Maturity-onset diabetes of the young

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Maturity-onset diabetes of the young (MODY)
Other namesMonogenic diabetes
Specialty Endocrinology

Maturity-onset diabetes of the young (MODY) refers to any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production. [1] Along with neonatal diabetes, MODY is a form of the conditions known as monogenic diabetes. While the more common types of diabetes (especially type 1 and type 2) involve more complex combinations of causes involving multiple genes and environmental factors, each forms of MODY are caused by changes to a single gene (monogenic). [2] HNF1A-MODY (MODY 3) are the most common forms.

Contents

Robert Tattersall and Stefan Fajans initially identified the phenomenon known as maturity onset diabetes of the young in a classic study published in the journal Diabetes in 1975. [3]

Signs and symptoms

MODY is the final diagnosis in 1%–2% of people initially diagnosed with diabetes. The prevalence is 70–110 per million people. 50% of first-degree relatives will inherit the same mutation, giving them a greater than 95% lifetime risk of developing MODY themselves. For this reason, correct diagnosis of this condition is important. Typically patients present with a strong family history of diabetes (any type) and the onset of symptoms is in the second to fifth decade.[ citation needed ]

There are two general types of clinical presentation.[ citation needed ]

MODY cases may make up as many as 5% of presumed type 1 and type 2 diabetes cases in a large clinic population. While the goals of diabetes management are the same no matter what type, there are two primary advantages of confirming a diagnosis of MODY.[ citation needed ]

As it occurs infrequently, many cases of MODY are initially assumed to be more common forms of diabetes: type 1 if the patient is young and not overweight, type 2 if the patient is overweight, or gestational diabetes if the patient is pregnant. Standard diabetes treatments (insulin for type 1 and gestational diabetes, and oral hypoglycemic agents for type 2) are often initiated before the doctor suspects a more unusual form of diabetes.[ citation needed ]

Pathophysiology

The recognised forms of MODY are all due to ineffective insulin production or release by pancreatic beta cells. Several of the defects are mutations of transcription factor genes. One form is due to mutations of the glucokinase gene. For each form of MODY, multiple specific mutations involving different amino acid substitutions have been discovered. In some cases, there are significant differences in the activity of the mutant gene product that contribute to variations in the clinical features of the diabetes (such as degree of insulin deficiency or age of onset).[ citation needed ]

Diagnosis

The following characteristics suggest the possibility of a diagnosis of MODY in hyperglycemic and diabetic patients: [4]

The diagnosis of MODY is confirmed by specific gene testing available through commercial laboratories.

Classification

Heterozygous

MODY is inherited in an autosomal dominant fashion, and most patients therefore have other members of the family with diabetes; penetrance differs between the types (from 40% to 90%).

Type OMIM Gene/proteinDescription
HNF4A-MODY (MODY 1) 125850 hepatocyte nuclear factor 4αDue to a loss-of-function mutation in the HNF4α gene. 5%–10% cases.
GCK-MODY (MODY 2) 125851 glucokinase Due to any of several mutations in the GCK gene. 30%–70% cases. Mild fasting hyperglycemia throughout life. Small rise on glucose loading. Patients do not tend to get diabetes complications and do not require treatment [11] outside of pregnancy. [12]
HNF1A-MODY (MODY 3) 600496 hepatocyte nuclear factor 1αMutations of the HNF1α gene (a homeobox gene). 30%–70% of cases. Most common type of MODY in populations with European ancestry. [13] Tend to be responsive to sulfonylureas. Low renal threshold for glucose.
PDX1-MODY (MODY 4) 606392 insulin promoter factor-1Mutations of the IPF1 homeobox (Pdx1) gene. < 1% cases. Associated with pancreatic agenesis in homozygotes and occasionally in heterozygotes.
HNF1B-MODY (MODY 5) 137920 hepatocyte nuclear factor 1βOne of the less common forms of MODY, with some distinctive clinical features, including atrophy of the pancreas and several forms of renal disease. Defect in HNF-1 beta gene. 5%–10% cases.
NEUROD1-MODY (MODY 6) 606394 neurogenic differentiation 1Mutations of the gene for the transcription factor referred to as neurogenic differentiation 1. Very rare: 5 families reported to date.
KLF11-MODY (MODY 7) 610508 Kruppel-like factor 11 KLF11 has been associated with a form of diabetes [14] that has been characterized as "MODY7" by OMIM. [15]
CEL-MODY MODY 8 609812 Bile salt dependent lipase CEL has been associated with a form of diabetes [16] that has been characterized as "MODY8" by OMIM. [17] It is very rare with five families reported to date. It is associated with exocrine pancreatic dysfunction.
PAX4-MODY MODY 9 612225 PAX4 Pax4 is a transcription factor. MODY 9 is a very rare medical condition.
INS-MODY MODY 10 613370 INS Mutations in the insulin gene. Usually associated with neonatal diabetes. Rare < 1% cases.
BLK-MODY MODY 11 613375 BLK Mutated B-lymphocyte tyrosine kinase, which is also present in pancreatic islet cells. Very rare.
AAPL1-MODY MODY 14 616511 APPL1 Mutated anchor protein in the insulin signalling pathway. Newly discovered.

