ABSTRACT

Lipodystrophy syndromes are a heterogeneous group of diseases, characterized by selective absence of adipose tissue. In one sense, these diseases are lipid-partitioning disorders, where the primary defect is the loss of functional adipocytes, leading to ectopic steatosis, severe dyslipidemia and insulin resistance. These syndromes have attracted significant attention since the mid-1990s as the understanding of adipose tissue biology grew, initially spurred by the discovery of the pathways leading to adipocyte differentiation and maturation, and then by the discovery of leptin. Although lipodystrophy syndromes are known since the beginning of the 20th century, significant progress in understanding these syndromes were made in the last two decades, placing these syndromes at the forefront of the translational metabolism field. Currently, more than 15 distinctive molecular etiologies have been attributed to cause human diseases most of which map to adipocyte differentiation or lipid droplet pathways. Seemingly acquired syndromes are recently reported to have a genetic basis, suggesting that our “pre-genome” understanding of the syndromes was inadequate and that we need to likely change our classification schemes. Regardless of the etiology, it is the selective absence of adipose tissue and the reduced ability to store long-term energy that perturbs insulin sensitivity and lipid metabolism. The treatment of these syndromes has also attracted considerable interest. The most successful example of the treatment of these syndromes came from the demonstration that leptin replacement strategy improved insulin resistance and dyslipidemia in the most severely affected forms of the disease, leading to an FDA approved therapy for generalized lipodystrophy syndromes. In the partial forms of the disease, the phenotypes are more complex and the efficacy of leptin is not as uniform. Currently, numerous trials are in progress for the development of potential new treatments for the partial forms of the disease. These rare metabolic diseases are likely to fuel novel breakthroughs in the metabolism field in the foreseeable future. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Lipodystrophy syndromes comprise a heterogeneous group of disorders characterized by either generalized or partial lack of adipose tissue depending on the type of lipodystrophy ^1,2. Lipodystrophy classically has been classified as congenital or acquired. Patients with partial lipodystrophy may exhibit excess adipose tissue accumulation in other areas of the body. Lipodystrophy syndromes usually manifest with several metabolic abnormalities associated with severe insulin resistance that include diabetes mellitus, hypertriglyceridemia, and hepatic steatosis which can progress to steatohepatitis. Other common manifestations are acanthosis nigricans, polycystic ovarian syndrome (PCOS), and eruptive xanthomas (due to severe hypertriglyceridemia) ^3,4. Metabolic derangements are mostly responsible for the serious comorbidities associated with lipodystrophy; some of which are chronic complications of poorly controlled diabetes, acute pancreatitis, hepatic cirrhosis, proteinuria and renal failure, and premature cardiovascular disease (Fig.1) ^1,2. Typically, standard treatments fail to achieve good glycemic control in most patients with lipodystrophy, although episodes of diabetic ketoacidosis have been rarely reported⁵. The severity of the comorbidities depends on the subtype, extent of fat loss, and other clinical characteristics such as gender and age. Major causes of mortality are cardiovascular diseases ^6-9, liver diseases^2,10, acute pancreatitis ², renal failure ¹⁰, and sepsis ³. Clinical characteristics of lipodystrophy are shown in Table 1. It is important to note that there are additional components of the disease that may be specific to each molecular etiology. In addition, we are beginning to recognize that patients often report reduced quality of life with increased overall pain (requiring frequent use of pain medications), sleep disturbances and sleep apnea, gastrointestinal dysmotility, mood disturbances such as depression and anxiety and psychiatric diseases ^11,12.

Figure 1Consequences of Lipodystrophy: The figure summarizes metabolic derangements and end-organ complications in patients with lipodystrophy (Left: MRI showing near total lack of adipose tissue; Right top: Liver biopsy shows hepatic steatosis in lipodystrophy (Hematoxylin and eosin staining; magnification 100X), Right bottom: CT of abdomen obtained during an episode of acute pancreatitis in lipodystrophy; Middle top: Diabetic foot ulcer in a patient with generalized lipodystrophy; Middle bottom: Renal biopsy specimens (Left: Electron microscopy image reveals lipid vacuoles which suggest ectopic lipid accumulation; Right: Light microscopy image documents chronic kidney disease in lipodystrophy (Hematoxylin and eosin staining; magnification 40X).

Lipodystrophy is an exciting rare disease that helps us obtain a better understanding of the pathophysiology of metabolic abnormalities associated with insulin resistance. The main cause of insulin resistance in lipodystrophy is the fact that the excess energy cannot be stored in adipose tissue, which is secondary to either the near total lack of adipocyte expandability in patients with generalized lipodystrophy or a limited capacity to expand in partial lipodystrophy. Limited lipid storage capacity causes the failure of buffering postprandial lipids and secreting substantial adipokines, which in turn results in excessive levels of triglycerides and lipid intermediates in circulation. The body stores fat at ectopic sites such as the liver as a result of inability to store energy in the subcutaneous adipose depots (Fig.1). Levels of adipokines and hormones secreted from the adipose tissue, most characteristically leptin, are decreased in these patients ^1,2,9,13,14. Leptin has a fundamental role in glucose and lipid homeostasis. Leptin is the key hormone responsible for regulating appetite ¹⁵. Low levels of leptin in lipodystrophy trigger hyperphagia, which is often extreme ^16-18. Leptin protects pancreatic beta cells from lipotoxicity at least in rodent models. Leptin improves insulin sensitivity by increasing glucose uptake in peripheral tissues such as muscle via sympathetic nervous system activation. Leptin also decreases hepatic gluconeogenesis ^19-21.

