CHAPTER 7 MONOGENIC FORMS OF Mark A. Sperling, MD, and Abhimanyu Garg, MD

Dr. Mark A. Sperling is Emeritus Professor and Chair, University of Pittsburgh, Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA. Dr. Abhimanyu Garg is Professor of Internal Medicine and Chief of the Division of Nutrition and Metabolic Diseases at University of Texas Southwestern Medical Center, Dallas, TX.

SUMMARY

Types 1 and 2 diabetes have multiple and complex genetic influences that interact with environmental triggers, such as viral infections or nutritional excesses, to result in their respective phenotypes: young, lean, and -dependence for patients or older, overweight, and often manageable by lifestyle interventions and oral medications for patients. A small subset of patients, comprising ~2%–3% of all those diagnosed with diabetes, may have characteristics of either type 1 or type 2 diabetes but have single defects that interfere with insulin production, , or action, resulting in clinical diabetes. These types of diabetes are known as MODY, originally defined as maturity-onset diabetes of youth, and severe early-onset forms, such as mellitus (NDM). Defects in involved in adipocyte development, differentiation, and death pathways cause syndromes, which are also associated with and diabetes. Although these syndromes are considered rare, more awareness of these disorders and increased availability of genetic testing in clinical and research laboratories, as well as growing use of next generation, whole genome, or exome sequencing for clinically challenging phenotypes, are resulting in increased recognition. A correct diagnosis of MODY, NDM, or lipodystrophy syndromes has profound implications for treatment, genetic counseling, and prognosis. This chapter summarizes the clin- ical findings, genetic basis, and prognosis for the more common forms of these entities.

MODY typically appears before age 25–35 years, in those with a strong family history affecting two to three successive generations, occurs in all races, affects both males and females, and is often misdiagnosed as type 1 or type 2 diabetes. Autoantibodies to islet components are absent, whereas residual insulin secretion is retained, as demonstrated by the concentration of C- in serum at diagnosis. Patients who present with these features should be considered for genetic testing. Three genetic defects (MODY3, MODY2, and MODY1, in order of frequency) comprise ≥85% of all known forms of these entities. MODY3 (more so) and MODY1 patients often respond to oral , especially at younger ages, and may not require insulin injections. MODY2 patients generally do not require any medication, except during to protect the fetus from , which may cause either macrosomia or small birth weight depending on whether both mother and child have the or not. A correct molecular diagnosis is cost-effective in savings from avoiding insulin, offers precise genetic counseling for a 50% chance of occurrence in each offspring of an affected indi- vidual, and generally has a substantially better prognosis for avoidance of the long-term complications of type 1 or type 2 diabetes.

NDM presents as transient or permanent diabetes in the newborn, may be corrected by medication in specific gene muta- tions, or may be associated with specific syndromes of congenital malformations. Some forms represent familial inheritance, with less severe defects in the same genes masquerading as type 2 diabetes in first-degree relatives, while many represent spontaneous new . NDM is rare, with an estimated incidence of ~1:100,000 live births; the incidence of NDM is significantly higher in popula- tions with high rates of consanguinity.

MODY and NDM gene defects have been associated with “typical” type 1 and type 2 diabetes clinical presentation; thus, these single gene defects play an important role in the global burden of diabetes.

The autosomal recessive congenital generalized lipodystrophy (CGL) and autosomal dominant familial partial lipodystrophy (FPL) are the two most common types of genetic . Patients with CGL present with near total lack of body fat, while those with FPL have variable loss of fat, mainly from the extremities. Both disorders present with severe insulin resistance, premature diabetes, hyper- triglyceridemia, and hepatic steatosis. Mutations in AGPAT2, BSCL2, CAV1, and PTRF have been reported in CGL and in LMNA, PPARG, AKT2, and PLIN1 in FPL. Management of diabetes in patients with genetic lipodystrophies involves low-fat diet and high doses of insulin and other antihyperglycemic agents. replacement therapy improves glycemic control, especially in patients with generalized lipodystrophies, and is approved for this specific use in the United States.

Received in final form May 1, 2015. 7–1 DIABETES IN AMERICA, 3rd Edition

INTRODUCTION

Diabetes, a syndrome characterized by is sometimes, and for the purposes of All monogenic forms of diabetes, including hyperglycemia and other metabolic abnor- this chapter, specified as type 1b (or idio- MODY, NDM, and lipodystrophies, are rare. malities, occurs when there is a critical pathic) diabetes. It is not known whether However, more awareness of these disor- degree of deficiency of insulin secretion these patients have a different underlying ders and increased availability of genetic or insulin action or combinations of pathology or if they have autoantibodies testing in clinical and research labora- insulin secretion inadequate to overcome that are not measured by common tories, as well as growing use of next moderate degrees of insulin resistance. assays. Type 2 diabetes is associated with generation sequencing, whole genome Because insulin synthesis, secretion, insulin resistance and variable degrees sequencing, or exome sequencing for and action are under complex genetic of insulin deficiency. However, mutations clinically challenging phenotypes, are controls, type 1 and type 2 diabetes are in single genes, either inherited or as de increasing recognition of these conditions. considered to be multifactorial diseases. novo mutations, may result in various Type 1 diabetes refers to severe insulin forms of monogenic diabetes that mimic This chapter focuses on common patterns deficiency as the primary abnormality type 1 diabetes, type 2 diabetes, and of clinical presentation as occurs with and is most often due to autoimmune other distinct types. Variants in the same MODY, NDM, and the lipodystrophy destruction of insulin-producing beta genes that cause maturity-onset diabetes syndromes. The presentation, incidence, cells in the in the context of of youth (MODY) and various forms of and prevalence of the more common clear insulinopenia and ketosis; this neonatal diabetes mellitus (NDM) or other forms of each entity are highlighted, and autoimmune form is sometimes, and for syndromes have been increasingly identi- the more rare forms are briefly described. the purposes of this chapter, specified fied in the more common forms, especially Specific genetic defects for all syndromes as type 1a diabetes. Some patients have type 2 diabetes, where the severity of the that fulfill the clinical criteria of MODY, a clinical picture that is consistent with gene defects are milder and, hence, mani- NDM or lipodystrophy syndromes are still type 1 diabetes, but the cause of beta fest later in life. Thus, the importance of not completely defined. cell failure is not known and no autoanti- understanding these less common entities bodies are detected; this form of diabetes far outweighs their incidence or prevalence.

MONOGENIC FORMS OF DIABETES

Table 7.1 summarizes the monogenic at ages <20–25 years, severe insulin years with a strong family history affecting forms of diabetes, including syndrome deficiency, and hence, dependence on two to three generations, suggesting names, associated genes, and key clinical exogenous insulin injections; and (b) autosomal dominant transmission, who findings. maturity-onset diabetes with variable were responsive in many instances to oral insulin secretion comparable or exceeding agents, such as sulfonylureas (1). MODY: GENERAL CONSIDERATIONS levels found in lean (non-obese subjects), MODY is generally referred to as “maturi- onset commonly after age 40 years, and The genetic bases for many of the classic ty-onset diabetes of youth” because when often responsive to oral agents, such forms of monogenic diabetes are known described in the 1970s, the classification as sulfonylureas. Among patients with to be factors or of diabetes consisted of two types: (a) maturity-onset types of diabetes were involved in insulin secretion or forma- juvenile ketosis-prone diabetes with onset adolescents and young adults age <30 tion of the pancreas and its endocrine

TABLE 7.1. Monogenic Forms of Diabetes

DEFECTIVE OMIM SYNDROME OR GENE NUMBER* KEY CLINICAL FINDINGS I. Transcription factors and enzymes affecting insulin synthesis/secretion (MODY) I.a. Common types of MODY†—autosomal dominant MODY3 Hepatocyte nuclear factor 600496 Most common form; present late in first decade to late twenties; islet antibody (HNF)1α negative; respond to sulfonylureas initially, but may require insulin later in life. MODY2 (GCK) 125851 Second most common form, but most common form in children; may be diagnosed as in lean, healthy young woman; do not need insulin or other drugs, except in pregnancy.

MODY1 HNF4α 125850 Third most common form; may have macrosomia and at birth, followed by diabetes later in life; treatment as for MODY3.

MODY5 HNF1β 189907 Associated with renal cysts, other vesicogenital anomalies, albuminuria, and renal failure unrelated to the control of diabetes. Table 7.1 continues on the next page.

7–2 Monogenic Forms of Diabetes

TABLE 7.1. (continued)

DEFECTIVE PROTEIN OMIM SYNDROME OR GENE NUMBER* KEY CLINICAL FINDINGS I.b. Other rarer types of MODY‡ MODY4 Insulin factor 1/ 606392 Heterozygous mutation can cause MODY or type 2 diabetes; homozygous pancreatic and duodenal mutation results in pancreas agenesis with severe diabetes and exocrine 1 (IPF1/PDX1) pancreas insufficiency. MODY6 NEUROD1/Beta-2, activates 606394 Presentation similar to MODY3 transcription of the insulin gene MODY7 Kruppel-like factor 1 (KLF11), 610508 regulates PDX1 MODY8 Carboxyl-ester lipase (CEL) 609812 Endocrine and exocrine pancreatic dysfunction MODY9 Paired box 4 (PAX4) 612225 Impaired development MODY10 Insulin 613370 Mild defect; progressively more severe defects cause type 2 diabetes, type 1 diabetes, and neonatal diabetes mellitus. MODY X Unknown Fit criteria of MODY with young onset, absent islet autoantibodies, and response to oral agents, but gene defect not identified, hence indicated by X. II. Other single gene defects associated with defective insulin synthesis/secretion and diabetes Wolfram syndrome/DIDMOAD Wolframin 1 (WFS1) 606201 Diabetes insipidus, diabetes mellitus, optic atrophy, deafness Wolfram syndrome/DIDMOAD Wolframin 2 (WFS2) 604928 Diabetes insipidus, diabetes mellitus, optic atrophy, deafness Mitochondrial form of Wolfram 598500 As above syndrome Thiamine-responsive Thiamine transporter 1 249270 Thiamine-responsive megaloblastic anemia, deafness, and diabetes megaloblastic anemia (TRMA)/ SLC19A2 Rogers syndrome Pigmented hypertrichosis and Nucleoside transporter 3 612373 Multiple associated anomalies insulin-dependent diabetes (PHID) SLC29A3 Mitochondrial inherited diabetes 3243A>G mitochondrial gene 520000 Same mutation as involved in Leber’s hereditary optic neuropathy (LHON) and deafness (MIDD) mutation and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); may be associated with Wolf-Parkinson-White syndrome, deafness, maternal inheritance. III. Genetic defects of insulin Transient or permanent neonatal Insulin gene (INS) 176730 Diabetes without any distinguishing features; see text and Table 7.2 for details. diabetes mellitus (NDM); type1 diabetes; type 2 diabetes presenting later in life IV. Genetic defects of insulin processing Prohormone convertase 1/3 600955 Obesity, low , high , hypogonadotropic hypogonadism (PCSK-1) Prohormone convertase 2 162151 High proinsulin and diabetes (PCSK-2) V. Genetic defects in insulin action: insulin and postreceptor defects Donohue syndrome (INSR) 246200 Intrauterine growth retardation, minimal subcutaneous fat, low glycogen (Leprechaunism) content in liver, fasting hypoglycemia, and postprandial hyperglycemia Rabson-Mendenhall syndrome Insulin receptor (INSR) 262190 Similar to Donohue syndrome with skeletal/bony deformities Insulin resistance syndrome type A Insulin receptor (INSR) 610549 May not be a specific syndrome distinct from obesity, diabetes, and . VI. Abnormal function of cilia Alstrom syndrome ALMS1 203800 Obesity, type 2 diabetes, blindness, hearing loss, cardiomyopathy Bardet-Biedl syndrome Obesity, type 2 diabetes, blindness, hearing loss, cardiomyopathy HNF, hepatocyte nuclear factor; MODY, maturity-onset diabetes of youth. * The Online Mendelian Inheritance in Man (OMIM) is an online catalog of human genes and genetic disorders. OMIM can be accessed at omim.org. † The common types of MODY (MODY3, MODY2, MODY1, and MODY5 in descending order of frequency) account for almost 90% of all cases of MODY (see also Figure 7.1). ‡ MODY4–MODY10 account for <1%, and MODY X accounts for ~10% of all cases of MODY. SOURCE: M. A. Sperling, personal communication

