PCSK1 Deficiency

Disease Overview

Summary

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, 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. Other symptoms include delayed puberty and low energy. PCSK1 deficiency is caused by changes (pathogenic variants or mutations) in the PCSK1 gene and is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms, laboratory testing and genetic testing. Treatment is available for this condition using a drug called setmelanotide.

Introduction

PCSK1 deficiency was first described in 1995. This condition is rare, making it difficult to predict exactly how it will affect someone who is newly diagnosed with this condition. 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 prohormone convertase deficiency
• obesity and endocrinopathy due to impaired processing of prohormones
• proprotein convertase 1/3 deficiency
• proprotein convertase-1 deficiency
• PC 1 deficiency
• prohormone convertase 1 deficiency

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Signs & Symptoms

The symptoms of PCSK1 deficiency are due to abnormalities of the endocrine glands. The endocrine glands make hormones that affect growth, sexual development, blood pressure and the way the body makes and uses energy. Babies with PCSK1 deficiency develop severe diarrhea and digestive problems in the first few months of life. Symptoms may last for several months and lead to poor growth and weight gain. Sometimes, the diarrhea is severe enough to lead to hospitalization. These symptoms eventually get better and other symptoms related to endocrine gland abnormalities develop. These include uncontrollable hunger and early-onset obesity which continues through adulthood. Other symptoms include the inability to absorb salt and water, causing extreme thirst (polydipsia) and frequent urination (polyuria). Other endocrine problems include low levels of sex hormones, thyroid gland insufficiency and growth hormone deficiency. Puberty may be delayed or absent. Adults with PCSK1 deficiency are shorter than average and obese.

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Causes

PCSK1 deficiency is caused by pathogenic variants (mutations) in the PCSK1 gene. This gene makes a protein that plays an important role in processing many of the endocrine gland hormones involved in energy, metabolism and appetite regulation. When the PCSK1 gene is not working, these hormones don’t work correctly.

PCSK1 deficiency 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

PCSK1 deficiency is very rare and has been reported in less than 50 people. Many of the people that have been diagnosed with this condition are from Turkey and the Middle East. It has been diagnosed more often in populations where marriage between relatives is customary.

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Disorders with Similar Symptoms

PCSK1 deficiency is one of several rare inherited conditions that lead to early-onset obesity. These conditions are due to variants in one of the genes that normally work together to help regulate hunger and energy production. These conditions may be difficult to diagnose based solely on clinical examination. Severe diarrhea in infancy may set PCSK1 deficiency apart from other early-onset obesity conditions, but often genetic testing is the only way to tell the difference between them. Some (but not all) of these conditions include:

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.

Congenital leptin deficiency

Obesity due to 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. Many people with CLD produce little or no sex hormones (hypogonadotropic hypogonadism) resulting in late or absent puberty and infertility. CLD is caused by variants 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 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.

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 due to variants in the LEPR gene and is inherited in a recessive pattern. Diagnosis is based on a clinical exam, symptoms and genetic testing. Treatment is available for this condition using setmelanotide, which decreases appetite and increases levels of sex hormones.

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 often 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 greatly, 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 with 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/

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. Affected individuals 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 deletions 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

PCSK1 deficiency is diagnosed based on a clinical examination, symptoms and the results of blood and genetic testing. Severe malabsorptive diarrhea is one of the first symptoms of PCSK1 deficiency, but has many other, more common causes. Because of that, PCSK1 deficiency is often not diagnosed until the other symptoms, especially early-onset obesity become apparent.

Because there are several inherited conditions that include excessive hunger and early onset obesity, genetic testing may be used 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 prior to having genetic testing to learn more about the risk, benefits and limitations.

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Standard Therapies

In early childhood, treatments for obesity may include weight management through diet and behavioral therapies. Gastric bypass surgery has been tried in at least one patient. Several medications are available for treating obesity, although all have limited effectiveness and may have side effects. Most of these treatments do not result in permanent weight loss.

Setmelanotide has been approved by the U.S. Food and Drug Administration (FDA) for people six years and older with obesity due to PCSK1 deficiency which has been confirmed by genetic testing. People taking setmelanotide are able to control their appetite, lose weight and maintain weight loss.

In addition, growth hormone may be given to increase height and other hormones may be given if they are deficient.

People with PCSK1 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

Meier DT, Rachid L, Wiedemann SJ, Traub S, Trimigliozzi K, Stawiski M, Sauteur L, Winter DV, Le Foll C, Brégère C, Guzman R, Odermatt A, Böni-Schnetzler M, Donath MY. Prohormone convertase 1/3 deficiency causes obesity due to impaired proinsulin processing. Nat Commun. 2022 Aug 13;13(1):4761.

Wabitsch M, Farooqi S, Flück CE, Bratina N, Mallya UG, Stewart M, Garrison J, van den Akker E, Kühnen P. Natural history of obesity due to POMC, PCSK1, and LEPR deficiency and the impact of setmelanotide. J Endocr Soc. 2022 Apr 15;6(6):bvac057.

Markham A. Setmelanotide: first approval. Drugs. 2021 Feb;81(3):397-403. doi: 10.1007/s40265-021-01470-9.

Clément K, Mosbah H, Poitou C. Rare genetic forms of obesity: from gene to therapy. Physiol Behav. 2020 Dec 1;227:113134. doi: 10.1016/j.physbeh.2020.113134. Epub 2020 Aug 14.

Pépin L, Colin E, Tessarech M, Rouleau S, Bouhours-Nouet N, Bonneau D, Coutant R. A new case of PCSK1 pathogenic variant with congenital proprotein convertase 1/3 deficiency and literature review. J Clin Endocrinol Metab. 2019 Apr 1;104(4):985-993.

Ramos-Molina B, Martin MG, Lindberg I. PCSK1 variants and human obesity. Prog Mol Biol Transl Sci. 2016;140:47-74. doi: 10.1016/bs.pmbts.2015.12.001. Epub 2016 Jan 29.

Stijnen P, Ramos-Molina B, O’Rahilly S, Creemers JW. PCSK1 mutations and human endocrinopathies: from obesity to gastrointestinal disorders. Endocr Rev. 2016 Aug;37(4):347-71. doi: 10.1210/er.2015-1117. Epub 2016 May 17.

INTERNET

Proprotein Convertase 1/3 Deficiency. Online Mendelian Inheritance in Man (OMIM). Last updated: November 8, 2022. Available from: https://www.omim.org/entry/600955 Accessed Jan 3, 2023.

Obesity due to prohormone convertase I deficiency. Orphanet. Last updated December 29, 2022. Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=71528 Accessed Jan 3, 2023.

Setmelanotide Injection. MedlinePlus. Updated August 15, 2022. Available from: https://medlineplus.gov/druginfo/meds/a622059.html Accessed Jan 3, 2023.

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