ANIMAL MODELS OF LIPODYSTROPHY

Several animal models of lipodystrophy have shown that adipose tissue dysfunction triggers the development of severe insulin resistance, which is associated with metabolic abnormalities and end-organ complications as mentioned above and also shown in Fig.1. An extensive and authoritative review of these studies can be found in an article by Dr. David B. Savage ²². The introduction of these animal models has allowed researchers to explore the fundamental characteristics of lipodystrophy and insulin resistance and allowed studies of the effects of different treatment approaches. Regardless of the strategy used, ablation of white adipose tissue led to the development of insulin resistance, hypertriglyceridemia, and hepatic steatosis (sometimes 6-fold elevation in total liver weight). In now classical experiments of Reitman and colleagues, fat transplantation from littermates rescued metabolic derangements in the famous A-ZIP mice ^23-25. Dr. Beutler’s group recently identified kelch repeat and BTB (POZ) domain containing 2 (KBTBD2) deficiency as a cause of lipodystrophy associated with insulin resistance and diabetes and they also showed that transplantation of wild-type adipose tissue rescued diabetes and the hepatic steatosis phenotypes of Kbtbd2^−/−mice ²⁶. The infusion of leptin into aP2–SREBP-1c transgenic mice from the Brown and Goldstein laboratory resulted in dramatic benefits in glycemic parameters, insulin action, and hepatic steatosis, which could not be explained by its effect on food intake alone, providing the premise to undertake leptin replacement in human patients ²⁷. What was also striking was that if fat from the leptin deficient obese mice was transplanted into littermates of the A-ZIP mice, the metabolic rescue was far less effective, suggesting that leptin played an important role in the regulation of metabolism in lipodystrophy in rodents ²⁸. The replacement of deficient leptin in a small but severely affected cohort of human patients with lipodystrophy with recombinant human leptin (metreleptin) was first reported in 2002 and attracted further attention to lipodystrophy research ²⁹. Longer-term studies subsequently confirmed the role of metreleptin therapy in lipodystrophy syndromes especially in the most severe forms ^30-32.

DIAGNOSIS

The diagnosis of lipodystrophy is usually made clinically based on history, body distribution of adipose tissue, physical examination, and metabolic profile. Lipodystrophy should be suspected in any person with partial or complete lack of subcutaneous adipose tissue. However, the diagnosis of lipodystrophy is often delayed because of the rarity of these syndromes and the failure of the physicians to recognize this disease. Although patients with congenital generalized lipodystrophy lack subcutaneous adipose tissue from birth, specific diagnosis is usually made during childhood or even adulthood when they start developing metabolic abnormalities. This is at least partly because of the fact that the awareness of lipodystrophy is still low among physicians. The problem of recognition is much more common for partial lipodystrophy. The distribution of fat loss varies in different types of partial lipodystrophy. At first glance, certain types of partial lipodystrophy cannot be clearly distinguished from other common metabolic diseases (e.g. poorly controlled diabetes mellitus with truncal obesity) based on phenotype unless the physicians is suspicious for lipodystrophy and checks carefully for certain characteristic such as the appearance of the limbs which look thinner than in a normal person. Also, the onset of fat loss may be gradual and delay the diagnosis both in genetic and acquired forms ^3,4. Lipodystrophy syndromes should be considered in the differential diagnosis in patients with relatively early onset insulin resistant diabetes mellitus, persistent hypertriglyceridemia, hepatic steatosis, PCOS and hepatosplenomegaly. Other diseases that should be considered in the differential diagnosis of lipodystrophy are listed in Table 2.

A thorough physical examination is required for clinical diagnosis of lipodystrophy. Clinicians should pay specific attention to evaluating the extremities and the gluteal region for leanness and muscularity. In addition, other body parts should be examined for accumulation of excessive amounts of fat. Due to marked abdominal obesity and excessive fat accumulation in the neck, patients with familial partial lipodystrophy (FPLD) may be misdiagnosed as Cushing’s syndrome ². In the genetic forms of lipodystrophy, parental consanguinity and the mode of inheritance should be questioned ².

The absence of subcutaneous fat can be quantified by using conventional anthropometric measurements, dual energy x-ray absorptiometry (DXA) scan, whole-body magnetic resonance imaging (MRI), and computed tomography (CT) scan ⁴. Anthropometry including skinfold thickness and limb circumference measurements are easy and affordable ways to estimate the fat loss and redistribution ⁹. For the facial fat loss, serial photography may be used to evaluate the gradual loss of facial fat. DXA, MRI, and CT scans are non-invasive modalities that may be used for quantification of fat on a tissue-specific basis, but at least in the United States, none are covered for this purpose by insurance companies ^3,4,33.

Laboratory testing is a valuable tool for physicians to support the diagnosis. If the physical phenotype is not recognized, hyperglycemia, insulin resistance and severe hypertriglyceridemia that is non-responsive to therapy may provide important clues for the diagnosis. When fat loss is not confirmed by the physical examination or by an imaging modality, hyperglycemia and hypertriglyceridemia that are resistant or unresponsive to conventional treatment may serve as surrogate indicators to the clinician that a patient may have lipodystrophy. Lipodystrophy should be suspected in patients requiring ≥200 units/day (≥2 units/kg/day) of insulin or triglyceride levels that remain persistently elevated (≥500 mg/dL) despite fully optimized therapy and diet modifications. All patients except those with localized lipodystrophy, should be tested for blood glucose levels, glycated hemoglobin (HbA1c), serum lipids (especially triglyceride levels), and liver function tests on the initial evaluation and during subsequent encounters. In addition to these laboratory evaluations, leptin levels may be used in support of the diagnosis. However, it should be noted that low leptin levels may be observed in other conditions such as hypothalamic amenorrhea and malnutrition. Thus, low leptin level is not specific for the diagnosis lipodystrophy ^4,30. Circulating adiponectin though not a clinically available test, may be helpful in differentiating patients with generalized lipodystrophy from those who have constitutional leanness, fat loss due to calorie imbalance or excessive exercise as well as poorly controlled diabetes mellitus with insulin deficiency. In all of the cases except lipodystrophy, adiponectin levels will be normal or even higher than normal whereas in lipodystrophy including familial partial lipodystrophy, serum adiponectin levels are usually low.

Genetic testing is available for several genes in certain clinical and research laboratories. Because additional loci for genetic lipodystrophy syndromes are presumed to be present, negative genetic tests do not rule out a genetic condition.

Lipodystrophy syndromes can be classified as genetic or acquired. However, they are simply classified as generalized and partial in the clinical practice most of the time (Table 3).