7–3 DIABETES IN AMERICA, 3rd Edition function (Figure 7.1) (1,2,3,4,5,6). Hence, FIGURE 7.1. Classification of Maturity-Onset Diabetes of Youth (MODY) these MODY entities could equally well RELATIVE be referred to as “monogenic diabetes TYPE GENE TREATMENT FREQUENCY (%) of youth.” These syndromes are defined MODY1 HNF4α 20q12-q13.1 Insulin/SU 5 by clinical presentation in pregnancy or MODY2 Glucokinase 7p15-p13 Exercise/diet 22 early childhood (i.e., MODY2, glucokinase MODY3 HNF1α 12q24.2 Insulin/SU 58 [GCK] loss of function mutation), symp- MODY4 IPF1/PDX1 13q12.2 Insulin <1 tomatic diabetes usually presenting in MODY5 17q12 Insulin/SU 2 teens (although a patient as young as age HNF1β 8 years has been reported) to late twen- MODY6 NEUROD1/Beta-2 2q32 Insulin <1 ties (but patients have been diagnosed MODY7 KLF11 2p25 Insulin <1 in their forties) (i.e., MODY3, hepatocyte MODY8 CEL 9q34.3 Insulin <1 nuclear factor (HNF) 1α mutation), large MODY9 PAX4 7q32 Insulin <1 size at birth with neonatal hypoglycemia MODY10 Insulin 11p15.5 Insulin <1 but later appearance of diabetes (i.e., MODY1, 2, and 3 together constitute 85% of all known MODY syndromes; if MODY5 is included, almost MODY1, HNF4α mutation), and diabetes 90% of all MODY syndromes are defined. associated with renal anomalies (i.e., MODY2 is stable, rarely requires insulin treatment except during pregnancy to protect the fetus from hyperglycemia, and has an excellent prognosis for avoidance of vascular complications. MODY5, HNF1β mutation). These four entities constitute close to 90% of all MODY1 and 3 frequently respond to sulfonylurea drugs (SU) initially but may progress to insulin depen- dence and risk for development of vascular complications dependent on metabolic control. known mutations in MODY (Figure 7.1). MODY constitutes about 1.5%–2.5% of new-onset childhood diabetes and should be suspected in those Affected patients typically are negative with: a family history of multiple affected members in two to three generations, with onset before age for autoimmune markers, such as various 35 years; absence of markers of autoimmunity; “mild diabetes” requiring <0.5 U/kg insulin from the islet antibodies, have positive family outset or unusually prolonged “honeymoon” phase. history indicative of autosomal dominant CEL, carboxyl-ester lipase; HNF, hepatocyte nuclear factor; IPF/PDX, insulin promoter factor/pancreatic and duodenal homeobox; KLF, Kruppel-like factor; MODY, maturity-onset diabetes of youth; PAX, paired homeobox; transmission, unless they harbor de novo SU, sulfonylurea drugs. mutations, and may appear to have low SOURCE: M. A. Sperling, personal communication; the clinical manifestations, pathophysiology, and treatment of insulin requirements. When measured, MODY are reviewed in Reference 2. insulin levels may be normal or low for the A clinical presentation before age 25–30 is smaller doses, down to 1.25 mg per day prevailing concentration. years of apparent mild type 1 diabetes or even less to achieve very reasonable or type 2 diabetes with negative diabetes glycemic control in hyper-responsive Epidemiology autoantibodies and positive C-peptide, as MODY3 patients. The early appearance Overall, MODY syndromes represent well as a positive family history in two to of albuminuria, or a family history of renal approximately 2%–3% of all patients three generations should prompt consider- cysts or other renal anomalies, should diagnosed with diabetes; in the United ation of a diagnosis of MODY and referral prompt consideration of MODY5. Subjects Kingdom, the minimum prevalence of for molecular diagnostics to confirm the with MODY5 generally require insulin for MODY was estimated to be 108 cases diagnosis. The correct diagnosis permits therapy and careful management of their per million (5). In the Search for Diabetes correct genetic counseling, because the renal manifestations. in Youth Study (6), of ~5,000 newly risk of affected offspring is 50%, rather presenting children with diabetes with than 5%–10% as in type 1 diabetes. Common Forms of MODY measurement of diabetes autoantibodies As shown in Figure 7.1, MODY3, MODY2, and fasting C-peptide, 14.5% (730 Appropriate management for patients MODY1, and MODY5 together constitute subjects) were diabetes autoantibodies with MODY2 is exercise and diet, which ~90% of all forms of MODY and almost negative and fasting C-peptide positive. Of usually suffice to control blood glucose, 98% of all known MODY mutations. Two these, 586 subjects were tested for MODY except in pregnancy when insulin may forms, MODY3 and MODY1, are caused (MODY1, 2, and 3), and 48 (8.2%) were be required to control blood glucose to by heterozygous mutations in the tran- MODY positive. Thus, about 1.2% of the avoid the consequences of hyperglycemia scription factors HNF1α and HNF4α, original cohort of children had genetically in the fetus. Patients with MODY3 and respectively, whereas MODY2 is caused proven MODY. Non-Hispanic white (35%), MODY1 usually respond to sulfonylureas, by a heterozygous inactivating mutation African American (24%), Hispanic (26%), though about one-third may lose this in the glucokinase, which acts as and Asian and Pacific Islander (13%) individ- responsiveness in time and progress to the sensing apparatus of glucose concen- uals were represented in the MODY group, require insulin (1,2,3,4). The response to tration within the beta cell (Figure 7.2) and most were considered to have either sulfonylureas is much more pronounced (1,2,3,4). MODY5 is similar to MODY1 type 1 diabetes and treated with insulin or in MODY3 patients, such that hypogly- or MODY3 in clinical presentation but is type 2 diabetes and treated with metformin cemia may ensue. Rather than transfer to associated with renal anomalies, predomi- and other oral hypoglycemic medications. insulin or other agents, the best approach nantly cystic changes.

7–4 Monogenic Forms of Diabetes

Figure 7.2 is a simplified cartoon of the FIGURE 7.2. Schematic Representation of a Beta (β) Cell beta cell that illustrates the interactions of these in the insulin synthesis/ secretion cascade (6,7). In the resting state (upper left quadrant of the figure), insulin synthesis and basal secretion are governed by the basal glucose concentration; insulin gene (INS) tran- scription is regulated by a number of regulatory factors that bind to upstream components of INS on . Also illustrated is one unit of the

ATP-regulated channel (K ATP), governed by the ratio of ATP:ADP. The channel remains open in the basal state, allowing of potassium from the interior to the exterior of the beta cell and leaving the plasma membrane in a hyperpolarized state. Each K ATP channel Please see text for detailed explanation of insulin synthesis and secretion. ATP/ADP, / consists of four subunits of the inward ; Cav, voltage-gated calcium channel; Glut 2, glucose transporter 2; K ATP, ATP-regulated potas- sium channel; Kir, inward rectifying ; SUR, sulfonylurea receptor. rectifying potassium channel (Kir6.2), SOURCE: M. A. Sperling, personal communication encoded by the KCNJ11 gene, and four surrounding regulatory units, the sulfo- insulin secretion when glucose is high and it returns to normal as adequate insulin nylurea receptor (SUR1), encoded by a fall in insulin secretion as glucose falls in secretion occurs at the higher glucose the ABCC8 gene (lower left quadrant); response to the actions of insulin. concentrations (Figure 7.3). The result both genes are located on chromosome is “mild” diabetes, as seen in MODY2.

11. Also illustrated are voltage-gated Activating mutations of K ATP components Homozygous inactivating mutations calcium channels, designated as CaV keep the channel open, preventing insulin of GCK result in the virtual absence of

1.2/1.3 and CaV 2.3. Stored insulin secretion, i.e., leading to neonatal diabetes, phosphorylating activity and, hence, granules lined up on the the severity of which is proportional to the NDM. By contrast, activating mutations constitute a quickly releasable pool of severity of the defect. In many instances, in GCK cause inappropriately high insulin insulin responsible for the first phase channel closure with resultant insulin secretion at lower glucose concentrations, insulin response after glucose is acutely secretion can be restored by sulfonylureas causing hyperinsulinemic hypoglycemia of raised. A slower releasable pool of insulin that act on the SUR1 regulatory unit infancy and a milder adult form of familial granules is more internal but can be even though the mutation is in the Kir6.2 hypoglycemia, the severity of which will be mobilized to constitute the second phase channel unit encoded by KCNJ11. By proportional to the degree of activation of insulin response when higher glucose is contrast, inactivating mutations of these GCK (1,2,3,4,6,7). maintained. In the stimulated state (lower KATP components prevent opening of the right quadrant), when blood glucose rises channel and result in insulin secretion MODY3. MODY3 is due to mutations after a meal, it enters the beta cell via the unregulated by glucose concentration in the HNF1α gene, GLUT2 glucose transporter, a non-insulin and, hence, hyperinsulinemic hypogly- located on chromosome 12q24.2 and regulated process. Glucokinase acts as cemia. The drug diazoxide acts to open expressed in liver and beta cells. The gene a glucose sensor and phosphorylates channels and may reduce insulin secretion, is regulated to some extent by HNF4α, glucose to glucose-6- (G6P), although it has many other side effects, providing a link between MODY1 and permitting its to produce ATP. including hypertension and edema (6,7). MODY3. In most series, this entity is the The higher ATP:ADP results in closure of most common form of MODY (Figure 7.1), the KATP channel, retention of intracellular Heterozygous inactivating mutations in with over 120 known mutations, though K+, which leads to membrane depolariza- GCK create a rightward shift in the ability MODY2 is as, or more, common when tion, opening of the voltage-gated Ca2+ of the enzyme to phosphorylate glucose, assessed in younger subjects (age <20 channel allowing for influx of calcium, and resulting in normal insulin secretion but years). Birth weight is normal in MODY3 the secretion of insulin as first and then at higher than normal glucose concentra- patients, and symptoms of diabetes second phase responses. In this way, the tions. Thus, the set point of glucose is on usually appear towards the end of the first chemical energy of glucose is converted the order of 90–120 mg/dL (5.00–6.66 decade or in the second to third decades; to the electrical activity of the beta cell, mmol/L) in the basal state and briefly in some patients are entirely asymptomatic creating a “rheostat” effect, with high the range of diabetes after a meal, but despite glucose values in the low-mid

7–5 DIABETES IN AMERICA, 3rd Edition

200 mg/dL (11.10 mmol/L) range and FIGURE 7.3. Mutations in the Glucokinase Gene Reduce Glucose Phosphorylating Capacity glycosylated hemoglobin (A1c) in the and Result in Diabetes 7.5%–8.5% (58–69 mmol/mol) range at diagnosis. Others present with diabetic . Females may be diagnosed with gestational diabetes; a lean young woman with a family in her parents, grandparents, or siblings, who is found to have gestational diabetes, should be tested for MODY2 and, if nega- tive, for MODY3. Glucose phosphorylating capacity (%) Most patients with MODY3 (and MODY1) are initially responsive to sulfonylureas, which promote endogenous insulin secre- VARIABLE WILD TYPE M210K MUTATION T228M MUTATION -1 tion and correct hyperglycemia, but about Turnover rate (sec ) 52.4±5.7 16.7±1.6 0.004±0.0004 Glucose S (mmol/liter) 7.7±0.1 38.7±1.9 5.5±1.5 one-third to one-half of affected subjects 0.5 may have progressive insulinopenia with Hill coefficient 1.66±0.00 1.63±0.04 0.71±0.07 ATP (mmol/liter) 0.35±0.01 1.38±0.11 0.62±0.16 increasing age, ultimately requiring insulin Km for treatment. However, newer agents The enzyme glucokinase (GCK) phosphorylates glucose to glucose-6-phosphate, permitting its metabolism to combined with sulfonylureas may prove generate ATP, thereby inducing insulin secretion as described in Figure 7.2. The glucose-stimulated insulin release useful for good glycemic control in the (GSIR) threshold requires a glucose phosphorylating capacity of ~30%, normally reached at a glucose concentration of ~90 mg/dL. With heterozygous inactivating mutations in GCK, such as those associated with MODY2, the GSIR absence of exogenous insulin. is right-shifted, so that the GSIR is reached at glucose concentrations of ~110–130 mg/dL, permitting adequate insulin secretion at somewhat higher glucose concentrations. This results in a “mild” diabetes phenotype, discovered by chance or during screening for gestational diabetes or other indications. Homozygous inactivating mutations Once the mutation is confirmed, genetic in GCK cannot reach the GSIR threshold and result in neonatal diabetes mellitus. Conversions for glucose values counseling must emphasize that these are provided in Diabetes in America Appendix 1 Conversions. ATP, adenosine triphosphate; MODY, maturity-onset diabetes of youth; NDM, neonatal diabetes mellitus. mutations are dominant, so statistically SOURCE: M. A. Sperling, personal communication 50% of offspring are likely to have the same condition. Other family members are also Hyperglycemia may be discovered as raise suspicion for the presence of this likely to have the mutation and should an incidental finding in a child or adult condition. In particular, the parents of also be considered for DNA sequencing. during a routine blood chemistry check an affected child should be investigated, Rare subjects have been reported to performed for an unrelated illness; islet as they may be unaware of their mild develop type 1a diabetes with markers cell antibodies are negative and glucose hyperglycemia. of autoimmunity, such as glutamic acid tolerance testing, if performed, shows mild decarboxylase 65kD (GAD65) and/or islet hyperglycemia, rarely exceeding 200 mg/dL Because of the mild hyperglycemia, most cell autoantibodies (ICA) being positive, with delayed return to modestly elevated patients with MODY2 do not require despite being negative for these markers basal glucose concentrations in the range treatment with pharmacologic agents; diet at initial diagnosis (8). Mutations in HNF1α of 90–130 mg/dL (5.00–7.22 mmol/L). and exercise are generally recommended have been described as an uncommon Insulin levels, if measured, are appropriate (but nonspecific for glycemic control), cause of “type 2 diabetes,” if in a mild form but occur at higher than normal glucose and microvascular complications are and discovered after age 35–40 years (8). concentrations. A1c values are generally extremely unlikely to occur (9). However, in the 6.3%–7.5% (45–58 mmol/mol) during pregnancy, treatment with insulin MODY2. MODY2 is due to decreased beta range. In the absence of a family history, may be recommended because a normal, cell sensing of glucose due to loss of func- such patients may be considered to have unaffected baby in utero will respond to tion mutations in glucokinase encoded type 1 diabetes in the early stages and the maternal hyperglycemia with exces- by the GCK gene on chromosome 7p15- be inappropriately treated with insulin, if sive insulin secretion and be at risk for p13 (Figure 7.3). The prevalence of GCK they are children, or considered to have macrosomia with attendant risk at delivery mutations causing MODY2 in the overall type 2 diabetes and be treated with oral and hypoglycemia after birth, as occurs in population is suggested to be 0.04%–0.1%; hypoglycemic agents or insulin sensitizers, an of a diabetic mother. thus, up to 1:1,000 women of childbearing if adults. More commonly, MODY2 due to age are likely to have a GCK mutation GCK mutations presents as gestational On the other hand, babies who inherit the when they present with gestational diabetes in women without the stigmata of maternal defect (50% risk) may have a diabetes (9). This form of MODY presents obesity or other features of insulin resis- lower birth weight due to relative deficiency as mild fasting and postprandial hyper- tance. A family history of other affected of fetal insulin secretion. If both parents glycemia and is usually asymptomatic. members (e.g., parents, siblings) should are heterozygous for GCK mutations, the

