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Disease Areas

Prader-Willi Syndrome (PWS)

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 8,000-11,000 patients in the United States and 13,000-18,000 in Europe.

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Hyperphagia, or unrelenting hunger, is the hallmark symptom of PWS
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.

References

  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.

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Classic Congenital Adrenal Hyperplasia (CAH)

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.

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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)

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Vasomotor Symptoms (VMS)

Vasomotor symptoms (VMS) are defined as hot flashes and night sweats in menopausal women. As estrogen levels fall during menopause, the neurons believed to be the key modulators of the heat dissipation response become hyperactive. This leads to VMS, including sensations of heat and/or perspiration that generally last several minutes and are often preceded or followed by sensations of cold and/or shivering.

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It is estimated that VMS are experienced by approximately 80% of women in menopausal transition, or approximately 20 million women in the United States at any given time. VMS interfere with the lives of affected women in many significant ways, including disrupting patients’ ability to sleep and concentrate, which can cause anxiety and depression. VMS tend to start in the peri-menopausal period and continue for an average of 7.4 years but may last for up to 12 years, according to recent data published in the Journal of the American Medical Association [Current standards of therapy include hormone replacement therapy, or HRT, selective serotonin reuptake inhibitors, or SSRIs, and a variety of over-the-counter treatments. While HRT is effective in treating VMS, many women are reluctant to use HRT due to the increased risk of breast cancer associated with prolonged exposure, which was first elucidated in the findings of the Women’s Health Initiative2. Currently approved non-hormonal therapies for VMS do not address the underlying hormonal dysregulation associated with this common symptom of menopause.

References

  1. Avis, NE, et al. Duration of Menopausal Vasomotor Symptoms Over the Menopause Transition. JAMA Intern Med. 2015 Apr 1; 175(4): 531–539. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433164/
  2. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 2003; 289:3243.

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