A newly discovered monogenetic form of diabetes is marked by a missense variant in the RyR2 gene [18] . It has not yet received a MODY type.

Homozygous

By definition, the forms of MODY are autosomal dominant, requiring only one abnormal gene to produce the disease; the severity of the disease is moderated by the presence of a second, normal allele which presumably functions normally. However, conditions involving people carrying two abnormal alleles have been identified. [19] Unsurprisingly, combined (homozygous) defects of these genes are much rarer and much more severe in their effects.[ citation needed ]

  • MODY2: Homozygous glucokinase deficiency causes severe congenital insulin deficiency resulting in persistent neonatal diabetes mellitus. About 6 cases have been reported worldwide. All have required insulin treatment from shortly after birth. The condition does not seem to improve with age.
  • MODY4: Homozygous IPF1 results in failure of the pancreas to form. Congenital absence of the pancreas, termed pancreatic agenesis, involves deficiency of both endocrine and exocrine functions of the pancreas.

Homozygous mutations in the other forms have not yet been described. Those mutations for which a homozygous form has not been described may be extremely rare, may result in clinical problems not yet recognized as connected to the monogenic disorder, or may be lethal for a fetus and not result in a viable child.[ citation needed ]

Treatment

In some forms of MODY, standard treatment is appropriate, though exceptions occur:

Chronic hyperglycemia due to any cause can eventually cause blood vessel damage and the microvascular complications of diabetes. The principal treatment goals for people with MODY — keeping the blood sugars as close to normal as possible ("good glycemic control"), while minimizing other vascular risk factors — are the same for all known forms of diabetes.[ citation needed ]

The tools for management are similar for all forms of diabetes: blood testing, changes in diet, physical exercise, oral hypoglycemic agents, and insulin injections. In many cases these goals can be achieved more easily with MODY than with ordinary types 1 and 2 diabetes. Some people with MODY may require insulin injections to achieve the same glycemic control that another person may attain with careful eating or an oral medication.[ citation needed ]

When oral hypoglycemic agents are used in MODY, the sulfonylureas remain the oral medication of first resort. When compared to patients with type 2 diabetes, MODY patients are often more sensitive to sulphonylureas, such that a lower dose should be used to initiate treatment to avoid hypoglycaemia. Patients with MODY less often suffer from obesity and insulin resistance than those with ordinary type 2 diabetes (for whom insulin sensitizers like metformin or the thiazolidinediones are often preferred over the sulfonylureas).[ citation needed ]

Epidemiology

According to data from Saxony, Germany, MODY was responsible for 2.4% of diabetes incidence in children younger than 15 years. [21]