7–6 Monogenic Forms of Diabetes infant has a 50% risk of inheriting each and so may be misclassified, especially if important for specifying the development parent’s mutation, but a 25% risk of inher- clinical onset of diabetes occurs later in of the pancreas and duodenum, as well as iting both mutations and therefore having life. Reports of markedly lower concentra- the transcription of insulin, somatostatin, permanent NDM. Rare cases have been tions of high sensitivity C-reactive protein and other islet hormones. Diabetes results described of patients with MODY2 who (hsCRP) in patients with MODY3 (4) have from a combination of reduced gene have gone on to develop autoimmune (anti- not been reported in MODY1 (1,2,3,4,11); dosage, together with a dominant-negative body positive) type 1a diabetes in addition moreover, the findings of low hsCRP in inhibition of transcription of INS and other to their genetic defect of insulin secretion; MODY3 were not confirmed in a more factors regulated by the mutant IPF1/ hence, periodic evaluation of patients recent report (6). Hence, hsCRP cannot PDX1 (14). MODY6 is due to mutation with MODY2 is recommended. In some be considered as a screening test to iden- in the transcription factor NEUROD1 series, MODY2 is the most common form tify patients suspected of having MODY1 that activates transcription of INS (15). of MODY identified, and it particularly is the before embarking on molecular diagnosis Presentation is similar to that of patients most common form in those diagnosed at (1,2,3,4,11). with MODY3. MODY7 is attributed to age <15–20 years (1,2,3,4,9). mutations in Kruppel-like factor 11 MODY5. MODY5 individuals have a muta- (KLF11), a transcription factor involved in MODY1. MODY1 occurs due to muta- tion in the HNF1β gene (12,13). HNF1β regulating PDX1. MODY8 is attributed to tions in the HNF4α gene located on regulates HNF4α and, hence, may provide mutations in the carboxyl-ester lipase gene chromosome 20q12-q13.1. It was the first a link between MODY5 and MODY1. (CEL), encoding an enzyme and associated transcription factor mutation discovered Originally discovered in Japanese families with both endocrine and exocrine pancre- for MODY; normally, the gene is expressed with MODY, the phenotype is character- atic dysfunction, leading to diabetes with in liver, kidney, intestine, and islets. ized by cystic renal disease and other evidence of malabsorption (16). The tran- HNF4α is a known key regulator of hepatic associated anomalies, including vaginal/ scription factor PAX4 (paired homeobox , and MODY1, like MODY3, uterine malformations, other genital 4) involved in beta cell development was is characterized by progressive insu- abnormalities, abnormal liver function, found to be mutated in two Thai families linopenia with increasing age. Likewise, hyperuricemia, and the early appearance with a MODY syndrome, designated the clinical features of MODY1 are similar of proteinuria that is not due to diabetic MODY9, a finding not replicated to date in to those of patients with MODY3. Clinical renal disease. The renal cystic manifesta- a selected European population of patients onset of symptoms and recognition of tions may predominate with unawareness with MODY after excluding the common hyperglycemia most commonly occurs in or absence of diabetes; patients may be forms (3,17). Mutations in the insulin gene the mid-twenties but may occur later in referred from a renal clinic for evaluation itself may cause a form of MODY desig- some families. Most affected individuals of incidentally discovered hyperglycemia. nated as MODY10, although mutations in are sensitive to the sulfonylurea drugs, Alternatively, MODY5 may be considered the insulin gene more commonly cause a which restore insulin secretion and lower because a patient with insulin-requiring form of NDM described below (18). MODY glucose, but about one-third of subjects diabetes has siblings or parents with renal X is a term applied to cases where the may develop progressive insulinopenia anomalies and early renal failure. Patients clinical phenotype is consistent with MODY and require a combination of oral hypo- with MODY5 display insulin resistance but a genetic cause has not been identified, glycemic agents or insulin for treatment. and hyperinsulinemia with associated i.e., X is the unknown. A distinguishing and perhaps defining . Unlike patients with MODY3 characteristic of MODY1 is that affected and MODY1, they do not respond to sulfo- All of these rare forms of MODY generally subjects weigh about 800 g more at birth nylurea drugs and usually require insulin present with a history and phenotype than their unaffected siblings, suggesting for management. Subclinical pancreatic similar to MODY3; diagnostic clues may hyperinsulinemia effects in utero (10). exocrine deficiency is present in most be provided by the presence of features, Moreover, hyperinsulinemia at birth with patients, so both exocrine and endocrine such as malabsorption (CEL, MODY8), symptomatic neonatal hypoglycemia pancreatic functions are affected, and but otherwise are so rare that they are that resolves spontaneously has been pancreatic size is smaller. Patients who best considered in the context of a likely reported in some patients (10). These are homozygous for mutations in HNF1β MODY syndrome, and if negative for findings suggest that HNF4α mutations have severe NDM associated with other the more common types, such patients at first cause excessive secretion of insulin, congenital anomalies (1,2,3,4,12,13). should be referred to a specialized directly or indirectly, and only later result center for possible molecular diagnosis in hypoinsulinemia and diabetes. The MODY4, 6–10, X. MODY4 is due to (1,2,3,4,18). Most subjects thought to be reasons for this paradox are not known. mutation in the gene for the transcription in these groups have benign sequence Patients with HNF4α have been reported factor PDX1 (pancreatic and duodenal polymorphisms that are not likely to be to have lower levels of lipoprotein A2 and homeobox), also known as IPF1 (insulin disease-causing. high-density lipoprotein (HDL) cholesterol, promoter factor), on chromosome features commonly seen in type 2 diabetes 13q12.2. This transcription factor is

7–7 DIABETES IN AMERICA, 3rd Edition

Differentiating the Common Wolfram Syndrome: Diabetes hereditary optic neuropathy (LHON) Forms of MODY From Type Insipidus, Diabetes Mellitus, Optic and mitochondrial encephalomyopathy, 1 and Type 2 Diabetes Atrophy, Deafness (DIDMOAD) lactic acidosis, and stroke-like episodes The typical patient with MODY differs Wolfram syndrome is an autosomal reces- (MELAS). Although diabetes does occur in from type 1 diabetes in being negative sive disorder, characterized by several MELAS, and optic atrophy is a feature of for islet antibodies, differs from type 2 associated abnormalities that tend to LHON, these syndromes are clearly due to diabetes in typically being lean, is more develop in a particular sequence over mitochondrial genome mutations (see the likely to have a family history of other time. This rare disorder has an estimated section on Maternally Inherited Diabetes affected family members in an auto- population prevalence of 1:770,000 and Deafness). Some heteroplasmic somal dominant pattern, and may have births and a carrier frequency of 1 in 354 deletions in mitochondrial DNA have been a prolonged “honeymoon” phase or low people (20,21). Optic atrophy closely found in patients with features similar to insulin requirements reflecting retention of follows or precedes the onset of diabetes. Wolfram syndrome, but examination of endogenous insulin secretion confirmed In one series, the median age of onset mitochondrial DNA in patients with classic by a C-peptide level ≥0.8 ng/mL. None of diabetes was 6 years, followed by Wolfram shows no evidence for specific of these characteristics is absolute; the progressive optic atrophy at 11 years with mutations or general mutations or dele- increasing prevalence of obesity is blur- near total loss of vision over the following tions (21). ring distinctions of phenotype between decade. Central diabetes insipidus is type 1 and type 2 diabetes, and Hispanic the next most common manifestation, Thiamine-Responsive and African patients with MODY1–3 are followed by sensorineural deafness in Megaloblastic Anemia being identified in the United States. the second decade. By the third decade, Thiamine-responsive megaloblastic For practical purposes, a diagnosis of patients may have incontinence and anemia (TRMA) and diabetes are due MODY1–3 should be sought in those evidence of neurologic degeneration with to a defect in the thiamine transporter considered to have MODY, and MODY5 cerebellar ataxia and myoclonus by the SLC19A2. TRMA, also known as Rogers should be considered in those with renal fourth decade. A wide arc of neurolog- syndrome, combines megaloblastic manifestations unlikely to be secondary ical manifestations includes autonomic anemia, diabetes, and sensorineural deaf- to the diabetes (1,2,3,4,18,19). Gene neuropathy, loss of sense of taste and ness, which respond by variable degrees mutation analysis is available from Clinical smell, hemiparesis, myoclonus, and to thiamine replacement. The SLC19A2 Laboratory Improvement Amendments absent or reduced reflexes. Magnetic gene encodes a transmembrane protein (CLIA)-certified commercial laboratories, resonance imaging demonstrates brain that acts as the thiamine transporter and as well as research centers in the United atrophy. Psychiatric illness characterized has homology to reduced folate carrier States and Europe. by dementia and short-term memory loss proteins. Cardiac anomalies and abnor- and suicidal ideation are common later in malities of the optic nerves and retina may OTHER SINGLE GENE DEFECTS the evolution of this syndrome. Presumed occur occasionally in the TRMA syndrome. ASSOCIATED WITH DIABETES carriers of this mutation have been Markers of autoimmunity are absent in DUE TO DEFECTIVE INSULIN reported to be predisposed to psychiatric this autosomal recessive form of diabetes. SYNTHESIS/SECRETION illness. Affected individuals have insulin Pharmacologic doses of thiamine may Table 7.1 lists the most common single deficiency requiring insulin for treat- reverse anemia and diabetes early in the gene defects associated with defective ment. The diabetes insipidus responds to course of the disease; however, some- insulin synthesis or secretion that may desmopressin. Some patients also benefit time during and after , thiamine result in clinical diabetes. Those defects from hearing aids for their deafness. supplements may become ineffective, so include the insulin gene (INS) itself, which Gonadal atrophy is also common later in all patients require insulin therapy with dependent on the severity of the mutation, males, although some females have been regular blood transfusions in adulthood result in variable degrees of hyper- reported to have successful . (22). glycemia, ranging from permanent or transient NDM presenting in the first 6–9 Heterozygous carriers of this mutation Pigmented Hypertrichosis and months of life to MODY and (rarely) later have an increased frequency of hearing Insulin-Dependent Diabetes onset of apparent type 1 diabetes (type 1b loss and diabetes. A second Yet another rare syndrome characterized diabetes) or type 2 diabetes. No unique (WFS2) on the long arm of chromosome by pigmented hypertrichosis and insu- features distinguish these forms of clinical 4 (4q22-24) has only been reported in a lin-dependent diabetes (PHID) with other diabetes. Variable patterns are, however, consanguineous Jordanian pedigree (21). multiple associated anomalies is due imparted by the autosomal dominant Here, gastrointestinal bleeding is a major to the SLC29A3 gene, which encodes a versus autosomal recessive forms, as manifestation. The function of the WFS1 transporter for nucleosides, nucleobases, subsequently detailed in the description remains unknown. There are some simi- and nucleoside analogue drugs. Loss- of NDM. larities between Wolfram syndrome and of-function mutations in this gene cause mitochondrial diseases, such as Leber’s PHID, as well as the related syndrome

