Last updated:
02/22/2023
Years published: 2023
NORD gratefully acknowledges Prof. Dr. Martin Wabitsch, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany for assistance in the preparation of this report.
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.
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.
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.
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.
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.
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.
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:
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https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
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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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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.
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).
View reportOrphanet 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.
View reportOnline 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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