It is important to note that this classical method of disease classification will likely become inadequate as more disease-causing genes and pathways are identified.

GENERALIZED LIPODYSTROPHY SYNDROMES

Generalized lipodystrophy syndromes are rare disorders that are either inherited (Berardinelli-Seip Syndrome) ^31,32,34or acquired (Lawrence Syndrome) ⁹.

Congenital Generalized Lipodystrophy

Congenital Generalized Lipodystrophy (CGL) or Berardinelli-Seip syndrome is a rare syndrome which manifests with near total absence of adipose tissue. It is inherited in an autosomal recessive manner. Fat loss is usually recognized shortly after birth or in the first years of life, although patients may be diagnosed later during teenage years or adulthood. There have been over 300 reported cases to date ^13,35,36.

In addition to lack of subcutaneous fat, patients may present with hepatomegaly and umbilical protuberance during infancy. Extensive acanthosis nigricans and prominent musculature may also contribute to the striking phenotype of these patients ³⁷. Affected females may have irregular menstrual cycles, oligomenorrhea, cliteromegaly, and hirsutism. Premature menarche and pubarche are also rarely seen. Most males were reported to be fertile whereas only a few females had successful pregnancies ³⁸. Sperm abnormalities have been reported in CGL similar to BSCL2 knock-out mice that also exhibit male sterility ³⁹. Other clinical manifestations include advanced bone age, mild mental retardation, cardiomyopathy and cardiac rhythm disturbances ⁴⁰.

Children with CGL usually have a voracious appetite and accelerated growth. Basal metabolic rate may be increased. Hypertriglyceridemia usually presents with high levels of chylomicrons and very low-density lipoproteins (VLDL) and reduced levels of high density lipoproteins (HDL). Severe hypertriglyceridemia usually results in recurrent acute pancreatitis. Insulin resistance commonly results in diabetes in adolescence or later. Diabetes is rarely responsive to insulin therapy. Serum leptin levels are very low ³⁰.

The genetic defect can be determined in vast majority of patients with CGL. There are at least four molecularly distinct types of CGL. Of note, several patients with CGL have been reported who do not possess any pathogenic variant in any of the following four genes.

CONGENITAL GENERALIZED LIPODYSTROPHY TYPE 1 (CGL1)

1-acylglycerol-3-phophate O-acyltransferase 2 (AGPAT2), a key enzyme in triglyceride synthesis, is deficient in CGL1. AGPAT2gene is located on chromosome 9q34. AGPAT2 catalyzes the acylation of lysophosphaditic acid to form phosphaditic acid, a key intermediate in the biosynthesis of triglyceride and glycerophospholipids ⁴¹. Precisely how AGPAT2 deficiency causes lipodystrophy remains unsolved, but possible mechanisms include impaired lipogenesis, altered differentiation of preadipocytes to adipocytes, altering normal activation of phosphatidylinositol 3-kinase (PI3K)/Akt and PPARγpathways in the early stages of adipogenesis, and apoptosis/necrosis of adipocytes ^2,42,43. Adiposity is preserved in certain body parts such as orbits, palms and soles, which constitute the mechanically adipose tissue ^30,44-46(Fig.2). AGPAT2pathogenic variants along with BSCL2pathogenic variants are responsible for the majority of the CGL cases.

Figure 2

Near total absence of adipose tissue in CGL1 (2A, 2C, 2D). Magnetic resonance images document the lack of subcutaneous fat (2B). Liver biopsy reveals severe hepatic steatosis with both micro and macrovesicular steatosis (Hematoxylin and eosin staining; magnification 200X), 2E).

CONGENITAL GENERALIZED LIPODYSTROPHY TYPE 2 (CGL2)

CGL2 is caused by pathogenic variants in the BSCL2gene which have been mapped to chromosome 11q13. This gene encodes a 398-amino acid integral endoplasmic reticulum membrane protein calledseipin⁴⁷. This protein is assumed to take part in lipid droplet formation and adipocyte differentiation ^48,49. Patients with BSCL2pathogenic variants have the most severe disease and are born without any adipose tissue. Hypertriglyceridemia and hepatic steatosis can be detected in early childhood; and hepatic involvement can be more severe in CGL2 than other subtypes ⁵⁰. Intellectual disability and cardiomyopathy are more common than in CGL1. CGL2 patients are also distinguished from the CGL1 patients with the loss of mechanical adipose tissue ⁵¹(Fig.3). Although the mechanism is not clear, adiponectin levels are relatively higher in patients with CGL2 despite severely suppressed leptin levels which can help in the differential diagnosis ⁵².

Figure 3

Near total absence of adipose tissue in a patient with CGL2 (3A, 3B). Also note that the patient shown now deceased was only 29 years old at the time the picture was taken, suggesting the possibility of accelerated aging.

CONGENITAL GENERALIZED LIPODYSTROPHY TYPE 3 (CGL3)

CGL3 is caused by pathogenic variants in the CAV1gene which are located on chromosome 7q31 ^9,14,53. This gene encodes the protein caveolin-1, which is an integral part of caveolaefound in plasma membranes. Caveolin 1 binds fatty acids on the plasma membranes and translocates them into lipid droplets. Mutated caveolin 1 disrupts lipid droplet formation and adipocyte differentiation ⁵⁴. CGL3 is distinguished from other CGLs by the presence of unique features such as preserved bone marrow fat, vitamin D resistance, hypocalcemia, hypomagnesemia, and decreased bone density ⁴⁰. In addition to this classical presentation, whole exome sequencing has identified de novoheterozygous null CAV1pathogenic variants in two patients of European origin with generalized fat loss, thin mottled skin, and progeroid features at birth; however, no differences in the number and morphology of caveolae have been found in dermal fibroblasts ⁵⁵, which suggests that this observation needs to be confirmed in further pedigrees. Heterozygous CAV1frameshift mutations have also been reported to be associated with partial lipodystrophy (Fig.4). Several features such as congenital cataracts and cerebellar progressive ataxia were also present ⁵⁶.

