Rare obesity disorders call for genetic testing, targeted therapies
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Severe obesity starting early in life is a hallmark of rare genetic disorders of obesity. A genetic diagnosis can alleviate feelings of guilt or blame and lessen social stigma for youths with these disorders and their families.
Obesity is a complex and multifactorial disease involving interactions between behavioral, environmental, genetic and metabolic factors that contribute to increased risk for comorbidities and mortality. Severe obesity, defined as BMI at or above 120% of the sex-specific 95th percentile in children and adolescents or BMI at least 40 kg/m2 in adults, affects about 6% and 8% of youths and adults in the United States, respectively.
Genetic pathways
Severe obesity beginning at age 2 to 5 years occurs in about 2% of U.S. youths and may signal a rare genetic disorder, including one associated with variants in the energy-regulating melanocortin-4 receptor (MC4R) pathway, a component of the central melanocortin pathway. Severe insatiable hunger, or hyperphagia, also often occurs in individuals with genetic disorders of obesity. In cases of genetic disorders associated with the MC4R pathway, severe obesity is often accompanied by additional clinical characteristics that suggest a diagnostic opportunity.
Bardet-Biedl syndrome (BBS) and Alström syndrome are characterized by multisystem dysfunction, including early-onset obesity, which may stem from MC4R pathway dysfunction. The estimated global prevalence of BBS ranges from 1 in 3,700 to 1 in 160,000 individuals, with the higher prevalence observed in isolated populations. The estimated global prevalence of Alström syndrome ranges from fewer than 1 in 100,000 to 1 to 9 in 1 million individuals.
Differentiating rare genetic disorders of obesity, including BBS and Alström syndrome from nongenetic obesity is critical for understanding obesity pathogenesis and the advancement of targeted therapies for individuals with rare genetic disorders of obesity. Obesity-associated primary cilia dysfunction may be involved in both BBS and Alström syndrome. Variants in at least 25 genes have been associated with BBS, and Alström syndrome is associated with variants in ALMS1. Both BBS-associated proteins and ALMS1 are essential to primary cilia development and function. The development of early-onset severe obesity in these disorders may be the result of impaired MCR4 signaling due to loss of cilia function.
Clinical features
Individuals presenting with early-onset severe obesity and hyperphagia should be considered candidates for genetic testing. Genetic testing is also useful for individuals who show characteristics of syndromic obesity, given that multisystem dysfunction and overlapping symptoms are common (Figure).
A clinical diagnosis of both BBS and Alström syndrome should be suspected when certain characteristics are present. In both syndromes, commonly observed clinical characteristics can be used to identify and differentiate affected individuals from those with nongenetic obesity. Similar to other rare genetic disorders of obesity, individuals with BBS or Alström syndrome often experience hyperphagia, a symptom that can be distressing for the affected individuals and their caregivers. Additionally, renal dysfunction and hypogonadism may be present in individuals with either syndrome. Visual impairment, sometimes leading to blindness, occurs in both diseases owing to retinal degeneration.
In addition to sensory and organ dysfunction, individuals with BBS often present with postaxial polydactyly, a major diagnostic feature of the disorder. Cognitive impairment and learning disabilities are also observed in many individuals. Additional characteristic features of BBS are polydipsia, polyuria (nephrogenic diabetes insipidus), diabetes, brachydactyly and syndactyly, poor coordination, anosmia, dental anomalies and congenital heart disease.
Similar to BBS, the clinical characteristics of Alström syndrome affect multiple systems and organs. In addition to visual impairments, these individuals often experience bilateral sensorineural hearing loss in the first decade of life, progressing to severe or moderately severe impairment by the second decade of life. Insulin resistance in early childhood and development of type 2 diabetes later in life are also common in Alström syndrome. Cardiomyopathy, hypothyroidism, hypertriglyceridemia and hepatic disease are also often present in the disorder.
Targeted therapy in development
There are currently no targeted treatments for BBS or Alström syndrome, and available therapies for managing obesity in these individuals are limited. Lifestyle changes, including diet, exercise and behavioral therapies, as well as bariatric surgery, can be used to manage obesity in these individuals but may not provide long-term management and do not manage other symptoms such as hyperphagia, leaving a significant need for targeted therapies.
Rare genetic disorders of obesity that result from MC4R pathway dysfunction have the potential to be managed with targeted therapies. In clinical studies, treatment with setmelanotide (Rhythm Pharmaceutical) — an MC4R agonist — has led to weight loss and hunger management in these disorders, including BBS or Alström syndrome. In a phase 2 trial of setmelanotide, weight loss of at least 5% from baseline was observed in all six participants with BBS completing 12 months of treatment, with four participants achieving weight loss greater than 10%. All three individuals with Alström syndrome completing 12 months of setmelanotide treatment achieved weight loss of at least 5% with one participant losing more than 10% of their original body weight. Additionally, hunger was reduced for all six participants with BBS and for two of three participants with Alström syndrome who completed the trial.
Adverse events observed with setmelanotide treatment were manageable and included injection site reactions and increased skin pigmentation. A phase 3 trial of setmelanotide in individuals with BBS or Alström syndrome is currently ongoing (NCT03746522). This novel therapy offers an important potential breakthrough for the management of obesity associated with BBS, Alström syndrome and other rare genetic disorders of obesity.
While new targeted therapies become available, it is critical for health care providers to be aware of the clinical features and characteristics of BBS and Alström syndrome to identify and diagnose individuals who could benefit from targeted therapies. Additionally, genetic testing can end the diagnostic journey and provide a definitive diagnosis. Individuals presenting with multisystem dysfunction and a history of severe obesity are ideal candidates for genetic testing and have the potential to gain substantial clinical benefit from targeted novel pharmacotherapies.
References:
- Forsythe E, et al. Front Pediatr. 2018;doi:10.3389/fped.2018.00023.
- Haws RM, et al. Clinical study experience of the MC4R agonist setmelanotide in the treatment of rare genetic disorders of obesity: Results from Bardet-Biedl syndrome and Alström cohorts in a phase 2 open-label study. Presented at: Keystone Symposia on Molecular and Cellular Biology: Functional Neurocircuitry of Feeding and Feeding Disorders. Feb. 10-14. 2019; Banff, Alberta, Canada.
- Huvenne H, et al. Obes Facts. 2016;doi:10.1159/000445061.
- Marshall JD, et al. Eur J Hum Genet. 2007;doi:10.1038/sj.ejhg.5201933.
For more information:
Robert M. Haws, MD, is a pediatric nephrologist in the pediatrics department at Marshfield Clinic Research Institute in Marshfield, Wisconsin. He can be reached at robert@marshfieldclinic.org.
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