History

The term MODY dates back to 1964, when diabetes mellitus was considered to have two main forms: juvenile-onset and maturity-onset, which roughly corresponded to what we now call type 1 and type 2. MODY was originally applied to any child or young adult who had persistent, asymptomatic hyperglycemia without progression to diabetic ketosis or ketoacidosis. In retrospect we can now recognize that this category covered a heterogeneous collection of disorders which included cases of dominantly inherited diabetes (the topic of this article, still called MODY today), as well as cases of what we would now call type 2 diabetes occurring in childhood or adolescence, and a few even rarer types of hyperglycemia (e.g., mitochondrial diabetes or mutant insulin). Many of these patients were treated with sulfonylureas with varying degrees of success.[ citation needed ]

The current usage of the term MODY dates from a case report published in 1974. [22] [23]

Since the 1990s, as the understanding of the pathophysiology of diabetes has improved, the concept and usage of MODY have become refined and narrower. It is now used as a synonym for dominantly inherited, monogenic defects of insulin secretion occurring at any age, and no longer includes any forms of type 2 diabetes. [24]

Related Research Articles

<span class="mw-page-title-main">Type 2 diabetes</span> Form of diabetes mellitus

Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, fatigue and unexplained weight loss. Other symptoms include increased hunger, having a sensation of pins and needles, and sores (wounds) that heal slowly. Symptoms often develop slowly. Long-term complications from high blood sugar include heart disease, stroke, diabetic retinopathy, which can result in blindness, kidney failure, and poor blood flow in the lower-limbs, which may lead to amputations. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.

Drugs used in diabetes treat diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists, and pramlintide, all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of diabetes, age, and situation of the person, as well as other patient factors.

<span class="mw-page-title-main">Wolfram syndrome</span> Human disease

Wolfram syndrome, also called DIDMOAD, is a rare autosomal-recessive genetic disorder that causes childhood-onset diabetes mellitus, optic atrophy, and deafness as well as various other possible disorders including neurodegeneration. Symptoms can start to appear as early as childhood to adult years. There is a 25% recurrence risk in children.

<span class="mw-page-title-main">Sulfonylurea</span> Class of organic compounds used in medicine and agriculture

Sulfonylureas or sulphonylureas are a class of organic compounds used in medicine and agriculture. The functional group consists of a sulfonyl group (-S(=O)2) with its sulphur atom bonded to a nitrogen atom of a ureylene group (N,N-dehydrourea, a dehydrogenated derivative of urea). The side chains R1 and R2 distinguish various sulfonylureas. Sulfonylureas are the most widely used herbicide.

<span class="mw-page-title-main">Type 1 diabetes</span> Form of diabetes mellitus

Type 1 diabetes (T1D), formerly known as juvenile diabetes, is an autoimmune disease that occurs when pancreatic cells are destroyed by the body's immune system. In healthy persons, beta cells produce insulin. Insulin is a hormone required by the body to store and convert blood sugar into energy. T1D results in high blood sugar levels in the body prior to treatment. Common symptoms include frequent urination, increased thirst, increased hunger, weight loss, and other complications. Additional symptoms may include blurry vision, tiredness, and slow wound healing. While some cases take longer, symptoms usually appear within weeks or a few months.

Slowly evolving immune-mediated diabetes, or latent autoimmune diabetes in adults (LADA), is a form of diabetes that exhibits clinical features similar to both type 1 diabetes (T1D) and type 2 diabetes (T2D), and is sometimes referred to as type 1.5 diabetes. It is an autoimmune form of diabetes, similar to T1D, but patients with LADA often show insulin resistance, similar to T2D, and share some risk factors for the disease with T2D. Studies have shown that LADA patients have certain types of antibodies against the insulin-producing cells, and that these cells stop producing insulin more slowly than in T1D patients. Since many people develop the disease later in life, it is often misdiagnosed as type 2 diabetes.

<span class="mw-page-title-main">Gliclazide</span> Chemical compound

Gliclazide, sold under the brand name Diamicron among others, is a sulfonylurea type of anti-diabetic medication, used to treat type 2 diabetes. It is used when dietary changes, exercise, and weight loss are not enough. It is taken by mouth.