7–8 Monogenic Forms of Diabetes without diabetes termed the H syndrome. TABLE 7.2. Classification of Neonatal Diabetes Mellitus PHID patients may have severe exocrine TRANSIENT (TNDM) PERMANENT (PNDM) SYNDROME—RARE pancreatic deficiency, as well as 45% 45% 10% pigmented hypertrichotic patches TNDM1 50% KCNJ11 EIF2AK3—spondyloepiphyseal with chronic inflammation 23( ). 70% of TNDM ±DEND syndrome dysplasia, renal anomalies Involves 6q24. 30% INS mutation FOXP3—IPEX (immuno ­d y s ­r e g ­ Maternally Inherited Disturbance of imprinted genes PLAGL (ZAC) and HYMAI caused by: u ­lation, polyendocrinopathy, Diabetes and Deafness 15% ABCC8 enteropathy, X-linked) §§Paternal ±DEND syndrome Maternally inherited diabetes and (sporadic) GLIS3—hypothyroid, hepatic deafness (MIDD) is associated with the §§Paternal duplication 3% GCK*, homozygous fibrosis, glaucoma, cystic kidneys, (dominant transmission) 3243A>G mitochondrial DNA point muta- 2% Others developmental delay §§Relaxation of imprinting maternal IPF1/PDX1*, homozygous tion, a condition that may affect up to hypomethylation—sporadic or PTF1A—pancreatic and cerebellar HNF1β* 1% of patients with diabetes. These gene mutation in the transcription factor agenesis ZFP57 mutations are nearly always inherited RFX6—digestive system defects, from the mother, since mitochondrial DNA known as Mitchell-Riley syndrome TNDM2 is present in oocytes but not in sperma- 15% of TNDM NEUROG3—with congenital tozoa. Therefore, relatives on the maternal ABCC8 (SUR1) mutations malabsorptive diarrhea and enteroendocrine cell dysgenesis side may also have manifestations of mito- 10% of TNDM chondrial gene defects, of which diabetes KCNJ11 (Kir6.2) mutations GATA6 and GATA4—with varying is the third most common systemic mani- degrees of pancreatic agenesis, 5% of TNDM pancreatic exocrine dysfunction festation after cardiac conduction defects Mutations in INS, HNF1β, SLC2A2 and cardiac malformations and cardiomyopathy. Other systemic DEND, developmental delay, epilepsy, neonatal diabetes; GCK, glucokinase; HNF, hepatocyte nuclear factor; manifestations include short stature, INS, insulin gene; Kir, inward rectifying potassium channel; PNDM, permanent neonatal diabetes mellitus; pigmentary retinopathy, lactic acidosis, PTF, pancreas transcription factor; RFX6, regulatory factor X, 6; SUR, sulfonylurea receptor; TNDM, transient neonatal diabetes mellitus. glomerulopathy with focal segmental * Heterozygous mutations in GCK, IPF1/PDX1, and HNF1β cause MODY2, MODY4, and MODY5, respectively. glomerulosclerosis, and strokes with cere- SOURCE: M. A. Sperling, personal communication bellar and cerebral atrophy. Because the 3243A>G mutation results in diminished with younger severe onset but may be Epidemiology ATP production, tissues with high energy managed conservatively, at least at first, The incidence of NDM is estimated to turnover, such as pancreatic islets and in older patients presenting with a pattern be approximately 1:100,000 live births, the cochlear stria vascularis, are affected, suggestive of type 2 diabetes. Genetic though in countries with high rates of explaining the presence of deafness and counseling is important in clarifying the consanguinity, the incidence has been diabetes. The diabetes may be variable in maternal inheritance of this entity to reported to be as high as 1:21,000 live its severity, presenting as diabetic keto- affected family members (24). births (6,25). with NDM have low acidosis in young patients and, therefore, insulin concentrations and generally are being misdiagnosed as type 1 diabetes. NEONATAL DIABETES MELLITUS small at birth, reflecting the important Alternatively, milder forms may present NDM is defined as diabetes that is role of insulin as a fetal growth factor. later in life and be diagnosed as type 2 diagnosed within the first 6 months of About one-half of all infants with NDM diabetes. LHON and MELAS may be part life, though some mutations may cause have permanent diabetes from the outset of the same familial spectrum and are diabetes that manifests up to age 9 (PNDM). The other half of infants affected due to the same gene mutation. Some months or later. Because of the benefit by diabetes in the first weeks to months patients with MIDD have been reported that occurs by transfer from insulin to of life demonstrate the phenomenon of to have classic islet cell antibodies, which sulfonylurea treatment in those with K ATP remission in clinical manifestations of may represent coincident autoimmune channel mutations, it has been suggested diabetes with near normal glucose homeo- mechanisms or represent secondary that K ATP mutations as a cause should be stasis in the absence of any treatment, but response to pancreatic beta cell destruc- sought in those presenting with diabetes relapse at variable times subsequently tion related to the mitochondrial gene up to 9 months of age. However, autoim- (Table 7.2) (25,26,27,28,29,30,31). This mutation and its potential effects on mune diabetes (type 1a diabetes) before condition is termed transient neonatal inducing within the islets. 6 months of life is unlikely to occur, so diabetes (TNDM), and of these cases, investigating the possible genetic basis of two-thirds to three-quarters will be due to The prognosis for MIDD is determined NDM should be undertaken in all babies abnormalities in imprinted genes or meth- by the associated systemic manifes- with diabetes diagnosed when less than ylation defects in the chromosome 6q24 tations, including cardiac failure and 6 months of age and later if they are not region (Table 7.2) (28). The remaining central nervous system dysfunction, and found to have islet antibodies. A classifica- transient forms of NDM have defects in the diabetes requires insulin in those tion of NDM is shown in Table 7.2. components of the K ATP channel, including

7–9 DIABETES IN AMERICA, 3rd Edition

Kir6.2 encoded by KCNJ11 or the SUR1 maternal copy of chromosome 6 renders Despite the near absence of insulin and regulatory subunit encoded by ABCC8; the genes inactive and permits the unop- C-peptide when tested and previous occasionally, INS mutations cause tran- posed action of the paternal genes on this dependence on exogenous insulin for sient NDM. More commonly, mutations in region. The actual genes involved are ZAC treatment, the majority of patients with these KATP subunits, along with mutations ( gene regulating apoptosis and KCNJ11 and ABCC8 mutations respond in INS itself, are responsible for PNDM. the ), also referred to as PLAGL1 to high doses of sulfonylurea therapy Those with KCNJ11 or ABCC8 mutations (pleiomorphic adenoma gene-like 1), and a using (glyburide), which can can be treated with sulfonylurea, thereby second gene termed HYMAI (hydatidiform restore normal insulin secretion in some restoring endogenous insulin secretion, mole associated and imprinted gene). 85% of subjects, along with restoration which improves metabolic control and Those who relapse can sometimes be of the incretin response to oral feeding prevents hypoglycemia and wide glycemic treated with oral hypoglycemic agents and (35). This holds true also for those with excursions (28,29,30,31,32). A second may not necessarily require insulin (28,31). the SUR1 mutations (36). There is debate category of PNDM is due to various gene whether the use of glibenclamide, partic- mutations associated with an array of In terms of genetic counseling, those ularly if started early, also improves the congenital malformations (Table 7.2) with uniparental disomy of chromosome neurological manifestations, since there (3,4,30,31,32,33,34). Because it is not 6 are sporadic. However, duplications is evidence that the glibenclamide also known at the time of clinical presentation of the 6q24 region in the father cause binds to SUR subunits found in nerve, in the newborn whether the diabetes familial paternal duplications, resulting muscle, and brain (17,37,38,39). Clinical will remit or remain permanent, the four in a 50% chance of transmission to each experience supports the notion that there essential mutations that must be checked of their subsequent children. Females is improvement in neurologic sequelae are the 6q24 imprinting defects, KCNJ11, who transmit the duplication do not have (38,39). Glibenclamide therapy at high ABCC8, and INS. affected children, but the sons may pass doses should be gradually introduced; if the risk to their subsequent children. The possible, treatment should not be begun Transient Neonatal Diabetes 6q24 type of TNDM is known as TNDM1, empirically without a genetic diagnosis,

Due to Imprinting Defects whereas the subtypes due to K ATP muta- and should be supervised in a hospital on Chromosome 6q24 tions are known as TNDM2 (28,32). In setting while transitioning the patient off Children born with TNDM are generally the TNDM2 category, comprising some insulin. quite small, weighing approximately 2,000 30% of TNDM, ~15% are due to muta- g at birth. The diabetes is generally diag- tions in ABCC8, ~10% are due to KCNJ11 Most children with K ATP mutations repre- nosed in the first week or so of life, but mutations, and about 5% are caused by sent de novo mutations without a family it may be delayed until age 2–3 months. mutations in INS, HNF1β, and the glucose history, though family history is present Initially, insulin is required for treatment, transporter SLC2A2 (Table 7.2). in some 10%–15%. In these instances of but requirements seem to diminish as a positive family history, sequencing in evidenced by hypoglycemia after injec- Permanent Neonatal Diabetes the affected family members should be tions, and remission occurs at a median of The most common mutations responsible performed because sulfonylureas may still about 3 months of life. Some patients with for PNDM are those in Kir6.2 (KCNJ11) be effective in those with mutations in the this form of TNDM have macroglossia and and INS, followed by SUR1 (ABCC8). KCNJ11 gene. Because the K ATP channel occasionally an umbilical hernia, which is Most patients have isolated diabetes only, mutations usually are dominant, each reminiscent of the Wiedemann-Beckwith but those with severe Kir6.2 mutations affected individual may pass on the gene syndrome, another condition character- and some with a SUR1 mutation also to 50% of their offspring. Some parents ized by defects observed in may have a syndrome characterized labeled as having “type 2 diabetes” actu- the chromosome 11 region rather than by developmental delay, epilepsy, and ally have INS mutations that are recessive chromosome 6q24. During remission, NDM (DEND), or intermediate forms of and can cause NDM in 25% of their insulin responses to various stimuli appear this entity characterized by diabetes and offspring (40). Parents of children with normal, and the infants have near normal some developmental delay but without what appears to be a de novo mutation glucose metabolism. Relapse, if it occurs, epilepsy. Patients are usually diagnosed must be counseled with the possibility of generally does so in the mid-pubertal within the first month, but diagnosis may a second child being affected, as a result years. The pathophysiology of TNDM be delayed beyond age 6 months. Those of germ line mosaicism in which the muta- results from overexpression of the pater- with SUR1 mutations causing NDM have tion is present in the gonads (sperm), but nally expressed genes with extinction of a similar presentation but are less likely not in the peripheral blood. the maternal genes in a region of chromo- to have DEND. As shown in Figure 7.2, some 6q24. A common cause is paternal these mutations cause a gain of function, Mutations in INS that are responsible for uniparental disomy or paternal duplication activating the potassium channel so that it dominantly inherited NDM generally are of 6q24 that is found in familial cases. stays open and, hence, preventing insulin associated with misfolding of the insulin In others, abnormal methylation of the secretion. molecule, which progressively impairs

