
Periodic cardiac examinations may be recommended for individuals with FPL to detect symptoms that can be potentially associated with the disorder including coronary heart disease and/or conduction defects. Affected individuals with heart abnormalities such as heart block or atrial fibrillation may require the use of a pacemaker. In some cases, a heart transplant may ultimately be necessary.
Additional therapies to treat individuals with FPL are symptomatic and supportive and follow regular, standard guidelines. Diabetes is treated with standard therapies. After the onset of diabetes, hyperglycemic drugs such as metformin and sulfonylureas may be recommended to treat hyperglycemia. Insulin can also be used to treat individuals with FPL and diabetes, although extremely high doses are often required. High blood pressure (anti-hypertensives) may also be recommended. Although drug therapy is commonly used, there have been no clinical trials to establish the optimal use of drug therapy to treat the metabolic complications in individuals with FPL.
Although metreleptin (an analog of leptin) has been approved by the the Food and Drug Administration (FDA) for treating metabolic complications in patients with generalized lipodystrophies, it is not approved for patients with FPL. An analog drug has the same or similar physical structure to another drug or chemical, but differs chemically. Further research is needed to evaluate which patients with FPL may benefits from metreleptin therapy. Initial studies have shown that leptin-replacement therapy (metreleptin) has been effective in improving some of the symptoms of FPL, Dunnigan variety in individuals with low leptin levels. Currently, the availability of leptin for FPL patients is restricted to clinical trials or compassionate basis.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at UT Southwestern Medical Center at Dallas, visit the website here.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Contact for additional information about familial partial lipodystrophy:
Abhimanyu Garg, M.D.
Professor of Internal Medicine,
Chief, Division of Nutrition and Metabolic Diseases,
Distinguished Chair in Human Nutrition Research
UT Southwestern Medical Center
5323 Harry Hines Boulevard, K5.214
Dallas, TX 75390-8537
Phone: 214-648-2895
Fax: 214-648-0553
Abhimanyu.garg@utsouthwestern.edu
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
TEXTBOOKS
Garg A. Lipodystrophies and dyslipidemia. In Garg A (ed). Dyslipidemias: Pathophysiology, Evaluation and Management. Springer, New York, NY, pp 287-302, 2015.
Garg A. Genetic lipodystrophies. In Rimoin DL, Connor JM, Pyeritz RE, Korf BR (eds). Emery and Rimoin’s Principles and Practice of Medical Genetics, 6th Edition. Churchill Livingstone, Elsevier 2013.
Simha V, Agarwal A. Inherited and Acquired Lipodystrophies. In: Nutrition and Health: Adipose Tissue and Adipokines in Health and Disease, Fantuzzi G, Mazzone T, editors. 2007 Humana Press, Totowa, NJ. pp. 237-254.
Garg A. Familial Partial Lipodystrophy. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:323.
JOURNAL ARTICLES
Diker-Cohen T1, Cochran E, Gorden P, Brown RJ. Partial and generalized lipodystrophy: comparison of baseline characteristics and response to metreleptin. J Clin Endocrinol Metab. 2015 May;100(5):1802-10. doi: 10.1210/jc.2014-4491. Epub 2015 Mar 3.
Simha V, Subramanyam L, Szczepaniak L, et al. Comparison of efficacy and safety of leptin replacement therapy in moderately and severely hypoleptinemic patients with familial partial lipodystrophy of the Dunnigan variety. J Clin Endocrinol Metab. 2012;97:785-792. https://www.ncbi.nlm.nih.gov/pubmed/22170723
Gandotra S, Le Dour C, Bottomley W, et al. Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med. 2011;364:740-748. https://www.ncbi.nlm.nih.gov/pubmed/21345103
Garg A. Clinical review: lipodystrophies: genetic and acquired body fat disorders. J Clin Endocrinol Metab. 2011;96:3313-3325. https://www.ncbi.nlm.nih.gov/pubmed/21865368
Subramanyam L, Simha V, Garg A. Overlapping syndrome with familial partial lipodystrophy, Dunnigan variety and cardiomyopathy due to Amino-terminal heterozygous missense lamin A/C mutations. Clin Genet. 2010;78:66-73. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150739/
Garg A, Agarwal AK. Lipodystrophies: disorders of adipose tissue biology. Biochim Biophys Acta. 2009;1791:507-513. https://www.ncbi.nlm.nih.gov/pubmed/19162222
Rubio-Cabezas O, Puri V, Murano I, et al. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol Med. 2009;1:280-287. https://www.ncbi.nlm.nih.gov/pubmed/20049731
Hegele RA, Joy TR, Al-Attar SA, Rutt BK. Thematic review series: adipocyte biology. Lipodystrophies: windows on adipose biology and metabolism. J Lipid Res. 2007;48:1433-1444. https://www.ncbi.nlm.nih.gov/pubmed/17374881
Park JY, Javor ED, Cochran EK, DePaoli AM, Gorden P. Long-term efficacy of leptin replacement in patients with Dunnigan-type familial partial lipodystrophy. Metabolism. 2007;56:508-516. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2595136/
Decaudin A, Vantyghem MC, Geuri B, et al. New metabolic phenotypes in laminopathies: LMNA mutations in patients with severe metabolic syndrome. J Clin Endocrinol Metab. 2007;92:4835-4844. https://www.ncbi.nlm.nih.gov/pubmed/17711925
George S, Rochford JJ, Wolfrum C, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004;304:1325-1328. https://www.ncbi.nlm.nih.gov/pubmed/15166380
Agarwal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab. 2002;87:408-411. https://www.ncbi.nlm.nih.gov/pubmed/11788685
Oral EA, Simha V, Ruiz E. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570-578. https://www.ncbi.nlm.nih.gov/pubmed/11856796
INTERNET
Vantyghem MC. Partial Acquired Lipodystrophy. Orphanet Encyclopedia, October, 2006. Available at: https://www.orpha.net Accessed June 16, 2015.
Vantyghem MC. Berardinelli-Seip congenital lipodystrophy. Orphanet Encyclopedia, January, 2009. Available at: https://www.orpha.net Accessed June 16, 2015.
Lipodystrophy. University of Texas Southwest Medical Center. Division of Nutrition and Metabolic Diseases. Available at: https://www.utsouthwestern.edu/education/medical-school/departments/internal-medicine/divisions/nutrition/lipodystrophy/index.html Accessed June 16, 2015.
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