Figure 4

Partial lipodystrophy associated with heterozygous CAV1 frameshift mutations in a male (4A, 4B, 4C) and female subject (4D, 4E). Patients shown were a father and a daughter pair.

CONGENITAL GENERALIZED LIPODYSTROPHY TYPE 4 (CGL4)

Type 4 CGL (CGL4) is caused by pathogenic variants in the PTRFgene. The product of this gene, cavin, is a polymerase 1 and transcript release factor which regulates caveolae 1 and 3 ⁵⁷. CGL4 can be recognized by distinct clinical characteristics. This rare subtype of CGL is associated with myopathy, pyloric stenosis, gastrointestinal dysmotility, arrhythmias that include exercise-induced ventricular tachycardia and sudden death, and skeletal abnormalities such as atlantoaxial instability and scoliosis ^58-60(Fig.5).

Figure 5Lack of subcutaneous fat (5A), scoliosis (5A), gastrointestinal dysmotility (5B), and exercise-induced ventricular arrhythmia (5C) in CGL4.

OTHER GENES ASSOCIATED WITH GENERALIZED LIPODYSTROPHY

Biallellic loss-of-function pathogenic variants in phosphate cytidylyltransferase 1 alpha (PCYT1A), the rate-limiting enzyme in the Kennedy pathway of de novo phosphatidylcholine synthesis, have been reported to be associated with generalized lipodystrophy, severe hepatic steatosis and low HDL cholesterol levels ⁶¹. Although widely involved in the familial partial lipodystrophy pathogenesis, several pathogenic variants in the LMNAand PPARGgenes have been associated with generalized lipodystrophy. Recently, heterozygous LMNAp.T10I pathogenic variant was reported to be associated with generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly (Fig.6) ⁶². Biallelic pathogenic variants at PPARGhas also been reported to cause generalized lipodystrophy ⁶³.

Figure 6

Generalized lack of subcutaneous fat (6A), eruptive xanthomata (6B), and lipemia retinalis (6C) secondary to severe hypertriglyceridemia in a patient with heterozygous LMNA p.T10I pathogenic variant.

Acquired Generalized Lipodystrophy

Acquired generalized lipodystrophy (AGL), also known as Lawrence Syndrome, is very rare. Generalized fat loss is not present at birth but develops later in life. It occurs over a variable time period, ranging from a few weeks to years (Fig.7) ⁹.

Figure 7

Generalized loss of subcutaneous fat in two patients with AGL (7A-D). Note the distal fat loss around the feet as opposed to patients with CGL phenotypes.

Although the pathogenesis of AGL is unknown, it is hypothesized to be linked to autoimmune destruction of adipocytes. Autoantibodies against adipocyte membranes have been reported ^64-66. AGL is associated with panniculitis in approximately 25% of the patients. This type may manifest with subcutaneous inflammatory nodules (panniculitis), which heal by localized loss of fat and eventually results in complete loss of subcutaneous fat ⁹. Another one fourth of the AGL patients present with an autoimmune disease that include juvenile dermatomyositis (JDM), Sjogren’s syndrome, rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus ^9,65. Of these, JDM particularly correlates with AGL. 8-40% of patients with JDM develop AGL (Fig.8) ^66-68. In the remaining 50% of the cases, AGL is not associated with any autoimmune or inflammatory condition ⁹. Some patients with AGL exhibit low serum complement 4 levels and auto-immune hepatitis, sometimes together with Type 1 diabetes, which suggests the involvement of classical complement pathway in AGL pathogenesis ⁶⁹.

As mentioned above, it is of note that some of the patients with AGL are recently recognized to have additional progeroid features and may harbor a specific pathogenic of LMNAgene at position 10 (p.T10I). We have reported clinical presentations of these patients recently in a case series report. One of these patients also had biopsy proven juvenile dermatomyositis suggesting that the long-recognized association between AGL and JDM may be linked through distinctive molecular mechanisms ⁶².

In patients with AGL, as a result of generalized fat loss, metabolic abnormalities associated with severe insulin resistance that include hypertriglyceridemia, diabetes mellitus, hepatic steatosis, acanthosis nigricans, menstrual irregularities and PCOS may develop soon after the recognition of fat loss. Patients have suppressed levels of leptin and adiponectin ^9,30.

Figure 8

Generalized loss of subcutaneous fat in a patient with juvenile dermatomyositis associated AGL (8A, 8B). Note the absence of muscle tissue as well in this severely affected patient.

PARTIAL LIPODYSTROPHY

Fat loss affects only part of the body in partial lipodystrophy. Partial lipodystrophy is categorized into inherited (familial partial lipodystrophy, FPLD) and acquired forms (acquired partial lipodystrophy, APL). Both patients with FPLD and APL start losing fat at some point during their life. Lower limbs are most frequently affected in FPLD. There might be accumulation of adipose tissue in the face and neck. On the other hand, APL is characterized by fat loss that spreads through a cephalocaudal distribution from the face, neck, shoulders, arms, and forearms and that extends to the thoracic region and upper abdomen. There are numerous genes associated with FPLD. Despite the growing number of proven genetic markers, about half of the patients do not have a discernible single gene variation.

Inherited Partial Lipodystrophy Syndromes

Patients with these syndromes usually notice partial fat loss around puberty. Fat loss pattern is very heterogeneous in patients with FPLD. Even among patients with pathogenic variants of the same gene, fat loss patterns may vary.