7–10 Monogenic Forms of Diabetes insulin secretion (33,40). Generally, there in PTF1A (pancreas transcription factor weight (-3.2 SD score vs. -2.0 SD score) are no associated abnormalities in neuro- 1A) cause an autosomal recessive form and earlier diagnosis (median of diagnosis logical function with INS mutations (40). of pancreatic agenesis with exocrine and at age 1 week vs. 10 weeks). Notably, (See the section on Genetic Defects of the endocrine pancreatic dysfunction, as well some patients with the recessively inher- Insulin Gene.) as cerebellar agenesis (47). RFX6 (regula- ited insulin mutations have TNDM, while tory factor X, 6) is a gene that regulates others with homozygous mutations may Other Causes of Neonatal pancreatic development together with not manifest clinical diabetes until the Diabetes Mellitus development of other organs derived teen years or later. Some heterozygous Table 7.2 lists the causes of NDM. from the endoderm; hence, mutations carriers of the recessive mutations Excluding the methylation defects in this gene result in NDM, hypoplastic have diabetes diagnosed in middle life, associated with chromosome 6q24, K ATP or annular pancreas, and duodenal suggesting less severe interference with channel defects, and INS defects, the and jejunal atresia. The constellation of insulin synthesis and resulting in the remaining causes are rare but provide defects caused by mutations in RFX6 phenotype of type 2 diabetes (40). insight into the regulation of pancreas is also known as the Mitchell-Riley formation and insulin secretion (3,4,18). syndrome and carries a poor prognosis GENETIC DEFECTS OF It must be emphasized that milder defects with death in the first year of life 48( ,49). INSULIN PROCESSING in the KCNJ11 gene are associated Mutation in NEUROG3 (Neurogenin3) The prohormone convertases, PC1/3 with “typical type 2 diabetes” and that is associated with NDM plus congenital and PC2, are enzymes that cleave KCNJ11 mutations/polymorphisms are malabsorptive diarrhea and enteroen- peptide hormones and the third most frequent genetic risk factor docrine cell dysgenesis (50). GATA6 and from precursor molecules in neuroen- for type 2 diabetes after TCF7L2 and GATA4 haploinsufficiency are reported to docrine cells, such as the brain, pituitary PPARG (19). As discussed in connection be associated with pancreatic agenesis and adrenal, as well as the islets in the with the monogenic forms of diabetes, and congenital heart defects. These gene pancreas. The enzymes, PCSK (proprotein homozygous mutation in GCK encoding mutations are more common causes of convertase subtilisin/kexin type)-1/3 and the glucokinase enzyme and homozygous pancreatic agenesis than homozygous -2, act in concert to process proinsulin mutation in PDX1 cause severe neonatal PDX1 mutations (51). and to yield the respective diabetes (see Table 7.2). Some mutations hormones in islets, as well as cleaving in the GLUT2 transporter encoded by the GENETIC DEFECTS OF the prohormones for adrenocortical SLC2A2 gene (41) and the HNF1β gene THE INSULIN GENE trophic hormone (ACTH) and gonado- (42) cause autosomal dominant NDM (see INS is located on chromosome 11p15.5, tropic-releasing hormone (GnRH). As a Table 7.2). Of the others listed in Table and defects in INS itself are responsible result, mutations in these genes result in 7.2, EIF2AK3 (eukaryotic initiation factor 2 for a spectrum of disordered glucose secondary hypocortisolism, hypogonad- alpha kinase 3) is likely the most common homeostasis ranging from NDM, either otropic hypogonadism, and diminished and is an autosomal recessive disorder permanent from the outset or initially insulin, but elevated proinsulin. The characterized by multiple congenital transient, as well as later onset apparent abnormal cleavage of pro-opiomelano- malformations, including spondyloepi­ type 2 diabetes. The permanent NDM cortin (POMC) is likely the cause of obesity, physeal dysplasia, renal failure, recurrent phenotypes can be due to dominantly due to faulty signaling to the melanocortin hepatitis, and mental retardation, also inherited mutations in critical regions of receptor family, including the melano- known as the Wolcott-Rallison syndrome the preproinsulin molecule, predicted to cortin-4 receptor involved in appetite (43,44). However, NDM may be the initial cause misfolding of the molecule that regulation. The abnormal processing presentation without other abnormalities. prevents normal insulin secretion (33). and lack of ACTH lead to the secondary In humans, these dominant mutations adrenal insufficiency with diminished The mutations responsible for NDM in represent the second most common cortisol synthesis and secretion. The the FOXP3 gene result in a syndrome cause of PNDM, where clinical manifes- hypogonadotropic hypogonadism is likely termed IPEX, which stands for immune tations may sometimes be delayed to age the result of impaired processing of GnRH dysregulation, with polyendocrinopathy 6–12 months or later, in contrast to the (52,53). The effect of abnormal cleavage of and enteropathy on the X chromosome, more common KCNJ11 mutations that the proinsulin molecule leads to a familial and is characterized by intractable diar- usually manifest within the first 6 months form of dominantly inherited hyperproinsu- rhea, skin rashes, immune dysregulation, of life (3,4,18,33,34). linemia (54,55). Since proinsulin has about and elevated IgE. This is an X-linked 5% of the biological activity of insulin, large condition (45). Mutations in GLIS3 cause Recessive mutations in INS causing NDM amounts of this molecule may compen- an autosomal recessive syndrome charac- also are reported (40). Compared to domi- sate for the lack of normal insulin and lead terized by congenital hypothyroidism, liver nant mutations, these recessive defects to minimal or no disturbances in glucose fibrosis, cystic kidney disease, and glau- cause a more severe form of insulin homeostasis under normal circumstances, coma in addition to NDM (46). Mutations deficiency and are manifest by lower birth but symptoms of glycemic dysfunction

7–11 DIABETES IN AMERICA, 3rd Edition manifest at times of physiological stress, feeding, due to virtual absence of insulin form of insulin receptor mutation defined such as pregnancy, resulting in gestational action, which is essential to enable periph- by the presence of hyperandrogenism, diabetes. A mutation in PC2 results in a eral glucose uptake and utilization, as acanthosis nigricans, and marked insulin dominant form of hyperproinsulinemia well as hypoglycemia during fasting due resistance with glucose intolerance with more severe effects on diminishing to the absence of insulin action, which is and hyperinsulinemia. This syndrome insulin biological activity that can lead necessary to enable storage of glucose as was named type A because it occurs to a type 2 diabetes phenotype. These glycogen. The dysmorphic features consist in younger females with virilization and insulinopathies had been described in the of prominent eyes, low-set and posteriorly accelerated growth, in whom it was 1980s without knowing the actual genetic rotated ears, thick lips, thick skin with believed that the receptor defect was basis (54,55). The PCSK-2 mutations absence of subcutaneous fat, distended primary, to contrast it from type B, a cause greater deficiency in insulin action abdomen, and the appearance of enlarged syndrome found in older females who resulting in mild diabetes, but without genitalia in the male and cystic ovaries in have circulating antibodies to the insulin obesity; whereas the PCSK-1/3 mutation the female. Birth weight is on the order receptor. Given the focus on the meta- is associated with obesity and low cortisol, of ≤2,000 g. Insulin concentrations in the bolic syndrome, in which polycystic ovary generally not found in the PCSK-2 muta- blood are around 1,000 microIU/mL (6,000 syndrome (PCOS) is a major feature and tions. The incidence of these mutations is pmol/mL), and C-peptide concentrations there are also variable degrees of insulin not known; they appear to be very rare. are markedly elevated. Exogenous insulin is resistance, hyperinsulinemia, and carbo- ineffective; insulin-like growth factor-1 may hydrate intolerance, it may be that the GENETIC DEFECTS IN INSULIN have some benefits, but data are sparse insulin resistance syndrome type A is not ACTION: INSULIN RECEPTOR and the indication is considered off-label a distinct entity (58). AND POSTRECEPTOR DEFECTS for investigational use only. Death usually The insulin receptor gene is located on occurs within 1–2 years after birth (57). ABNORMAL FUNCTION OF CILIA chromosome 19p13.2 and codes for a Alstrom syndrome is a rare disease heterotetramer consisting of two extra- Rabson-Mendenhall Syndrome with incidence of <1:100,000 births in cellular α subunits that bind insulin and Patients with Rabson-Mendenhall European populations due to a mutation two membrane-spanning β subunits with syndrome have some residual insulin in the ALMS1 gene, located on chromo- an intracellular tyrosine kinase domain action and, therefore, somewhat different some 2p13. This gene codes for a protein that initiates a signaling cascade. Both dysmorphic features, primarily involving that is believed to be involved in the orga- subunits are encoded by the single gene, abnormalities of teeth and nails, which nization of microtubules and transport of and mutations in this gene may cause are dysplastic and differ from those with various materials, as well as the normal distinct syndromes depending on the Donohue syndrome. Pineal hyperplasia function of cilia. The protein plays a role severity of disrupted insulin signaling. has been reported as well in Rabson- in processes such as hearing, vision, the As many as 0.1%–1% of the population Mendenhall syndrome. Because the regulation of body weight, and normal is suspected of having some mutations mutation is not as severe, these patients function of the heart, lungs, kidneys, that interfere with insulin action, but most are not at risk of dying early and, later in liver, and pancreatic insulin synthesis can be overcome by increasing insulin life, manifest the classic signs of insulin and secretion. Clinically, the diagnosis secretion (56). Among mutations that resistance, including acanthosis nigri- depends on the presence of the onset of impair insulin action and cause diabetes cans and hirsutism. They also manifest retinal dystrophy with photodysphoria are three syndromes: Donohue syndrome postprandial hyperglycemia and fasting and either obesity or cardiomyopathy in (Leprechaunism), Rabson-Mendenhall hypoglycemia for reasons discussed an infant. During childhood, adolescence, syndrome, and insulin resistance for the Donohue syndrome. Those with and adulthood, additional phenotypes syndrome type A. All are rare, and no severe forms of Rabson-Mendenhall evolve, including insulin resistant diabetes, data on the precise incidences of these syndrome may develop diabetic ketoac- which manifests at around the time of syndromes are available. idosis because of a decline in later life puberty and is associated with acanthosis in the ability to maintain high insulin nigricans. The clinical manifestations Donohue Syndrome concentrations required to overcome the of cardiomyopathy may not become Donohue syndrome is the most severe and insulin resistance. Although there is no apparent until adolescence. Nonalcoholic rare form of insulin resistance and is due to absolute genotype-phenotype correlation, develops during puberty. near total absence of insulin receptor func- in general, insulin receptor mutations Chronic renal failure appears in about tion. Affected individuals are characterized that retain some residual insulin binding 25% of patients during the second decade by severe intrauterine growth retardation, correlate with prolonged survival (57). of life. The differential diagnosis should dysmorphic features, hyperinsulinemia, include Bardet-Biedl syndrome, which has and abnormal glucose homeostasis. The Insulin Resistance Syndrome Type A similar clinical features and, like Alstrom abnormal glucose homeostasis is charac- The insulin resistance syndrome type A syndrome, is generally classified with the terized by hyperglycemia during and after is a relatively mild and more common ciliopathies (18,59).

7–12 Monogenic Forms of Diabetes

CONCLUDING REMARKS FOR common forms of what clinically appears §§ www.diabetesgenes.org, an information MONOGENIC DIABETES to be type 1 and type 2 diabetes. Correct resource on genetic types of diabetes Monogenic forms of diabetes are diagnosis requires molecular confirmation, located in the United Kingdom at the uncommon, ranging in prevalence from which enables correct treatment, avoids University of Exeter ~2%–3% of new cases of diabetes for MODY unnecessary use of insulin or other inap- §§ www.kovlerdiabetescenter.org/portfolio/ to 1:100,000 births for NDM and rarer propriate agents, and permits genetic monogenic-diabetes-registry-genetics- still for the syndromic forms of diabetes. counseling. As the ability to sequence of-diabetes-studies, a monogenic Defining their genetic bases has shed light genes at reduced costs becomes an diabetes registry located in the United on the complexity of pancreas formation established part of medical management States at the University of Chicago and function and the regulation of insulin (60,61), these discoveries are likely to §§ www.genetests.org, a compendium secretion. In turn, knowing the genes have wide impact on practice. of sites and locations of mutational regulating these processes has enabled analysis performed for research or via a clearer understanding of the nature of RESOURCES CLIA-certified laboratories MODY and NDM, enabled rational treat- The following websites provide access to ments based on the pharmacogenetics of expert advice and assistance with possible

the KATP channel, and demonstrated that mutation analysis in patients suspected of the same genes are involved in the more having monogenic forms of diabetes:

GENETIC LIPODYSTROPHIES

A classification of the genetic lipodystro- care hospital. Urbanek et al. (63) deter- AUTOSOMAL RECESSIVE phies is presented in Table 7.3. Detailed mined variants in LMNA in 43 women LIPODYSTROPHIES discussion of the most common types of presenting with PCOS and identified two Congenital Generalized Lipodystrophy genetic lipodystrophies that predispose missense novel variants. None of the In 1954, Berardinelli from Rio de Janeiro, patients to diabetes follows the listing and variants previously found in patients with Brazil, reported two boys (2 and 6 years notations in Table 7.3. FPL were observed. Further analysis of old) with an undiagnosed endocrine-met- these variants in a case-control study of abolic syndrome presenting with marked EPIDEMIOLOGY 624 women with PCOS and 544 controls hepatosplenomegaly, acromegaloid gigan- Overall, based on literature reports of failed to show any statistically significant tism, fatty liver, and (64). fewer than 2,000 patients, the estimated association with PCOS. Thus, the authors In 1959, Seip reported a detailed descrip- prevalence of genetic lipodystrophies concluded that genetic variation in LMNA tion of the phenotype of three additional may be less than 1 in a million. The auto- was not a major contributor to the etiology patients and highlighted the onset of somal recessive congenital generalized of PCOS. generalized lipodystrophy from birth, and lipodystrophy (CGL) has been reported in thus, they were recognized as having CGL about 300–500 patients, with clustering Thus, precise estimates for popula- (65). The diagnosis of CGL is usually made of patients reported from Lebanon and tion prevalence of these monogenic at birth or soon thereafter. However, some Brazil where there is increased prevalence syndromes are not available. However, patients may have a normal appearance of consanguinity. The autosomal dominant it is expected that as investigators at birth and subsequently lose body fat. familial partial lipodystrophy (FPL) has collect data from next generation, whole been reported in ~500–1,000 patients. genome, or exome sequencing in healthy Overall, approximately 300–500 cases of Affected females are recognized easily controls and patients with diabetes, this syndrome have been reported thus far and, thus, are reported more often than , and PCOS, better (66,67,68). Clusters of cases have been males. estimates of the prevalences of these reported from Brazil and Lebanon from disorders will emerge. The population regions where there is an increased prev- Dutour et al. (62) studied 100 consecutive prevalence of autosomal recessive alence of consanguinity (69,70). Based patients from Marseille, France, with the syndromes may be estimated based on the assumption that only one-quarter presenting with on the frequency of heterozygous vari- of the actual number of cases may be obesity, diabetes, or thyroid disorders and ants in candidate genes. Such studies reported in the literature, the estimated identified only one male and one female are underway; however, most subjects prevalence of CGL is about 1 in 10 million patient with missense mutations in the participating in these consortia are of (68). lamin A/C (LMNA) gene. Of these, only European origin. Enrollment of many the female patient was described to have subjects from all over the world will Patients with CGL have the appearance slight lipoatrophy. Thus, the prevalence of be required to determine the world- of extreme muscularity at birth due to FPL could be ~1% among those presenting wide prevalence of these monogenic near complete absence of with the metabolic syndrome to a tertiary syndromes. in the body. They are known to grow at

7–13 DIABETES IN AMERICA, 3rd Edition an accelerated rate during early child- childhood or adolescence (71) and can later on in life (74,75), and many patients hood, and the bone age may be greater be very severe, involving extensive areas develop splenic enlargement. In females, than the chronological age at this time of the body. Besides the typical neck, mild hirsutism, clitoromegaly, and irreg- (71,72). They have a markedly increased axillae, and groin regions, acanthosis ular menstrual periods are common, and appetite and slight enlargement of the nigricans can also affect the trunk, hands, some present with primary or secondary hands, feet, and mandible, termed acro- knees, elbows, and ankles. Liver enlarge- amenorrhea and polycystic ovaries. megaloid features. Nearly all patients ment due to hepatic steatosis is usually Some patients have hypertrophic cardio- have an umbilical prominence (71,73). noticed during infancy. A few patients myopathy and mild mental retardation Acanthosis nigricans is noted later during develop cirrhosis and its complications (76,77).