<span class="mw-page-title-main">Hepatocyte nuclear factor 4 alpha</span> Protein-coding gene in the species Homo sapiens

Hepatocyte nuclear factor 4 alpha (HNF4A) also known as NR2A1 is a nuclear receptor that in humans is encoded by the HNF4A gene.

<span class="mw-page-title-main">HNF1A</span> Protein-coding gene in the species Homo sapiens

HNF1 homeobox A, also known as HNF1A, is a human gene on chromosome 12. It is ubiquitously expressed in many tissues and cell types. The protein encoded by this gene is a transcription factor that is highly expressed in the liver and is involved in the regulation of the expression of several liver-specific genes. Mutations in the HNF1A gene have been known to cause diabetes. The HNF1A gene also contains a SNP associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Wolcott–Rallison syndrome</span> Medical condition

Wolcott–Rallison syndrome,WRS, is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the eukaryotic translation initiation factor 2-alpha kinase 3. Other disease names include multiple epiphyseal dysplasia and early-onset diabetes mellitus. Most patients with this disease do not survive to adulthood. The majority of WRS patients die from fulminant hepatitis during childhood. There are few reported cases for this disease. Of the 54 families worldwide with reported WRS cases, 22.2% of them are from the Kingdom of Saudi Arabia. Of the 23 WRS patients in Saudi Arabia, all but one is the result of consanguineous marriages. Another country where WRS cases have been found is Kosovo. Here, the Albanian population is also known for consanguineous marriages, but there were some cases involving patients from non-consanguineous parents that were carriers for the same mutant allele.

<span class="mw-page-title-main">MODY 1</span> Medical condition

MODY 1 or HNF4A-MODY is a form of maturity onset diabetes of the young.

MODY 2 or GCK-MODY is a form of maturity-onset diabetes of the young. It is due to any of several mutations in the GCK gene on human chromosome 7 for glucokinase. Glucokinase serves as the glucose sensor for the pancreatic beta cell. Normal glucokinase triggers insulin secretion as the glucose exceeds about 90 mg/dl. These loss-of-function mutations result in a glucokinase molecule that is less sensitive or less responsive to rising levels of glucose. The beta cells in MODY 2 have a normal ability to make and secrete insulin, but do so only above an abnormally high threshold. This produces a chronic, mild increase in blood sugar, which is usually asymptomatic. It is usually detected by accidental discovery of mildly elevated blood sugar. An oral glucose tolerance test is much less abnormal than would be expected from the impaired (elevated) fasting blood sugar, since insulin secretion is usually normal once the glucose has exceeded the threshold for that specific variant of the glucokinase enzyme.

MODY 3 or HNF1A-MODY is a form of maturity-onset diabetes of the young. It is caused by mutations of the HNF1-alpha gene, a homeobox gene on human chromosome 12. This is the most common type of MODY in populations with European ancestry, accounting for about 70% of all cases in Europe. HNF1α is a transcription factor that is thought to control a regulatory network important for differentiation of beta cells. Mutations of this gene lead to reduced beta cell mass or impaired function. MODY 1 and MODY 3 diabetes are clinically similar. About 70% of people develop this type of diabetes by age 25 years, but it occurs at much later ages in a few. This type of diabetes can often be treated with sulfonylureas with excellent results for decades. However, the loss of insulin secretory capacity is slowly progressive and most eventually need insulin.

MODY 4 or PDX1-MODY is a form of maturity onset diabetes of the young.

<span class="mw-page-title-main">Renal cysts and diabetes syndrome</span> Medical condition

Renal cysts and diabetes syndrome (RCAD), also known as MODY 5 or HNF1B-MODY, is a form of maturity onset diabetes of the young.

Permanent neonatal diabetes mellitus (PNDM) is a newly identified and potentially treatable form of monogenic diabetes. This type of neonatal diabetes is caused by activating mutations of the KCNJ11 gene, which codes for the Kir6.2 subunit of the beta cell KATP channel. This disease is considered to be a type of maturity onset diabetes of the young (MODY).