FAMILIAL PARTIAL LIPODYSTROPHY TYPE 1 (FPLD1)

The loss of adipose tissue is mainly limited to the extremities in patients with FPLD1 or Kobberling-type lipodystrophy ⁷⁰. There is a normal or slightly increased fat in the face and neck. Truncal obesity is a common finding. The hallmark of this syndrome is the formation of a palpable “ledge” between the normal and lipodystrophic areas ⁷¹. It is believed that women are diagnosed more easily as they usually present with a more severe disease. Metabolic complications usually develop in early adulthood. Insulin resistant diabetes and metabolic syndrome are common and may cause premature coronary artery disease. Hypertriglyceridemia may trigger episodes of acute pancreatitis. Acanthosis nigricans is commonly seen. Leptin levels are variable and correlate with body mass index (BMI) which suggests that the levels of leptin are appropriate for the fat content in FPLD1 ⁷¹. The Cambridge group recently reported that this form of lipodystrophy may have a polygenic etiology ⁷². There is a remarkable phenotypical heterogeneity among patients with FPLD1. In this spectrum of FPLD1, patients with significant central obesity are likely polygenic. This type of presentation is relatively more common, and it is sometimes difficult to make a distinction between FPLD1 and truncal obesity complicated with metabolic syndrome. The use of radiological methods such as DXA, CT or MRI can help in this population to further define body fat distribution in addition to physical examination and skinfold measurements. On the other hand, some FPLD patients without increased truncal fat are classified as FPLD1 by definition, if no disease-causing gene is identified to date. These latter patients will likely turn out to have a monogenic form of FPLD eventually. These two different presentations of FPLD1 are shown in Fig.9.

Figure 9

Heterogeneity in FPLD1. Patient in A to D presented with decrease in peripheral fat depots and preservation of abdominal fat. Patient in E to H has increased abdominal adiposity. The formation of a palpable “ledge” between the normal and lipodystrophic areas is shown (9C and 9E). (Images E-H used with permission by Dr. Jonathan Q. Purnell from publication Diabetes Care 2003;26(6):1819-24)

FAMILIAL PARTIAL LIPODYSTROPHY TYPE 2 (FPLD2)

FPLD2 or Dunnigan Variety lipodystrophy is an autosomal dominant syndrome which is characterized by gradual onset of subcutaneous fat loss from the extremities during puberty. Affected individuals have prominent muscularity in their extremities. Excess fat accumulates in the neck causing a buffalo hump (Fig.10). This phenotype sometimes can be misdiagnosed as Cushing’s syndrome at first glance ¹⁴. Pathogenic variants in the LMNAgene, which is located on chromosome 1q21-22, cause FPLD2. The LMNAgene codes nuclear lamina proteins, lamin A and C. Pathogenic variants in the LMNAgene can be scattered across many exons of the gene and are missense mutations ⁷³. Mutant lamins disrupt the interaction between nuclear lamina and chromatin and may result in apoptosis, which may be followed by premature adipocyte death ⁷⁴.

Figure 10Subcutaneous adipose tissue loss from the extremities, excess fat accumulation in the face and neck, and Cushingoid appearance in FPLD2 (10A-D; Note that one of the patients (10A) previously underwent liposuction for removal of unwanted excess fat from the neck).

Females have a more recognizable phenotype and more severe metabolic complications ⁷⁵. Most patients with FPLD2 develop diabetes in their twenties and thirties. Other components of insulin resistance are usually present. Patients with FPLD2 are at high risk for cardiovascular diseases that usually develop at relatively younger ages ⁷⁶.

There is phenotypic heterogeneity among patients with FPLD2. For instance, less severe loss of fat has been reported in patients with exon 11 LMNApathogenic variants which affects only lamin A protein ⁷⁷. LMNAR349W pathogenic variant (exon 6) is associated with facial fat loss which is uncommon in FPLD2 ^76,78,79. Exon 1 variants are associated with severe cardiac disease that require cardiac transplant at an early age and may be coupled with arrhythmias and conduction system abnormalities. Variants across exon 4 through 8 have been noted to cause muscular dystrophy related symptoms together with fat distribution abnormalities. LMNAgene pathogenic variants are also involved in the pathogenesis of progeroid disorders including Hutchinson-Gilford progeria syndrome (HGPS), mandibuloacral dysplasia, and atypical progeroid syndrome (APS).

FAMILIAL PARTIAL LIPODYSTROPHY TYPE 3 (FPLD3)

FPLD3 is caused by pathogenic variants in the PPARGgene, a key regulator of adipocyte differentiation. Patients with FPLD3 usually show milder fat loss; and there is no accumulation of adipose tissue in the face and neck (Fig.11); however, they manifest metabolic complications at a similar rate and severity to those with FPLD2 ^76,80-84.

Figure 11Moderate partial subcutaneous adipose tissue loss in a patient with FPLD3 (11A-C).

FAMILIAL PARTIAL LIPODYSTROPHY TYPE 4 (FPLD4)

FPLD4 is caused by pathogenic variants in the PLIN1gene encoding perilipin 1, which is an essential lipid droplet coat protein ⁸⁵. Perilipin plays a key role in coordinating access of lipases to the core triacylglycerol. It is characterized by the loss of adipose tissue which is most striking in the lower limbs and femorogluteal depot, severe insulin resistance, diabetes, hypertriglyceridemia, and hepatic steatosis ^86,87.

FAMILIAL PARTIAL LIPODYSTROPHY TYPE 5 (FPLD5)

FPLD5 is an autosomal recessive syndrome caused by pathogenic variants in the CIDECgene. It is characterized by partial lipodystrophy, acanthosis nigricans, severe insulin resistance leading to diabetes, and hepatic steatosis. The CIDECgene is located on chromosome 3 (3p25.3) and encodes the CIDEC protein, which is expressed in the lipid droplets. Pathogenic variants of the CIDECgene are postulated to result in the loss of ability of lipid droplets to store fat ⁸⁸.

FAMILIAL PARTIAL LIPODYSTROPHY TYPE 6 (FPLD6)

FPLD type 6 is caused by pathogenic variants in the LIPE(lipase E, hormone sensitive type) gene which has an autosomal recessive inheritance ⁸⁹. This FPLD subtype is characterized by late-onset partial fat loss from the lower extremities and also multiple symmetric lipomatosis and progressive distal symmetric myopathy at least in some cases ^89,90. Hormone sensitive lipase is the predominant regulator of lipolysis from adipocytes. Pathogenic variants in the LIPEgene appear to result in impaired lipolysis which may induce lipomatosis and partial fat loss at the same time that is associated with hypertriglyceridemia, hepatic steatosis, and insulin resistant diabetes ⁹⁰.