TABLE 7.3. Classification, Clinical Features, and Pathogenetic and Molecular Bases of Genetic Lipodystrophies With Predisposition to Diabetes SUBTYPES OMIM SYNDROME (GENE) NUMBER* KEY CLINICAL FEATURES MOLECULAR BASIS I. Autosomal recessive lipodystrophies Congenital CGL1 (AGPAT2) 608594 Lack of metabolically active adipose tissue AGPATs are key enzymes for synthesis of triglyceride and generalized since birth. phospholipids. AGPAT2 isoform is highly expressed in lipodystrophy (CGL)† adipose tissue. CGL2 (BSCL2) 269700 Lack of both metabolically active and BSCL2 encodes seipin, which appears to play a role in mechanical adipose tissue since birth, droplet formation and in adipocyte differentiation. mild mental retardation, cardiomyopathy. CGL3 (CAV1) 612526 Single patient reported. Extreme lack of Caveolin-1 is an integral component of caveolae, present body fat, short stature, and vitamin D on adipocyte membranes. Caveolin-1 binds fatty acids resistance. and translocates them to lipid droplets. CGL4 (PTRF) 613327 Extreme lack of body fat, congenital PTRF (also known as cavin) is involved in biogenesis of myopathy, pyloric stenosis, and caveolae and regulates expression of caveolin-1 and -3. cardiomyopathy. Mandibuloacral Type A (LMNA) 248370 Skeletal anomalies, loss of subcutaneous Defective lamins A and C may disrupt nuclear function, dysplasia (MAD)† fat from the extremities and trunk. resulting in death of adipocytes and skeletal tissue. Type B 608612 Skeletal anomalies, generalized loss of Zinc metalloproteinase is critical for posttranslational (ZMPSTE24) fat, premature renal failure, progeroid processing of prelamin A to its mature form, lamin A. features. Accumulation of farnesylated prelamin A may be toxic and disrupt nuclear function in several tissues. Familial partial FPLD5 (CIDEC) 615238 Single patient reported. Histopathology of subcutaneous fat showed multilocular, lipodystrophy (FPL) small lipid droplets in adipocytes. II. Autosomal dominant lipodystrophies Familial partial FPLD1, Kobberling NA Loss of subcutaneous fat from the Molecular basis is unknown. lipodystrophy (FPL) variety (unknown) extremities. FPLD2, Dunnigan 151660 Loss of subcutaneous fat from the LMNA encodes nuclear lamina proteins, lamins A and C. variety (LMNA) extremities and trunk (sparing the face Defective lamins A and C may disrupt nuclear function, and neck) at puberty. resulting in death of adipocytes.

FPLD3 (PPARG) 604367 Loss of subcutaneous fat from the distal PPARγ is essential for adipogenesis. Dominant negative extremities. PPARγ mutations may inhibit adipocyte differentiation. FPLD4 (PLIN1) 613877 Loss of subcutaneous fat from the Perilipin is an integral component of lipid droplet extremities. membranes. Histology revealed small adipocytes with increased fibrosis of adipose tissue. (AKT2) NA Single family reported with loss of AKT2 is involved in adipocyte differentiation and subcutaneous fat from the extremities. downstream insulin receptor signaling. Atypical progeroid (LMNA) NA Variable loss of subcutaneous fat. Different heterozygous mutations in LMNA cause partial syndrome or generalized lipodystrophy.

SHORT syndrome (PIK3R1) 269880 Short stature, Hyperextensibility or PIK3R1 encodes the p85α regulatory unit of inguinal hernia, Ocular depression, Rieger phosphatidylinositol 3 kinase, which is known to play a anomaly, and Teething delay role in insulin signaling. AGPAT, 1-acylglycerol-3-phosphate O-acyltransferase; AKT2, v-AKT murine thymoma oncogene homolog 2; BSCL2, Berardinelli-Seip congenital lipodystrophy 2; CAV1, caveolin-1; CGL, congenital generalized lipodystrophy; CIDEC, cell death-inducing DNA fragmentation factor a-like effector c; FPLD, familial partial lipodystrophy; LMNA, lamin A/C; NA, not applicable; PLIN1, perilipin 1; PPAR, peroxisome proliferator-activated receptor; PTRF, polymerase I and transcript release factor. * The Online Mendelian Inheritance in Man (OMIM) is an online catalog of human genes and genetic disorders. OMIM can be accessed at omim.org. † Additional rare types for which the genetic bases are not known are not included. SOURCE: Reference 67, copyright © 2011 Endocrine Society, adapted with permission.

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CGL is characterized by high levels of FIGURE 7.4. Severe Islet Amyloidosis in Congenital Generalized Lipodystrophy fasting and postprandial insulin, noted very early in life (71). This extreme A B hyperinsulinemia suggests severe insulin resistance in childhood. Patients also have extreme hypertriglyceridemia, which can predispose them to recurrent episodes of acute pancreatitis (73). The levels of HDL cholesterol also tend to be low. The C D onset of diabetes usually occurs during the pubertal years; however, diabetes has been reported as early as 6 weeks of life. In some patients, diabetes occurs during the neonatal period and is subsequently followed by a euglycemic period; they again develop diabetes after puberty. Garg (A) Hematoxylin and eosin stain showing marked hyaline deposits in the islet of Langerhans. The hyaline deposits et al. (78) reported marked amyloidosis stained red on Congo red staining and showed apple-green birefringence on polarization diagnostic of amyloid. of pancreatic islets and beta cell atrophy (B) Immunostaining with anti- antibody showing intense staining for amylin in an islet with amyloidosis. (C) Immunostaining with anti-insulin antibody showing marked reduction of beta cells in an islet with amyloidosis. on autopsy of a young adult female with (D) Immunostaining with anti- antibody showing presence of alpha cells in an islet with amyloidosis. CGL (Figure 7.4). Thus, it appears that The patient had congenital generalized lipodystrophy (CGL) type 1, and histopathology was studied on autopsy. prolonged and extreme insulin resistance SOURCE: Reference 78, copyright © 1996 American Diabetes Association, reprinted with permission from birth causes amyloidosis and beta been reported to be linked to CGL. A homo- lack of triglyceride in the cell death due to similar mechanisms zygous nonsense mutation in caveolin-1 adipocytes or by lack of phospholipid involved in patients with type 2 diabetes. (CAV1) has been reported in a single patient synthesis, which may affect adipocyte Diabetes is challenging to manage in CGL with CGL type 3 (84). CGL type 4 has function. Most patients harbor null patients and may require extremely high been linked to mutations in polymerase I mutations with no enzymatic activity doses of insulin to control hyperglycemia and transcript release factor (PTRF) (85). demonstrable in vitro. However, some (79). Patients are reportedly resistant to compound heterozygotes have a null ketosis due to endogenous hyperinsu- CGL Type 1: AGPAT2 Mutations. Besides and a missense mutation (with some linemia. Since patients with CGL have the clinical features mentioned above, residual enzymatic activity), and a few extreme paucity of body fat, they have patients with CGL type 1 have an have homozygous missense mutations. markedly low levels of serum adipocy- increased prevalence of focal lytic lesions However, the type of mutation does not tokines, such as and in the appendicular skeleton. Metabolically determine the severity of lipodystrophy, (80,81). Extreme hypoleptinemia may active adipose tissue located in most as all the patients have near complete loss contribute to excessive appetite and meta- subcutaneous areas, intra-abdominal and of adipose tissue. Nearly all patients of bolic complications in patients with CGL. intrathoracic regions, and bone marrow is African origin harbor the founder mutation, totally deficient, but mechanical adipose c.589-2A>G (p.Val197Glufs*32), on one or At this time, four distinct genetic varieties of tissue, which is located in the palms, soles, both alleles (77). CGL are known. However, type 1 and type under the scalp, orbital, and periartic- 2 are the most common subtypes of CGL. ular regions, is spared (Figure 7.5A–C) CGL Type 2: BSCL2 Mutations. Patients The first locus for CGL was discovered on (73,86,87). with CGL type 2 display an increased chromosome 9q34 using a genome-wide prevalence of cardiomyopathy and mild linkage analysis approach by Garg et al. There are 11 distinct isoforms of AGPATs, mental retardation (76,77). Both metaboli- (82). The authors also reported genetic the key enzymes belonging to the acyl- cally active and mechanical adipose tissue heterogeneity and a possibility of another transferase family, which play a critical are lacking in CGL type 2 patients (Figure locus. Subsequently, the second locus was role in the biosynthesis of triglycerides 7.5D–F) (86,87). Serum leptin levels are found on chromosome 11q13 (70). By posi- and phospholipids in cells (Figure 7.6) lower in patients with CGL type 2 than tional cloning of the 9q34 region, Agarwal (83,88). The AGPATs acylate lysophos- type 1, but serum adiponectin levels are et al. (83) identified mutations in the 1-acyl- phatidic acid (1-acylglycerol-3-phosphate) higher (81); the reason for this observation glycerol-3-phosphate-O-acyltransferase 2 to phosphatidic acid (1, 2 diacylglycer- is not clear. (AGPAT2) gene in patients with CGL type 1. ol-3-phosphate). The AGPAT2 isoform is Mutations in a new gene called Berardinelli- highly expressed in the adipose tissue. It BSCL2 encodes a 398 trans- Seip Congenital Lipodystrophy 2 (BSCL2) is also expressed in the liver and skeletal membrane protein called seipin (70). on chromosome 11q13 were reported by muscle, but at lower levels. Thus, AGPAT2 Research suggests a role for seipin in Magre et al. (70). Two new genes have deficiency may cause lipodystrophy by lipid droplet formation and in adipocyte

7–15 DIABETES IN AMERICA, 3rd Edition

FIGURE 7.5. Clinical Features of Patients With Congenital Generalized Lipodystrophy Types 1 and 2

(A) Anterior view of a 19-year-old female of African American origin with congenital generalized lipodystrophy type 1, showing generalized lack of fat, extreme muscularity, and acromegaloid features. She developed diabetes at age 14 years. Acanthosis nigricans was present in the neck, axillae, and groin. She had a homozygous splice site mutation (c.589-2A>G; p.Val197Glufs*32) in AGPAT2. (B) Palms of the patient shown in panel A showing normal subcutaneous fat. (C) Soles of the patient shown in panel A showing normal subcutaneous fat. (D) Anterior view of an 8-year-old boy from Spain with congenital generalized lipodystrophy type 2, showing generalized lack of fat and extreme muscularity. Only mild acanthosis nigricans was present in the neck and axillae. He had compound heterozygous mutations in BSCL2: c.193delCinsGGA (p.Pro65Glyfs*28) and c.325_326insA (p.Thr109Asnfs*5). (E) The palms of the patient shown in panel D showing loss of subcutaneous fat. (F) Soles of the patient shown in panel D showing loss of subcutaneous fat. SOURCE: Panel A, Reference 87, copyright © 2009 Elsevier B.V., reprinted with permission. Panels B-F, A. Garg, personal communication. differentiation (89,90). Studies with the cell, and they may contribute this material also contribute to lipid droplet formation seipin homolog in yeast suggest that it to lipid droplets. Thus, caveolin-1 mutation (Figure 7.6) (85). may play a role in fusion of lipid droplets may cause lipodystrophy due to defective (Figure 7.6). Nearly all BSCL2 mutations lipid droplet formation (Figure 7.6). Molecular Diagnosis. Patients with CGL reported in patients with CGL type 2 are should be easily diagnosed at birth or null. CGL Type 4: PTRF Mutations. CGL soon thereafter by pediatricians. The two type 4 due to PTRF mutations has been main types of CGL can be distinguished CGL Type 3: Caveolin-1 Mutation. reported in approximately 20 patients based upon their clinical features. CGL CGL type 3 has only been reported in (85,92,93). These patients have a peculiar type 4 has a distinct phenotype of myop- a Brazilian girl who had short stature phenotype besides having CGL. They athy. Molecular diagnosis at research and presumed vitamin D resistance (84). manifest developmental delay, as well as laboratories is available for confirmation. This patient also had hepatospleno- congenital myopathy with percussion-in- Molecular diagnosis may be helpful for megaly with hepatic steatosis and onset duced myoedema, pyloric stenosis, and understanding the risk of having another of diabetes at age 13 years. Additionally, atlantoaxial instability (94,95). Patients child with CGL and can also be used for she had acanthosis nigricans and severe with CGL type 4 also have increased levels prenatal screening. Besides patients with hypertriglyceridemia. She had primary of creatine kinase in the serum, sugges- known genotypes, a few patients with CGL amenorrhea at age 20 years and func- tive of myopathy. These patients are do not have mutations in any of the four tional megaesophagus. The patient had prone to developing serious arrhythmias, known loci, and thus, there may be novel well-preserved mechanical and bone such as catecholaminergic polymor- genes to be discovered for CGL. marrow fat. phic ventricular tachycardia, prolonged QT interval, and sudden death (92,93). Differential Diagnosis. CGL should be Caveolin-1 is expressed in abundance Patients have well-preserved mechanical differentiated from acquired general- in caveolae, specialized microdomains and bone marrow fat. PTRF, also known ized lipodystrophy, Donohue syndrome, on cell membranes of adipocytes (91). as cavin, plays a critical role in the biogen- atypical , generalized Caveolae bring phospholipids and other esis of caveolae. PTRF regulates the lipodystrophy due to LMNA mutations, lipid material from outside to inside the expression of caveolin-1 and -3 and may and neonatal progeroid syndrome.