<span class="mw-page-title-main">Transient neonatal diabetes</span> Medical condition

Transient neonatal diabetes mellitus (TNDM) is a form of neonatal diabetes presenting at birth that is not permanent. This disease is considered to be a type of maturity onset diabetes of the young (MODY).

<span class="mw-page-title-main">Neonatal diabetes</span> Medical condition

Neonatal diabetes mellitus (NDM) is a disease that affects an infant and their body's ability to produce or use insulin. NDM is a kind of diabetes that is monogenic and arises in the first 6 months of life. Infants do not produce enough insulin, leading to an increase in glucose accumulation. It is a rare disease, occurring in only one in 100,000 to 500,000 live births. NDM can be mistaken for the much more common type 1 diabetes, but type 1 diabetes usually occurs later than the first 6 months of life. There are two types of NDM: permanent neonatal diabetes mellitus (PNDM), a lifelong condition, and transient neonatal diabetes mellitus (TNDM), a form of diabetes that disappears during the infant stage but may reappear later in life.

Most cases of type 2 diabetes involved many genes contributing small amount to the overall condition. As of 2011 more than 36 genes have been found that contribute to the risk of type 2 diabetes. All of these genes together still only account for 10% of the total genetic component of the disease.

<span class="mw-page-title-main">Diabetes</span> Group of endocrine diseases characterized by high blood sugar levels

Diabetes mellitus, often known simply as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body becoming unresponsive to the hormone's effects. Classic symptoms include thirst, polyuria, weight loss, and blurred vision. If left untreated, the disease can lead to various health complications, including disorders of the cardiovascular system, eye, kidney, and nerves. Diabetes accounts for approximately 4.2 million deaths every year, with an estimated 1.5 million caused by either untreated or poorly treated diabetes.