OTHER GENES ASSOCIATED WITH FAMILIAL PARTIAL LIPODYSTROPHY

FPLD has been reported to be caused by pathogenic variants in the AKT2gene ⁹¹. AKT is a serine/threonine protein kinase, which is involved in cell signaling/growth, glycogen synthesis, and insulin-stimulated glucose transport. Lipodystrophy in patients with AKT2mutations is thought to be due to defective adipocyte differentiation and post-receptor insulin signaling ⁹². Exome sequencing has identified a heterozygous variant in the adrenoceptor α 2A (ADRA2A) gene, which encodes the main presynaptic inhibitory feedback G protein–coupled receptor regulating norepinephrine release, in an African-American pedigree with atypical FPLD ⁹³, which needs to be confirmed in additional pedigrees.

Progeroid Syndromes And Lipodystrophy

Mandibuloacral Dysplasia (MAD) is a rare progeroid syndrome which manifests with craniofacial, skeletal and cutaneous abnormalities and lipodystrophy (Fig.12) ⁹⁴. The clinical manifestations present gradually over time, most commonly during childhood. There are two types of MAD currently recognized. Mandibuloacral dysplasia type A (MADA) is characterized by the loss of subcutaneous fat from the extremities along with normal or excessive fat in the face and the neck. Mandibuloacral dysplasia type B manifests with a more generalized loss of subcutaneous fat ^94-97.

Figure 12Hypoplasia of the mandible in a patient with Mandibuloacral Dysplasia.

MAD is caused by mutations in the LMNAgene which results in the accumulation of prelamin A protein ⁹⁸. This, in return disrupts the interaction between nuclear lamina and chromatin ^97-99. Compound heterozygous pathogenic variants in the zinc metalloproteinase (ZMPSTE24) gene have been reported to cause MADB associated lipodystrophy ^100,101. ZMPSTE24is essential in the post-translational proteolytic cleavage of carboxy terminal residues of farnesylated prelamin A to form mature lamin A and vimentin processing ^100,102,103.

MDP (mandibular hypoplasia, deafness and progeroid features syndrome) has been reported to be caused by pathogenic variants of thePOLD1gene that encodes catalytic subunit of DNA polymerase δ which play an essential role in the lagging-strand DNA synthesis during DNA replication ¹⁰⁴. In addition to progressive lipodystrophy and severe insulin resistance, patients with MDP suffer from mandibular hypoplasia, sensorineural deafness, progeroid features, scleroderma and skin telangiectasia, ligament contractures, reduced mass of limb muscles, hypogonadism and undescended testes in males ^104-107. We recently observed a mother daughter pair with a different POLD1variant near the carboxyl terminal of the protein at a very highly conserved residue (Fig.13).

Figure 13Partial lipodystrophy in a patient with POLD1 variant (13A-E).

Biallelic WRNnull mutations linked to partial lipodystrophy with severe insulin resistance in adult progeria Werner syndrome (Fig.14) ¹⁰⁸. The WRNgene encodes a RecQ DNA helicase which plays a critical role in repairing damaged DNA ¹⁰⁹.

Figure 14Partial lipodystrophy in a patient with adult progeria also known as Werner syndrome.

Fibrillin-1 (FBN1) gene pathogenic variants are found in more than 90% of patients with Marfan syndrome ¹¹⁰. Pathogenic variants in the penultimate exon of FBN1have been reported to be associated with a distinct phenotype of generalized lipodystrophy that share some clinical features with neonatal progeroid syndrome (Wiedemann–Rautenstrauch syndrome), a very severe disorder with only a few patients described who could reach their late childhood ^111-113. Although these patients have marfanoid/progeroid appearance, skeletal features, dilated aortic bulb, bilateral subluxation of the lens, myopia in addition to the severe generalized lipodystrophy, no significant metabolic abnormality caused by the lack of adipose tissue has been reported ^111,112,114.

Pathogenic variants in BANF1have been reported to be associated with progeroid features, growth retardation, decreased subcutaneous fat, thin limbs, and stiff joints. This disease is also called Néstor-Guillermo progeria syndrome (NGPS) ¹¹⁵.

Heterozygous pathogenic variants in KCNJ6(GIRK2), which encodes an inwardly rectifying potassium channel, cause Keppen-Lubinsky syndrome that is characterized by severe developmental delay and intellectual disability, microcephaly, large prominent eyes, an open mouth, progeroid appearance, and generalized lipodystrophy ¹¹⁶.

Pathogenic variants of the Spartan (SPRTN) gene, which encodes a protein that is essential in the maintenance of genomic stability, have reported to be associated progeroid features, lipodystrophy and hepatocellular carcinoma ¹¹⁷.

Other Syndromes And Genes Associated With Lipodystrophy

Pathogenic variants in the phosphatidylinositol 3-kinase, regulatory subunit 1 (PIK3R1), which mediates insulin’s metabolic actions, have been reported in patients with SHORT syndrome (short stature, joint hyperextensibility, ocular depression, Rieger anomaly, and teething delay) that is associated with lipodystrophy in many patients ^118,119. It has also been reported that patients with C-terminal PIK3R1pathogenic variants exhibit severe insulin resistance but normolipidemia and no hepatic steatosis ¹²⁰.

Pathogenic variants in the proteasome subunit, beta-type, 8 (PSMB8) gene, which encodes a catalytic subunit of the 20S immunoproteasomes called β5i, has been linked to an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome)^121-123.

CANDLE syndrome is another rare autoinflammatory syndrome characterized by chronic atypical neutrophilic dermatitis, recurrent fever, and partial loss of adipose tissue from the upper limbs and face ¹²⁴. An eponym for the syndrome was proposed as Nakajo–Nishimura syndrome ^125,126. Homozygous or compound heterozygous mutations in the gene PSMB8have been reported in patients with CANDLE syndrome ^127,128.

Recently a pathogenic variant in the MFN2gene that encodes mitofusin 2, a membrane-bound mediator of mitochondrial membrane fusion and inter-organelle communication, have been reported to be associated with partial lipodystrophy, upper body adipose hyperplasia, and suppression of leptin expression ¹²⁹(Fig.15).