7–16 Monogenic Forms of Diabetes

FIGURE 7.6. Lipid Droplet Formation in Adipocytes AUTOSOMAL DOMINANT LIPODYSTROPHIES Familial Partial Lipodystrophies The characteristic clinical feature of patients with FPL is the loss of body fat from the upper and lower extremities, as well as in some patients, from the truncal region (101,102). Most patients follow an autosomal dominant inheritance pattern. The phenotype can be easily recognized in affected women; however, recognition of men affected with FPL is difficult because even some normal healthy men also appear very muscular and have markedly low subcutaneous fat. Therefore, most of the ascertainment of affected patients and pedigrees has been through female probands. The diagnosis should be suspected in patients who show signs of Lipid droplets (LD) are organelles that store triglycerides (TG) intracellularly. In the adipocytes, they form as budding insulin resistance early in life manifested vesicles at the endoplasmic reticulum (ER) that fuse together to form one large LD. Many proteins, such as CIDEC (shown in blue triangles), seipin (pink squares), and perilipin 1 (green circles), are present on the LD membrane. by acanthosis nigricans or PCOS and CIDEC and seipin may be involved in fusion of LDs to form a larger LD, whereas perilipin 1 is essential for lipid early onset of diabetes and severe hyper- storage and hormone-mediated lipolysis. Caveolae are formed from lipid rafts on the cell surface, which include triglyceridemia. Patients who have these cholesterol (yellow symbols), glycosphingolipids (green symbols), and caveolin-1 (black hairpin-like symbols). Endocytosis of caveolae forms caveolin vesicles that may directly merge with lipid droplets and thus translocate fatty manifestations but do not have generalized acids to LDs. PTRF controls expression of caveolin-1 and -3. The classic and alternative pathways involved in the obesity should be suspected to have FPL, biosynthesis of TG are shown inside the lipid droplet. In the adipose tissue, TG synthesis requires glycerol-3-phos- phate as the initial substrate (classical pathway), whereas in the small intestine, synthesis of TG can occur via an and physicians should examine for fat loss alternative pathway using monoacylglycerol (MAG) as the initial substrate. Acylation of glycerol-3-phosphate using from the extremities, particularly from fatty acyl coenzyme A (FA-CoA) at the sn-1 position is catalyzed by glycerol-3-phosphate acyltransferases (GPATs), resulting in the formation of 1-acylglycerol-3-phosphate or lysophosphatidic acid (LPA). LPA is then acylated at the the gluteal region. Many patients gain fat sn-2 position by AGPATs to yield phosphatidic acid (PA). Removal of phosphate group from PA by PA phosphatases in nonlipodystrophic regions, such as the (PAP) produces diacylglycerol (DAG). Further acylation of DAG at the sn-3 position by DAG acyltransferases (DGATs) finally produces TG. Lamin A/C are integral components of nuclear lamina (shown in blue color) and interact with face, under the chin, posteriorly in the neck nuclear membrane proteins, as well as chromatin. Zinc metalloproteinase (ZMPSTE24) is critical for posttranslational resulting in a dorsocervical hump, and in processing of prelamin A to its mature form, lamin A. SOURCE: Reference 87, copyright © 2009 Elsevier B.V., adapted with permission; and Reference 91, copyright © the intra-abdominal region. Some women 2008 Endocrine Society, reprinted with permission also gain fat in the perineal region, espe- cially in the labia majora and pubic region. Mandibuloacral Dysplasia which is involved in posttranslational Several distinct subtypes of FPL have Associated Lipodystrophy processing of prelamin A to mature lamin been reported, and the molecular genetic Mandibuloacral dysplasia (MAD) is a rare A (98). Hyperinsulinemia, insulin resistance, bases of four distinct subtypes are known. autosomal recessive disorder reported in impaired glucose tolerance, diabetes, and about 40 patients so far. It is characterized hyperlipidemia have been reported but are Type 1: Kobberling Variety (FPLD1). by hypoplasia of the mandible and clavi- usually mild to moderate in severity (96). After the original description by Dunnigan cles, as well as acro-osteolysis (resorption et al. (101), Kobberling et al. (102) from of the terminal phalanges) (96,97). Other Familial Partial Lipodystrophy Germany reported a distinct phenotype clinical features include delayed closure of Due to CIDEC Mutation (FPLD5) of FPL. The Kobberling variety is less cranial sutures, joint contractures, mottled A 19-year-old Ecuadorian girl with auto- common and has been reported in only cutaneous pigmentation, and short stature. somal recessive FPL has been reported to two small pedigrees and four sporadic Patients also show “progeroid features,” harbor a homozygous missense mutation cases (102,103,4 10 ). The age of onset of such as bird-like faces, high-pitched voice, in cell death-inducing DNA fragmentation lipodystrophy and the mode of inheritance skin atrophy, pigmentation, alopecia, and factor a-like effector c (CIDEC) (99). She are not clear. On the basis of clinical nail dysplasia. Patients with MAD either developed at age 14 findings, the loss of adipose tissue in the have partial loss of subcutaneous fat from years and also had hypertriglyceridemia Kobberling variety is restricted to extremi- the extremities (type A) due to mutations and hypertension. On biopsy of subcuta- ties only. Patients have normal amounts of in LMNA (97) or more generalized loss of neous fat, multilocular, small lipid droplets fat in the face area and may have normal, subcutaneous fat involving the face, trunk, were reported in adipocytes consistent or even excess, subcutaneous fat in the and extremities (type B) due to mutations with the findings in a mouse model of FPL truncal area. The genetic basis for this in zinc metalloproteinase (ZMPSTE24), (99,100). particular variety is unknown.

7–17 DIABETES IN AMERICA, 3rd Edition

Type 2: Dunnigan Variety Associated FIGURE 7.7. Clinical Features of Patients With Familial Partial Lipodystrophy With LMNA Mutations (FPLD2). FPL type 2, the Dunnigan variety (FPLD), was initially described in an abstract form by Ozer et al. (105), who reported a 52-year-old woman and several members of her family with “fat neck syndrome” but loss of subcutaneous fat from the limbs. All affected patients had hypertriglyceri- demia, and some had impaired glucose tolerance and diabetes. Subsequently, Dunnigan et al. (101) provided a detailed phenotypic description of two families with an autosomal dominant variety of FPL. Initial reports of this syndrome were restricted to the description of affected females only, possibly because recog- nition of affected males was difficult. It was also thought that the syndrome may have an X-linked dominant inheritance pattern with lethality in hemizygous males (103). Ascertainment of additional pedigrees subsequently showed that it clearly followed an autosomal dominant inheritance pattern (106). Since the orig- inal description, approximately 500–1,000 patients may have been reported with (A) A 28-year-old Hispanic woman with familial partial lipodystrophy, Dunnigan variety (FPL, type 2) due to heterozy- FPLD. Most are of European origin, but gous missense mutation in the LMNA gene. She had loss of fat from the extremities and trunk beginning at puberty and had excess fat accumulation in the face, neck, and perineal region. She had acanthosis nigricans in the axillae other ethnicities have been reported to and groins. (B) A 64-year-old white woman with familial partial lipodystrophy (FPL, type 3) due to heterozygous have FPLD, such as Asian Indians and missense mutation in PPARG. She had loss of fat from the face, extremities and trunk and had excess fat accumula- tion in the truncal region. (C) A 48-year-old white woman with familial partial lipodystrophy (FPL, unknown variety). African American patients. She had loss of fat from the extremities but had excess fat accumulation in the face, neck, and truncal region. SOURCE: Panel A, Reference 107, copyright © 2012 McGraw Hill, reprinted with permission. Panel B, Reference The onset of FPLD occurs in late child- 119, copyright © 2002 Endocrine Society, reprinted with permission. Panel C, A. Garg, personal communication. hood or at puberty. Therefore, children at birth have normal body fat distribution. (109). Excess accumulation of fat is seen multiparity and excess fat deposition Even as young children, their appear- in the intra-abdominal and intrathoracic in the nonlipodystrophic regions, such ance is completely normal, but during regions as well. Some patients develop a as the chin. Autopsy study in a patient late childhood or with onset of puberty, round face, dorsocervical hump, double revealed severe amyloidosis of pancreatic patients start losing subcutaneous fat in chin, and enlargement of supraclavic- islets, which may be related to the onset the upper and lower extremities, including ular fat pads, and these patients are of hyperglycemia and diabetes in patients the gluteal region. At the same time, they mistaken as having Cushing’s syndrome. with FPLD (111). Some patients with FPLD start gaining subcutaneous fat in nonli- Although the data are limited, it appears also develop cardiomyopathies, which podystrophic regions, such as the face, that affected women are more severely manifest both as cardiac conduction neck, and in the intra-abdominal region affected by metabolic derangements system disturbances resulting in atrial (Figure 7.7A) (107). Acanthosis nigricans than affected males (108,110). The prev- fibrillation requiring pacemaker implan- also appears at the time of puberty alence of diabetes in affected women is tation and premature congestive heart and approximately one-third of women approximately 50% compared to 20% in failure requiring cardiac transplantation affected with FPLD have irregular periods, the affected men (108). Women also show (1123 ,11 ). oligoamenorrhea, and hirsutism sugges- extreme hypertriglyceridemia and low tive of PCOS (108). Characterization of levels of HDL cholesterol and increased Using a genome-wide linkage analysis the phenotype by whole body magnetic prevalence of coronary heart disease. approach, Peters et al. (106) reported resonance imaging has revealed marked the FPLD locus on chromosome 1q21-22 loss of subcutaneous fat from the extrem- Diabetes usually develops after the in five large informative pedigrees. ities but preservation of intermuscular second decade of life, and the risk factors Subsequently, Cao and Hegele (114) fat present in between the muscle fascia for development of diabetes include screened for candidate genes in the