References

  1. ↑ "Monogenic Diabetes (Neonatal Diabetes Mellitus & MODY)". National Institute of Diabetes and Digestive and Kidney Diseases. Retrieved 2023-02-01.
  2. ↑ "Monogenic Diabetes (Neonatal Diabetes Mellitus & MODY)". National Institute of Diabetes and Digestive and Kidney Diseases. Retrieved 2023-02-10.
  3. ↑ Chennai, India, Dr. V Mohan (2020-07-15). "'Maturity Onset Diabetes of the Young (MODY) | Dr Mohans". Dr Mohan's Diabetes Center in Chennai.
  4. ↑ Urakami T (2019). "Maturity-onset diabetes of the young (MODY): current perspectives on diagnosis and treatment". Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 12. Diabetes Metabolic Syndrome & Obesity: 1047–1056. doi: 10.2147/DMSO.S179793 . PMC   6625604 . PMID   31360071.
  5. ↑ MODY (Report). Retrieved Jan 25, 2010.
  6. ↑ Urbanova J, Rypackova B, Prochazkova Z, Kucera P, Cerna M, Andel M, Heneberg P (2014). "Positivity for islet cell autoantibodies in patients with monogenic diabetes is associated with later diabetes onset and higher HbA1c level". Diabetic Medicine. 31 (4): 466–71. doi:10.1111/dme.12314. PMID   24102923. S2CID   1867195.
  7. ↑ Maturity Onset Diabetes, SparkPeople, retrieved Jan 21, 2010
  8. ↑ MODY (Report). Harvard. Retrieved January 23, 2010.
  9. ↑ Lerario, A. M.; Brito, L. P.; Mariani, B. M.; Fragoso, M. C.; Machado, M. A.; Teixeira, R. (2010). "A missense TCF1 mutation in a patient with MODY-3 and liver adenomatosis". Clinics. 65 (10): 1059–1060. doi:10.1590/S1807-59322010001000024. PMC   2972616 . PMID   21120312.
  10. ↑ Renal Cysts and Diabetes Syndrome (Report). Retrieved May 19, 2011.
  11. ↑ Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT (2014). "Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia". JAMA. 311 (3): 279–86. doi: 10.1001/jama.2013.283980 . hdl: 10871/15378 . PMID   24430320.
  12. ↑ Dickens LT, Letourneau LR, Sanyoura M, Greeley SA, Philipson LH, Naylor RN (2019). "Management and pregnancy outcomes of women with GCK-MODY enrolled in the US Monogenic Diabetes Registry". Acta Diabetologica. 56 (3): 405–411. doi:10.1007/s00592-018-1267-z. PMC   6468988 . PMID   30535721.
  13. ↑ Frayling, TM; Evans, JC; Bulman, MP; Pearson, E (February 2001). "beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors". Diabetes. 50 Suppl (1): S94-100. doi: 10.2337/diabetes.50.2007.S94 . PMID   11272211.
  14. ↑ Neve B, Fernandez-Zapico ME, Ashkenazi-Katalan V, et al. (March 2005). "Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function". Proc. Natl. Acad. Sci. U.S.A. 102 (13): 4807–12. doi: 10.1073/pnas.0409177102 . PMC   554843 . PMID   15774581.
  15. ↑ Online Mendelian Inheritance in Man (OMIM): MATURITY-ONSET DIABETES OF THE YOUNG, TYPE VII; MODY7 - 610508
  16. ↑ Raeder H, Johansson S, Holm PI, et al. (January 2006). "Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction". Nat. Genet. 38 (1): 54–62. doi:10.1038/ng1708. PMID   16369531. S2CID   8338877.
  17. ↑ Online Mendelian Inheritance in Man (OMIM): MATURITY-ONSET DIABETES OF THE YOUNG, TYPE VIII, WITH EXOCRINE DYSFUNCTION; MODY8 - 609812
  18. ↑ Bansal, V; Winkelmann, BR; Dietrich, JW; Boehm, BO (2024). "Whole-exome sequencing in familial type 2 diabetes identifies an atypical missense variant in the RyR2 gene". Frontiers in Endocrinology. 15: 1258982. doi: 10.3389/fendo.2024.1258982 . PMID   38444585.
  19. ↑ Dhavendra Kumar; D. J. Weatherall (2008). Genomics and clinical medicine. Oxford University Press US. pp. 184–. ISBN   978-0-19-518813-4 . Retrieved 12 June 2010.
  20. ↑ Urbanova, J.; et al. (2015). "Half-Life of Sulfonylureas in HNF1A and HNF4A Human MODY Patients is not Prolonged as Suggested by the Mouse Hnf1a-/- Model". Current Pharmaceutical Design. 21 (39): 5736–5748. doi:10.2174/1381612821666151008124036. PMID   26446475.
  21. ↑ Galler, Angela; Stange, Thoralf; Müller, Gabriele; Näke, Andrea; Vogel, Christian; Kapellen, Thomas; Bartelt, Heike; Kunath, Hildebrand; Koch, Rainer; Kiess, Wieland; Rothe, Ulrike (2010). "Incidence of Childhood Diabetes in Children Aged Less than 15 Years and Its Clinical and Metabolic Characteristics at the Time of Diagnosis: Data from the Childhood Diabetes Registry of Saxony, Germany". Hormone Research in Paediatrics. 74 (4): 285–91. doi:10.1159/000303141. PMID   20516654. S2CID   1313999.
  22. ↑ Tattersall RB (1974). "Mild familial diabetes with dominant inheritance". Q J Med. 43 (170): 339–357. PMID   4212169.
  23. ↑ Tattersall, R (1998). "Maturity-onset diabetes of the young: A clinical history". Diabetic Medicine. 15 (1): 11–4. doi:10.1002/(SICI)1096-9136(199801)15:1<11::AID-DIA561>3.0.CO;2-0. PMID   9472858. S2CID   31690226.
  24. ↑ American Diabetes, Association (2009). "Diagnosis and Classification of Diabetes Mellitus". Diabetes Care. 32 (Suppl 1): S62–S67. doi:10.2337/dc09-S062. PMC   2613584 . PMID   19118289.
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