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The most common genetically caused form of obesity

Prader-Willi syndrome (PWS) is caused by the lack of expression of several genes on chromosome 15. The suppression of these genes leads to intellectual disability, short stature, incomplete sexual development and hyperphagia among other symptoms. The incidence of PWS is approximately 1 in 15,000 births1. PWS patients suffer from premature mortality, usually by the age of 30-40, mainly from obesity related conditions such as cardiovascular disease, respiratory distress and also from accidents2. The prevalence of PWS is estimated between 8,000-12,000 patients in the United States.

Hyperphagia is the hallmark symptom

While PWS patients experience a multitude of symptoms, hyperphagia is the greatest concern. Patients develop a chronic insatiable appetite early in childhood, which when coupled with a low resting energy expenditure leads to significant weight gain. Although the complications of obesity and hyperphagia are the leading causes of death, hyperphagia causes significant burden on both the patients and the caretakers of PWS patients, often parents. In an effort to manage the access and intake of food, cupboards are often padlocked and strict controls are instituted to manage both the hyperphagia and the behaviors associated with the disease.

There is no treatment for PWS hyperphagia

Currently, there is no effective or approved treatment for hyperphagia and abnormal eating behaviors associated with PWS. The only way to effectively manage hyperphagia, obesity and the related complications is strict control over access to food. This is particularly difficult to institute as PWS patients have low resting energy expenditures and thus reduced caloric needs. Growth hormone is used for improvement in height, cognition and body composition, but has no effect on appetite and over-eating3.

  1. www.fpwr.org Foundation for Prader-Willi Research
  2. Butler M, Manzardo A, Heinemann J, Loker C, Loker J (2016) Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year Mortality Survey Genetics in Medicine, doi:10.1038/gim.2017.92
  3. Carrel, AL, Myers SE, Whitman BY, Eickhoff J, Allen DB, Long-term growth hormone therapy changes the natural history of body composition and motor function in children with Prader Willi syndrome J Clin Endocrinol Metab. 2010 Mar, 95(3): 1131-6

Genetic disease that prevents natural synthesis of certain hormones

Classic congenital adrenal hyperplasia (CAH) is a rare inherited endocrine disorder caused by a genetic mutation in a crucial enzyme for cortisol synthesis, and is characterized by overgrowth of the adrenal glands, adrenal insufficiency, mineralocorticoid deficiency, and androgen excess. The most frequent form of CAH, responsible for 95% of cases, is a deficiency in the enzyme 21-hydroxylase, which is required for the production of cortisol and aldosterone in the adrenal glands. There are two main types, classic and non-classical CAH. Classic CAH is diagnosed at birth and is characterized by adrenal insufficiency. It can lead to severe virilization in women, testicular tumors in men, and infertility. Non-classical CAH is a milder form of CAH, usually not diagnosed until adolescence, but with a larger prevalence of 0.1-0.2% of the general population. Classic CAH is the current focus of ATR-101.

CAH is an orphan disease with universal screening

Classic CAH has an incidence of 1 in 10,000-15,000 births in North American and European populations1. CAH occurs in both males and females, but its presentation from patient to patient can be quite different. Adrenal crisis, a life-threatening condition that occurs when the body cannot produce sufficient cortisol in response to stress, is a risk in both males and females with classic CAH. For this reason, all newborns in the US and in many other countries are screened for CAH at birth and treated as appropriate with corticosteroid replacement (glucocorticoids and, in many cases, mineralocorticoids) to make up for their inability to synthesize these hormones. CAH also causes hormonal imbalances in adults.

Despite taking corticosteroids, most patients are unable to achieve hormonal balance

Corticosteroids are the current standard of care for classic CAH and are used to address the endogenous cortisol deficiency of CAH patients. Such exogenous cortisol administration, however, has its own complications and side effects, and it is difficult to mimic normal glucocorticoid levels. Elevated ACTH levels can result and cause excess adrenal production of various androgens, including testosterone. In women, these excess androgens cause hirsutism, alopecia, acne, and irregular menstruation. In men, testicular adrenal rest tumors occur at a high rate that, in turn leads to a high rate of infertility. Increasing exogenous corticosteroids is the current means of addressing such issues, but often results in iatrogenic Cushing’s syndrome. The patient and the physician are often trapped between over-treating with corticosteroids and suffering from elevated levels of androgens.

References

  1. Speiser PW, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2010 Sep;95(9):4133-60. (PMID: 20823466)

A rare disease with limited treatment options

Endogenous Cushing's syndrome (CS) is a rare endocrine disorder characterized by increased cortisol production from the adrenal gland, which is the result of a pituitary, adrenal or ectopic tumor. Cushing's syndrome caused by a pituitary tumor is called Cushing's disease. The incidence of endogenous CS is about two persons per million annually1. It most commonly affects people who are 20 to 50 years of age, and women are three times more likely than men to have CS. Many cases of CS can be cured through surgery, but for those cases that are refractory to surgery, medical management can be quite challenging. New broad-acting agents are needed, as currently approved treatments are only for subsets of CS patients and are limited by side effects.

Impact to the patient goes beyond cortisol

The chronic cortisol excess in Cushing's syndrome can cause a multitude of issues for the patient such as weight gain, fatigue, hypertension, diabetes, bone loss, purple stretch marks, and a range of neurologic symptoms. In men, symptoms can also include decreased fertility and erectile dysfunction, while women may demonstrate menstrual irregularities and facial hair growth. With chronic exposure to higher than normal levels of cortisol, patients also exhibit cognitive impairment and mood disorders. The cumulative impact of these symptoms decreases the quality of life of the patients to an extent comparable to multiple sclerosis and cancer2. Untreated CS can be life-threatening.

References

  1. Sharma ST, et al. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015 Apr; 17(7):281-93. (PMID: 25945066)
  2. Feelders RA, et al. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol. 2012 Sep;167(3):311-26. (PMID: 22728347)