7–18 Monogenic Forms of Diabetes chromosome 1q21 region and reported a these mutations lead to severe congestive with FPL of European origin. All of them single missense mutation, p.Arg482Gln heart failure in the third decade, resulting had fatty liver, hypertriglyceridemia, and in LMNA in a Canadian pedigree. Since in a need for cardiac transplantation. hyperinsulinemia. Three patients had then, several missense mutations in LMNA diabetes, and four had reduced levels of have been reported in patients with FPLD, By clinical examination, it is difficult HDL cholesterol. Lipodystrophy was most most of them affecting the C-terminal to diagnose affected men, as well striking in the lower limbs and femoro- amino acids (115,116,117). as prepubertal children, with FPLD. gluteal depots. Acanthosis nigricans was Therefore, molecular diagnosis may be present in all probands, and two patients Mutations in LMNA interestingly have helpful in characterizing these patients. also had a cushingoid appearance. The also been reported in various other disor- Furthermore, genotyping for mutations investigators reported the histopathology ders, such as idiopathic cardiomyopathy, which are also associated with cardiomy- of subcutaneous adipose tissue from four muscular dystrophies, Hutchison-Gilford opathies may be particularly important for patients with PLIN1 mutations, revealing Progeria syndrome, Charcot-Marie-Tooth predicting prognosis. reduced size of adipocytes and increased neuropathy, MAD, and atypical progeroid macrophage infiltration and adipose tissue syndrome (117). Some patients with FPLD Type 3: FPL Associated With PPARG fibrosis. Upon overexpression ofPLIN1 in harboring LMNA mutations show features Mutations (FPLD3). Using a candidate 3T3-L1 preadipocytes, the investigators of overlap syndrome and have some mild gene approach, Agarwal and Garg (119) noted that mutant perilipin 1 resulted in muscular dystrophy, as well as cardiac identified a heterozygous missense muta- smaller lipid droplets compared to the conduction system disturbances (112,113). tion, p.Arg397Cys, in PPARG, a gene that wild type perilipin 1 (121). Perilipin 1 is Thus, LMNA mutations may also cause a encodes peroxisome proliferator-activated the most abundant protein coating lipid multisystem dystrophy syndrome that can receptor gamma (PPARγ), in a 64-year-old droplets in adipocytes (122). It is essential affect various tissues, including adipose, woman who presented with diabetes, for formation and maturation of lipid drop- cardiac, skeletal muscle, nerve, cutaneous, hypertriglyceridemia, hypertension, and lets and storage of triglycerides, as well and skeletal tissue (112). hirsutism. She also had lipodystrophy of as release of fatty acids from these lipid the face and extremities that was noticed droplets. Mutant forms of perilipin 1 fail to How specific mutations in LMNA cause much later in life (Figure 7.7B). Since then, bind to AB-hydrolase-containing 5, which adipocyte loss from mainly extremities approximately 30 patients with FPL due results in constitutive coactivation of remains unknown. Disruption of interac- PARGto P mutations have been reported adipose triglyceride lipase and increased tions of lamins A and C with chromatin (120). These patients manifest insulin basal lipolysis (123). or other nuclear lamina proteins during resistance with diabetes, hypertension, the cell division may lead to premature and hypertriglyceridemia. The age of Type AKT2: FPL Associated With AKT2 cell death or apoptosis of adipocytes. onset of this variety of lipodystrophy is not Mutations. George et al. (124) reported The accumulation of excess fat in nonli- precisely known but may range from the a heterozygous missense mutation, podystropic regions may be a secondary second decade or later. Also, the pattern p.Arg274His, in AKT2 in four subjects phenomenon. of progression of fat loss is not very clear. from a family who presented with insulin Patients have more fat loss from the resistance and diabetes. The proband, a Most missense mutations in FPLD accu- distal extremities than from the proximal 35-year-old Caucasian female, developed mulate in or affect exon 8 of LMNA, which extremities. Patients have variable loss of diabetes at age 30 years, whereas her encodes the globular C-terminal (tail) fat from the face, and some patients have affected mother and grandmother devel- portion of the protein. Particularly, the argi- normal or increased fat on the face. Given oped diabetes during their late thirties. nine residue at position 482 seems to be the role of PPARγ as a transcription factor A maternal uncle, a middle-aged person, a hot spot, and about 75% of patients with in adipogenesis and adipocyte differen- had no diabetes but had hyperinsulinemia. FPLD have a substitution of this residue tiation, mutations in PPARG may result Three of the four affected subjects had to tryptophan, , or (117). in lipodystrophy due to defective differ- hypertension. The proband also had loss Some patients who have mutations in entiation of adipocytes. PPARG is highly of subcutaneous fat from the extremities exon 11, which can only affect lamin A expressed in adipose tissue; however, why (Stephen O’Rahilly, personal communi- and not lamin C, seem to have a milder, patients with PPARG mutations develop cation). However, the precise pattern of atypical FPLD (118). More importantly, lipodystrophy of the extremities and not subcutaneous fat loss is not clear. AKT2 patients who have mutations in exon 1 or other adipose tissue depots is not clear. is a phosphoinositide-dependent serine/ nearby exons affecting the amino terminal threonine kinase and is also known as residues have associated cardiomyop- Type 4: FPL Associated With PLIN1 B. AKT2 is predominantly athy (112,113). Some of these patients Mutation (FPLD4). Gandotra et al. (121) expressed in insulin sensitive tissues. also show evidence of mild muscular reported two heterozygous frameshift Overexpression of the mutant form, dystrophy with slightly increased serum mutations in PLIN1 (which encodes peri­ p.Arg274His, in 3T3-L1 mouse preadipo- creatine kinase levels. In some families, lipin 1) in five patients from three families cytes resulted in markedly reduced lipid

7–19 DIABETES IN AMERICA, 3rd Edition accumulation. Previously, a mouse model of transmission (128,129,130). Reiger able to suppress appetite especially in of AKT2 deficiency showed features of anomaly consists of eye abnormalities, patients with generalized lipodystrophy lipodystrophy, insulin resistance, and such as iris hypoplasia, Schwalbe ring, (79,136). However, enough energy diabetes with increasing age (125). Thus, iridocorneal synechiae, micro- or mega- should be provided for proper growth and taken together, lipodystrophy in patients locornea, and dental anomalies, such as development. Subcutaneous metreleptin with AKT2 mutations may be related to hypodontia, microdontia, enamel hypo- replacement in low doses has been reduced adipocyte differentiation and plasia, and atypical teeth. Other clinical reported to dramatically improve diabetes may be likely due to dysfunctional insulin features include intrauterine growth retar- control, hepatic steatosis, and hypertri- signaling at the postreceptor level. dation, failure to thrive, delayed speech glyceridemia in severely hypoleptinemic development, small head circumference, patients with generalized lipodystrophies Other Types of FPL. The four known FPL bilateral clinodactyly, and sensorineural (79,136,137,138). Metreleptin replacement, genes are not able to explain the genetic hearing loss. Different patterns of fat loss however, is only modestly efficacious basis of all FPL patients, and additional have been reported. In many patients, in patients with FPL (79,136,139). loci are likely to be discovered (Figure 7.7C) lipodystrophy affects the face, upper Metreleptin therapy has been approved (119,126). In depth characterization of the extremities, and sometimes the trunk, by the U.S. Food and Drug Administration clinical phenotype related to the pattern with relative sparing of the lower extrem- for improving metabolic complications in of fat loss in FPL patients with mutations ities. Others had lipodystrophy affecting patients with generalized lipodystrophies. in different genes may be helpful in iden- only the face, gluteal region, and elbows tification of different phenotypes without (131,132). Diabetes occurs as early as Since many patients with lipodystrophies resorting to molecular diagnosis. the second and third decade of life and is have extreme insulin resistance, they may usually associated with insulin resistance. require high doses of insulin, including Differential Diagnosis. FPL should be Patients with SHORT syndrome harbor administration of U-500 insulin (500 units differentiated from conditions such as de novo heterozygous mutations in the of insulin per mL). Other patients can Cushing’s syndrome, truncal obesity, phosphatidylinositol 3-kinase regulatory achieve good glycemic control with oral multiple symmetric , and subunit 1 (PIK3R1) gene (4133,13 ,135). hypoglycemic drugs, such as metformin acquired generalized lipodystrophy, as The molecular genetic basis of the and sulfonylureas. Metformin can improve well as highly active antiretroviral thera- autosomal recessive variety of SHORT insulin sensitivity, reduce appetite, and py-induced lipodystrophy in HIV-infected syndrome remains to be determined. induce ovulation in patients with PCOS. patients. can also be used; MANAGEMENT OF DIABETES IN however, they can induce unwanted Atypical Progeroid Syndrome PATIENTS WITH LIPODYSTROPHY growth of adipose tissue in non-lipodystro- Due to LMNA Mutations Diabetes control in patients with lipo- phic regions in patients with FPL (140,141). About 30 patients have been reported to dystrophies can be challenging. A Although, patients with PPARG mutations have partial or generalized lipodystrophy, multipronged strategy should be used, and FPL should respond better to thiazo- insulin resistant diabetes, and progeroid including diet, physical activity, and drug lidinediones, there are not much data features with missense mutations in therapy. Reduction of energy intake and to support that assumption. Three FPL LMNA (127). Additional clinical features increased physical activity are important patients have been reported to have had include mottling, pigmentations and in patients with FPL to avoid excess marked improvement in diabetes control sclerosis of skin, liver steatosis, cardio- fat deposition in non-lipodystrophic and dyslipidemia following roux-en-y myopathy, short stature, cardiac valvular regions. Many patients with FPL have (142,143,144). abnormalities, and deafness. Particularly increased risk of coronary heart disease, striking is the lack of breast tissue in and they should limit intake of saturated CONCLUDING REMARKS many females. Some women also develop and trans-unsaturated fats and dietary FOR LIPODYSTROPHIES premature ovarian failure. These patients cholesterol. Patients presenting with Genetic lipodystrophies are rare monogenic are also predisposed to developing prema- acute pancreatitis and extreme chylomi- syndromes with an estimated prevalence ture diabetes. cronemia should be advised to consume of less than 1 in one million. In the last an extremely low fat diet. However, two decades, elucidation of the molecular Short Stature, Hyperextensibility of whether such diet will be beneficial in the basis of many of these syndromes has Joints and/or Inguinal Hernia, Ocular long term to reduce hepatic steatosis and revealed the important role of adipose Depression, Reiger Anomaly, and serum triglycerides and improve glycemic tissue development, differentiation, and Teething Delay (SHORT) Syndrome control remains unclear. death pathways in adipocyte biology A total of 30 patients have been reported (87,107). Studies of lipodystrophy patients with SHORT syndrome. The pedigrees Controlling excessive hunger in chil- and the mouse models of these syndromes reveal both autosomal recessive (128,129) dren with generalized lipodystrophy is will further reveal the mechanisms by and dominant (130,131,132) modes extremely difficult. Metreleptin may be which lack of triglyceride storage capacity

7–20 in the adipose tissue induces metabolic generalized lipodystrophy, who are usually §§ www.utsouthwestern.edu/education/ complications, especially diabetes. These severely hypoleptinemic. In the future, medical-school/departments/ developments are expected to lead to next generation sequencing is expected to internal-medicine/divisions/nutrition/ discoveries of targeted therapies for these unravel the molecular basis of extremely lipodystrophy/index.html, an syndromes. Diagnosis of genetic lipodystro- rare subtypes of genetic lipodystrophies. information resource on genetic phies is based on clinical criteria. In many lipodystrophies at the UT Southwestern patients, genetic testing can confirm the RESOURCES Medical Center, Dallas, TX diagnosis and allow for genetic counseling. The following websites provide access to §§ www.genetests.org, a compendium Metreleptin replacement therapy has been expert advice and assistance with possible of sites and locations of mutational approved in the United States to treat mutation analysis in patients suspected of analysis performed for research or via metabolic complications in patients with having genetic lipodystrophies: CLIA-certified laboratories

LIST OF ABBREVIATIONS A1c ���������� glycosylated hemoglobin Kir ������������ inward rectifying potassium channel ACTH �������� adrenocorticotropic hormone LHON �������� Leber’s hereditary optic neuropathy ADP ���������� adenosine diphosphate LMNA �������� lamin A/C AGPAT ������ 1-acylglycerol-3-phosphate-O-acyltransferase MAD ���������� mandibuloacral dysplasia syndrome AKT ���������� a phosphoinositide-dependent serine/threonine MELAS ������ mitochrondrial encephalomyopathy, lactic acidosis, kinase, also known as protein kinase B and stroke-like episodes ATP ���������� adenosine triphosphate MIDD �������� maternally inherited diabetes and deafness BSCL �������� Berardinelli-Seip congenital lipodystrophy MODY ������ maturity-onset diabetes of youth

Cav ������������ voltage-gated calcium channel NDM �������� neonatal diabetes mellitus CEL ���������� carboxyl-ester lipase PC ������������ prohormone convertases CGL ���������� congenital generalized lipodystrophy PCOS �������� polycystic ovary syndrome CLIA ���������� Clinical Laboratory Improvement Amendments PCSK �������� proprotein convertase subtilisin/kexin type DEND �������� developmental delay, epilepsy, and neonatal PDX ���������� pancreatic and duodenal homeobox diabetes mellitus PHID �������� pigmented hypertrichosis and insulin-dependent FPL ���������� familial partial lipodystrophy diabetes FPLD �������� familial partial lipodystrophy, Dunnigan variety PLIN ���������� perilipin G6P ���������� glucose-6-phosphate PNDM ������ permanent neonatal diabetes mellitus GCK ���������� glucokinase PPAR �������� peroxisome proliferator-activated receptor GLUT �������� glucose transporter PTRF �������� polymerase I and transcript release factor GnRH �������� gonadotropic-releasing hormone SHORT ������ Short Stature, Hyperextensibility of Joints HDL ���������� high-density lipoprotein and/or Inguinal Hernia, Ocular Depression, HIV ������������ human immunodeficiency virus Reiger Anomaly and Teething Delay Syndrome HNF ���������� hepatocyte nuclear factor SUR ���������� sulfonylurea receptor hsCRP ������ high sensitivity C-reactive protein TNDM �������� transient neonatal diabetes mellitus IPF ������������ insulin promoter factor TRMA �������� thiamine-responsive megaloblastic anemia

KATP ������������ ATP-regulated potassium channel WFS ���������� wolframin

CONVERSIONS ACKNOWLEDGMENTS/FUNDING Conversions for A1c, glucose, and Dr. Garg was supported by grants from the National Institute of Diabetes and insulin values are provided in Diabetes Digestive and Kidney Diseases (DK054387, DK074959, and DK105448); and in America Appendix 1 Conversions. by Amylin; Bristol-Myers Squibb; AstraZeneca; Aegerion; and Pfizer.

7–21 DIABETES IN AMERICA, 3rd Edition

DUALITY OF INTEREST Drs. Sperling and Garg reported no conflicts of interest. Dr. Garg possesses rights to the following intellectual property: 1) DePaoli AM, Taylor S, Oral EA, Garg A. (2007) Use of leptin for treating human lipoatrophy and method of determining predis- position to said treatment. U.S. Patent 7,183,254; and 2) DePaoli AM, Oral EA, Taylor S, Garg A. (2010) Use of leptin for treating human lipoatrophy and method of determining predisposition to said treatment. European Patent No. 10165256.8-2107/2219031.

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