Congenital Leptin Deficiency

Disease Overview

Summary

Congenital leptin deficiency (CLD) is a rare, inherited condition that affects how the body processes energy, responds to food and stores fat. Infants with CLD are constantly hungry and quickly gain weight and become obese. Children with CLD have extreme hunger (hyperphagia), low energy and abnormal behaviors related to food. People affected with CLD produce little or no sex hormones (hypogonadotropic hypogonadism) resulting in late or absent puberty and infertility. CLD is caused by changes (pathogenic variants or mutations) in the LEP gene, which is responsible for making a protein called leptin. Leptin is important for regulating appetite and growth of body fat. This condition is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and the results of genetic testing. Diet, behavior modification, exercise programs and bariatric surgery have been used to help manage the symptoms of CLD. Treatment is available for this condition using a drug called metreleptin, a recombinant form of human leptin, which reverses the symptoms of CLD. With treatment, people with CLD develop a normal appetite, lose weight and fat and regain normal sex hormone levels.

Introduction

CLD is rare, making it difficult to predict exactly how it will affect someone who is newly diagnosed. It is one of several conditions that include early-onset obesity, and these conditions can be difficult to distinguish from each other without a careful physical examination and genetic testing.

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Synonyms

• obesity due to congenital leptin deficiency
• LEPD
• leptin deficiency or dysfunction
• obesity, morbid due to congenital leptin deficiency
• CLD
• leptin deficiency

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Signs & Symptoms

Most babies with CLD have a normal weight at birth. The earliest symptoms of CLD are constant hunger and excessive eating leading to rapid weight gain and obesity before one year of age. People with CLD always feel hungry even after eating a full meal and often have abnormal behaviors related to food. Many have low levels of sex hormones (hypogonadotropic hypogonadism) causing delayed or absent puberty and infertility. Other symptoms include low energy levels, low blood pressure and insulin resistance, which can lead to type 2 diabetes. Children with CLD are often prone to infections, due to an immune system that doesn’t work correctly. Excessive weight gain can lead to other symptoms such as abnormal bone growth, liver disease and difficultly walking.

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Causes

CLD is caused by pathogenic variants (mutations) in the LEP gene. The LEP gene is responsible for making the protein, leptin.  Leptin is made by fat cells and helps regulate energy storage in the body by balancing how much fat is made and how much is burned for energy. Without leptin, the body doesn’t recognize when the body has enough energy and it’s time to stop eating.

CLD is inherited in families in a recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

Congenital leptin deficiency is a very rare disorder. It has been estimated that 1 in 4.4 million people may have this condition. Many come from parts of the world where it is customary for relatives to marry.

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Disorders with Similar Symptoms

CLD is one of several rare inherited conditions that include early-onset extreme obesity with few or no other signs or symptoms. These conditions are due to variants in one of the genes that normally work together to help regulate hunger and growth of body fat. These conditions may be difficult to diagnose based solely on clinical examination and sometimes genetic testing is the only way to tell the difference between them.

Some of these conditions include:

PCSK1 deficiency

PCSK1 deficiency is a very rare inherited disorder that affects the metabolism and appetite. Severe diarrhea, digestive problems and slow growth are the earliest symptoms which tend to diminish slightly with time, followed by extreme hunger and obesity in early childhood. Excessive thirst and frequent urination (polyuria polydipsia syndrome) are common. Other symptoms related to abnormalities of the endocrine glands include growth hormone deficiency, low thyroid hormone and adrenal gland disorders. PCSK1 deficiency is caused by variants in the PCSK1 gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms, laboratory testing and the results of genetic testing. Treatment is available for this condition using a drug called setmelanotide. This drug has been approved for treating people age six and over with PCSK1 deficiency and reverses the symptoms including obesity. Less than 50 people have been reported with PCSK1 deficiency.

POMC deficiency

POMC deficiency affects the way the body stores and uses energy. The main symptoms include constant hunger and excessive feeding, known as hyperphagia. Hyperphagia leads to obesity by one year of age, and without treatment, people with POMC deficiency remain obese throughout life. Other symptoms include low levels of a hormone called adrenocorticotropic hormone (ACTH) and adrenal insufficiency, which can be fatal if not treated early. Many individuals with POMC deficiency also have pale skin and hair. POMC deficiency is caused by variants in the POMC gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and genetic testing. Treatment is available for people with POMC deficiency over the age of six using a drug called setmelanotide. This drug reverses the constant hunger and allows people with POMC deficiency to lose weight. This condition is very rare, and it is difficult to predict how this condition will impact someone with a new diagnosis.