Figure 15Disease progression in a patient with a pathogenic variant in the MFN2 gene (15A-D).

Two families with AREDYLD syndrome that is characterized by acrorenal field defect, ectodermal dysplasia, generalized lipodystrophy, and multiple abnor

malities have been reported ^130,131. The genetic basis of this very rare syndrome is still unknown.

Acquired Partial Lipodystrophy

Acquired partial lipodystrophy (APL) is characterized by fat loss typically starting in childhood or early adulthood. Loss of adipose tissue first manifests in the face and gradually progresses to the upper extremities, thorax and upper abdomen symmetrically. It typically proceeds in a cephalocaudal fashion but spares the lower extremities (Fig.16). There might be accumulation of fat in the lower abdomen, gluteal region, and lower extremities.

Figure 16

Typical cephalocaudal adipose tissue loss pattern in two patients with APL (16A-D). Note preservation of fat depots below the waist line.

Although the etiology of APL is still unknown, some patients may have coinciding autoimmune conditions. Systemic lupus erythematosus and dermatomyositis/polymyositis are among the most frequently associated auto-immune diseases ¹³². APL has been associated with abnormalities of the alternative complement pathway that may cause membranoproliferative glomerulonephritis (MPGN) ¹³³. Subsequent chronic renal disease constitutes the major cause of morbidity in these patients. It has been suggested that C3-nephritic factor might be the cause for the lysis of adipocytes expressing factor D, although there is no solid evidence supporting this hypothesis ¹³⁴.

Rare variants in LMNB2were previously reported in five patients with APL, but two of four variants were also present in normal controls ¹³⁵. In addition, subcutaneous loss of fat from the legs and the gluteal region, presence of diabetes, type IV and V hyperlipoproteinemias were atypical presentations in these patients ¹³⁵.

Metabolic complications are less common compared to other types of lipodystrophy syndromes ⁴. Not all patients develop insulin resistance, diabetes, or hypertriglyceridemia. Leptin levels vary from hypoleptinemia to normal range ^30,132. However, patients may develop metabolic abnormalities such as diabetes, hypertriglyceridemia, low HDL cholesterol levels and hepatic steatosis in later stages of the disorder. In addition, several patients with APL has been reported to develop diabetes or other metabolic abnormalities at a relatively young age, which are apparently associated with insulin resistance ¹³⁶. Thus, patients with APL should also be followed for metabolic abnormalities as is done for other subtypes of lipodystrophy.

TREATMENT

Currently, treatment modalities are restricted to ameliorating or preventing the comorbidities of the lipodystrophic syndromes. There is no cure for these syndromes. For the metabolic disturbances, lifestyle modification (diet and exercise as needed), metformin, and fibrates (and/or statins) are generally required. Insulin or other antidiabetics (e.g., metformin, thiazolidinediones) can also be used if needed. Metreleptin, a leptin analog, is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with generalized lipodystrophy.

Leptin

A large group of lipodystrophy patients present with low leptin levels. Metreleptin (r-metHuLeptin) is an analog of human leptin made through recombinant DNA technology. It has been tested in congenital and acquired forms of lipodystrophy and has been shown to ameliorate the metabolic derangements ^29,34. Several studies show that leptin (0.04 to 0.08 mg/kg/day by subcutaneous injection) in patients with generalized lipodystrophy results in significant weight loss due to its effect on appetite and resting energy expenditure ³⁴. Leptin replacement therapy is approved in Japan as a therapy indicated specifically for the treatment of diabetes and/or hypertriglyceridemia in patients with congenital or acquired lipodystrophy. In the United States, metreleptin, now called MYALEPT, has been approved by the FDA in 2014 for use in patients with congenital generalized or acquired generalized lipodystrophy for the treatment of metabolic complications of these diseases as an adjunct to diet and lifestyle modifications. There is no lower age limit for initiation of Myalept nor a specific degree of metabolic abnormality so long as the diagnosis of generalized lipodystrophy can be substantiated. However, it is not approved for use in human immunodeficiency virus (HIV)-related lipodystrophy, or in patients with metabolic diseases such as diabetes and hypertriglyceridemia, or partial lipodystrophy. The effects of leptin treatment in patients with lipodystrophy are summarized below.

APPETITE

Metreleptin decreases hyperphagia, leading to weight loss that usually stabilize with long-term treatment ^29,154-156. This effect can be noted by the patients right after the treatment with metreleptin. Functional MRI studies combined with behavioral assessments showed that metreleptin treatment is associated with long-term improvements of hedonic and homeostatic central nervous networks regulating appetite and food intake ^157-159. Food related neural activity and formation of satiety feeling have been shown to be effectively restored by leptin replacement in lipodystrophy ¹⁶⁰.

METABOLIC PARAMETERS

Metabolic changes become prominent in several weeks after metreleptin. Metreleptin therapy has been shown to improve fasting plasma glucose levels starting from the first week ¹⁵¹. In a subset of patients undergoing hyperinsulinemic-euglycemic clamp studies, leptin replacement therapy improved peripheral glucose disposal and decreased both hepatic glucose output and hepatic steatosis ¹⁶¹. Metreleptin lowered HbA1c by 2% within the first year ¹⁶². It is recommended to lower the insulin doses by 50% on initiation of metreleptin therapy to avoid hypoglycemia in well-controlled diabetic patients. Metreleptin treatment has no suppressive effect on beta cell function in patients with lipodystrophy ¹⁶³. On the contrary it has been reported that metreleptin therapy improves insulin secretion in diabetic patients with lipodystrophy ¹⁶⁴.

Metreleptin lowers triglycerides starting from the first week. It is effective in providing a 60% reduction in triglyceride levels within the first year ¹⁶². It should be noted that acute withdrawal of metreleptin therapy might result in acute pancreatitis episodes ^165,166. Metreleptin also decreased total cholesterol and LDL-cholesterol levels but did not alter HDL cholesterol levels ^165,167.