Leptin receptor deficiency (LEPR deficiency)

Individuals with LEPR deficiency have almost the same symptoms as individuals with congenital leptin deficiency. Early symptoms of both conditions include constant hunger and feeding (hyperphagia) and rapid weight gain leading to obesity in the first few months of life. In addition, endocrine gland abnormalities affecting levels of sex hormones are common, and puberty may be absent or delayed. This condition is caused by variants in the LEPR gene and is inherited in a recessive pattern. Diagnosis is based on a clinical exam, symptoms and the results of genetic testing. Treatment is available for this condition using setmelanotide, which decreases appetite and increases levels of sex hormones.

Obesity due to melanocortin 4 receptor (MC4R) gene variants

This is the most common cause of early-onset obesity due to a single gene. People with only one MC4R gene variant are affected. Affected people show severe hunger and develop obesity during childhood. Weight and length are normal at birth. People with MC4R deficiency are often taller than average, which is one of the distinguishing features of this condition.

People with two MC4R gene variants develop an extreme form of obesity comparable to people with leptin or leptin receptor deficiency. During the first year of life, affected babies develop extreme hunger and rapidly gain weight. Other symptoms include increased insulin in the blood which can lead to type 2 diabetes. For more information see: Welcome to the Melanocortin 4 Receptor website at https://www.mc4r.org.uk/

There are other inherited conditions that include obesity in childhood as one of several features. People with these conditions have other signs and symptoms along with excess weight. These conditions include:

Bardet-Biedl syndrome (BBS)

BBS impacts multiple body systems and is classically defined by six features. People with BBS gain excessive weight, especially around the abdomen. They often also have intellectual disabilities. The kidneys, eyes and function of the genitalia may be compromised. People with BBS may also be born with an extra digit on the hands. The severity and symptoms of BBS vary, even among individuals in the same family. For more information on this disorder, choose “Bardet-Biedl syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/bardet-biedl-syndrome/

Alström syndrome

Alström syndrome is a rare complex disorder that includes a wide variety of symptoms affecting multiple organ systems of the body. The disorder is characterized by vision and hearing abnormalities, obesity in childhood, insulin resistance and diabetes mellitus. Other symptoms include heart disease (dilated cardiomyopathy) and slowly progressive kidney dysfunction, potentially leading to kidney failure. Additional symptoms include lung, liver, kidney and endocrine dysfunction. Although some children may experience delays in reaching developmental milestones, intelligence is usually unaffected. Alström syndrome is caused by variants in the ALMS1 gene. The protein made by this gene is involved in ciliary function, cell cycle control and intracellular transport. Alström syndrome is inherited in an autosomal recessive pattern. For more information on this disorder, choose “Alstrom syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/alstrom-syndrome/

Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is characterized by symptoms and physical findings that vary in range and severity from person to person. Associated features include above-average birth weight, increased growth after birth (macrosomia), a large tongue (macroglossia), enlargement of certain internal organs (organomegaly) and abdominal wall defects (omphalocele, umbilical hernia or diastasis recti). BWS may also be associated with low blood sugar levels, distinctive grooves in the ear lobes (ear creases and ear pits), facial abnormalities and abnormal enlargement of one side or structure of the body (lateralized overgrowth). People with BWS also have an increased risk of developing certain childhood cancers, most commonly Wilms tumor (kidney tumor) and hepatoblastoma (liver tumor). Beckwith-Wiedemann syndrome has been recently reclassified as Beckwith-Wiedemann spectrum as the clinical presentation can vary from patient to patient. Approximately 80% of BWS occurs due to genetic changes that occur randomly. Inherited forms occur in about 5-10% of people with BWS. About 14% of people with BWS have an unknown cause. BWS affects at least one in 10,340 live births. Researchers have determined that BWS results from various abnormalities affecting the normal expression of certain genes that control growth on one part of chromosome 11 (BWS critical region). For more information on this disorder, choose “Beckwith-Wiedemann syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/beckwith-wiedemann-syndrome/

Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), a weak suck and feeding difficulties with poor weight gain and growth and other hormone deficiencies. In childhood, features of this disorder include short stature, small genitals and an excessive appetite. People with PWS do not feel satisfied after completing a meal (satiety). Without intervention, overeating can lead to life-threatening obesity. The food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes, respiratory problems and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior and skin picking. Motor milestones and language development are often delayed. PWS occurs due to changes of specific genes on part of the chromosome 15 inherited from the father. This condition is referred to as a genomic imprinting disorder which depends on which parent passes on the chromosome with the genetic changes to the child. For more information on this disorder, choose “Prader-Willi syndrome” as your search term in the Rare Disease Database. https://rarediseases.org/rare-diseases/prader-willi-syndrome/

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Diagnosis

Congenital leptin deficiency is diagnosed based on a clinical examination, symptoms and the results of laboratory and genetic testing. Because there are several inherited conditions that include excessive hunger and early-onset obesity, genetic testing may be done to help make a specific diagnosis. This testing often involves using a gene panel, allowing the lab to look for genetic variants in several different genes at the same time. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations.

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Standard Therapies

Congenital leptin deficiency is treatable with leptin replacement using recombinant human leptin, also known as metreleptin. Treatment results in a decreased appetite and significant weight and fat loss.  In addition, leptin replacement leads to normal sexual development, decreased insulin levels and restores the immune system.

People with congenital leptin deficiency may be treated by a variety of different medical specialists, including gastroenterologists, nutritionists and endocrinologists. A psychologist or other mental health professional can help people cope with the symptoms of this condition.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

Salum KCR, Rolando JM, Zembrzuski VM, Carneiro JRI, Mello CB, Maya-Monteiro CM, Bozza PT, Kohlrausch FB, da Fonseca ACP. When leptin Is not there: A review of what nonsyndromic monogenic obesity cases tell us and the benefits of exogenous leptin. Front Endocrinol (Lausanne). 2021 Aug 24;12:722441.

Yeo GSH, Chao DHM, Siegert AM, Koerperich ZM, Ericson MD, Simonds SE, Larson CM, Luquet S, Clarke I, Sharma S, Clément K, Cowley MA, Haskell-Luevano C, Van Der Ploeg L, Adan RAH. The melanocortin pathway and energy homeostasis: From discovery to obesity therapy. Mol Metab. 2021 Jun; 48:101206.

Clément K, Mosbah H, Poitou C. Rare genetic forms of obesity: From gene to therapy. Physiol Behav. 2020 Dec 1;227:113134. Epub 2020 Aug 14.

Yupanqui-Lozno H, Bastarrachea RA, Yupanqui-Velazco ME, Alvarez-Jaramillo M, Medina-Méndez E, Giraldo-Peña AP, et al. Congenital leptin deficiency and leptin gene missense mutation found in two Colombian sisters with severe obesity. Genes. 2019; 10(5):342.

Wasim M, Awan FR, Najam SS, Khan AR, Khan HN. Role of leptin deficiency, inefficiency, and leptin receptors in obesity. Biochem Genet. 2016 Oct;54(5):565-72. doi: 10.1007/s10528-016-9751-z. Epub 2016 Jun 16.

Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment: facts and expectations. Metabolism. 2015 Jan;64(1):146-56.

Farooqi S, O’Rahilly S. 20 years of leptin: Human disorders of leptin action. J of Endocrinology 2014; 223:1, T63-70,  DOI: https://doi.org/10.1530/JOE-14-0480

Farooqi IS, Keogh JM, Yeo GS et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med, 2003; 348: 1085–1095.

INTERNET

LEPD Deficiency. Online Mendelian Inheritance in Man (OMIM) MIM 614962, Last updated: 5/8/2019. https://omim.org/entry/614962 Accessed Jan 11, 2023.

Congenital Leptin Deficiency. MedlinePlus. Updated Dec, 2013 Available from: https://medlineplus.gov/. Accessed Jan 11, 2023.

Obesity due to congenital leptin deficiency. Orphanet. Last updated May, 2007. Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=66628 Accessed Jan 11, 2023.

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Programs & Resources

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RareCare^® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

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More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

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Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

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OMIM

Online Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.

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