The beneficial effect of metreleptin on glycemic and lipid measures in generalized lipodystrophy are clear and usually dramatic. Although the response is variable in patients with partial lipodystrophy and it is not approved yet in this patient population, studies have shown that these patients can benefit from metreleptin treatment. A selected cohort of partial lipodystrophy patients with moderately to severely low leptin and significant baseline metabolic abnormalities is more likely to benefit from metreleptin therapy ^{12,162,168,169}.

LIVER

Leptin replacement therapy improves hepatic steatosis and lowers serum transaminases within 6-12 months (Fig.17) ^156,161,170. The liver volume decreases ^155,170. Although the mechanism is not fully understood, leptin therapy resulted in significant increase in insulin suppression of hepatic glucose production ¹⁶¹. This improvement in insulin action helps reverse hepatic steatosis by decreasing triglyceride content ¹⁶¹. Nonalcoholic steatohepatitis (NASH) score has been reported to improve after metreleptin treatment and no progression in hepatic fibrosis has been reported ¹⁷¹. When treated at least for a year, the vast majority of patients showed improved liver histology, steatosis and hepatocyte ballooning, and only 33% of patients continued fulfilling the criteria for NASH after 1 year of treatment with metreleptin ^172,173. A significant improvement in the non-alcoholic fatty liver disease (NAFLD) score has been reported after metreleptin treatment in pediatric patients who underwent liver biopsies ¹⁷⁴. Metreleptin has also been reported to result in rapid clearance of fat from the liver and normalization of liver histology in an AGL patient with recurrence of NAFLD in the first few months of liver transplantation ¹⁷⁵.

Figure 17Liver histology shows regression of hepatic steatosis and ballooning injury after metreleptin treatment (left before metreleptin and right 4 months on metreleptin treatment, Hematoxylin and eosin staining; magnification 200X).

KIDNEYS

Patients with lipodystrophy may develop proteinuric kidney disease. Metreleptin decreased proteinuria in most patients ^156,176. The reduction in proteinuria coincided with improvement in hyperfiltration in 11 of 15 patients treated with metreleptin. However, four patients had worsening renal function. Hence, renal functions should be closely monitored during metreleptin therapy ¹⁷⁶.

REPRODUCTIVE SYSTEM

In females, metreleptin was found to normalize gonadotropin secretion. It led to normal progression of puberty, normalized menstrual cycles, and improved fertility ^156,177-179. Leptin replacement improved low estradiol levels and corrected the attenuated luteinizing hormone (LH) response to luteinizing hormone-releasing hormone (LHRH) in young women with lipodystrophy and leptin deficiency ¹⁷⁷. One-year treatment with metreleptin resulted a significant decrease in testosterone and sex hormone binding globulin (SHBG) levels in lipodystrophic women with PCOS ¹⁸⁰. Several pregnancies have occurred in patients with lipodystrophy while they were on metreleptin without any evidence for teratogenicity ^38,181, although it has not been approved for use in pregnancy. Leptin replacement was associated with a small increase (clinically non-significant) in serum testosterone and SHBG in males. No change was observed in serum LH response to LHRH ¹⁷⁸. No impact of leptin therapy on bone mineral density and content and bone metabolism has been reported in both sexes ^170,182,183.

ADVERSE EFFECTS

Approximately 30% of patients treated with metreleptin experienced adverse effects ¹⁶⁵. The most common side effects were hypoglycemia, and injection site reactions e.g. erythema and urticaria. Headache, fatigue, weight loss, and abdominal pain were also seen. There may also be a need to make dose adjustments or cessation of concomitant treatments such as insulin, oral antidiabetics, and lipid lowering drugs after metreleptin therapy. In some cases, in vivo neutralizing antibodies to metreleptin have been reported ^184,185and is the main reason underlying the FDA's restriction of metreleptin use. Anti-metreleptin antibodies developed in most patients with lipodystrophy; however, neutralizing activity concurrent with worsened metabolic control has been reported only in a small number of patients treated with metreleptin ^181,184. In addition, in the few patients who presented with neutralizing antibody formation, occurrence of severe infections such as sepsis has been reported. Two of these patients developed multiple sepsis episodes around the time of detection of neutralizing antibody ¹⁸⁴. T-cell lymphoma has been reported in three patients with acquired generalized lipodystrophy receiving metreleptin ¹⁸⁶. In acquired lipodystrophy patients with autoimmunity and immunodeficiency before metreleptin therapy, T-cell lymphoma development was also described ^186,187, suggesting that lymphoma development in acquired lipodystrophy is more likely to be associated with the disease itself rather than being related to metreleptin treatment.

In other cases with acquired generalized lipodystrophy, progression of kidney disease and liver disease have been observed while receiving metreleptin therapy ¹⁸⁸. Since patients with AGL with distinct autoimmune conditions clearly benefit from metreleptin, treatment for their metabolic abnormalities should be considered in patients with AGL with close clinical follow up in light of the cautionary preclinical data ^189,190.

More recently attention has been devoted to emergence of new cancers while on metreleptin therapy. Data on these parameters will be reported in short order.

CONCLUSION

Lipodystrophy syndromes are a group of fascinating diseases that are caused by mechanisms that disrupt predominantly adipocyte differentiation or lipid droplet formation. LMNAgene defects, the most common single gene defects leading to the development of lipodystrophy syndromes, leads to lipodystrophy possibly due to inducing adipocyte apoptosis or death, but more work is needed on this front. Regardless of the mechanism and whether the diseases present with generalized or partial fat loss, common metabolic complications include severe insulin resistance, hypertriglyceridemia, and ectopic fat deposition, especially hepatic steatosis. This common theme is recapitulated in numerous animal models as well. The diseases are typically progressive and lead to multi-organ involvement and increased mortality. Molecular advances in the understanding of disease mechanisms may lead to better and specific treatments for lipodystrophy syndromes. So far, the most exciting therapeutic development for the treatment of lipodystrophy syndromes has been the approval of leptin replacement therapy for generalized lipodystrophy in the form of metreleptin. While Metreleptin is not approved for treatment of partial lipodystrophy syndromes in the United States, there are a number of global studies ongoing for the treatment of predominant partial lipodystrophy syndromes with other agents at this time.

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