IDENTIFYING RARE GENETIC DISORDERS OF OBESITY

Distracted by food, woman with insatiable hunger in lecture hall

Rare genetic disorders of obesity are different from common obesity in that they are characterized by early-onset, severe obesity and often associated with insatiable hunger (hyperphagia).1 Each disorder appears to have a unique phenotype, but most patients present with the following symptoms:

Early-onset, Severe obesity

Patients with rare genetic disorders of obesity rapidly gain weight early in childhood and present with a BMI greater than the 95th percentile for their age.2 The onset of obesity is usually between 2 to 5 years of age, although cases with an onset as early as 6 months or as late as prepubescence have been reported.1

Insatiable hunger

Behaviors associated with hyperphagia

Learn about the behaviors associated with insatiable hunger from the mother of a patient who is POMC heterozygous.

What hyperphagia feels like

Listen to a patient with a variant of unknown significance (VOUS) explain the physical experience of hyperphagia in her own words.

The impact of hyperphagia

Hear from the mother of a patient who is POMC heterozygous about the challenges of living with insatiable hunger.

Behaviors associated with hyperphagia

What hyperphagia feels like

The impact of hyperphagia

DISORDERS RELATED TO MC4R PATHWAY DYSFUNCTION

Dysfunction in the MC4R pathway has been implicated in several rare genetic disorders of obesity. Currently recognized disorders include1:

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Proopiomelanocortin (POMC) deficiency is a disorder caused by mutations in the POMC or PCSK1 genes.5

Features of POMC deficiency may include5,6:

  • Severe obesity beginning early in life
  • Insatiable hunger
  • Endocrine abnormalities (including adrenocorticotropic hormone deficiency and mild hypothyroidism)
  • Red hair and light skin pigmentation
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Leptin receptor (LEPR) deficiency is a disorder caused by mutations in the LEPR gene.7

Features of LEPR deficiency may include6,7:

  • Severe obesity beginning early in life
  • Insatiable hunger
  • Endocrine abnormalities (specifically, hypogonadotropic hypogonadism and hypothyroidism)
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Bardet-Biedl syndrome (BBS) is a genetic disorder caused by mutations in one or more of the 20+ BBS genes that have been identified.1

Features of Bardet-Biedl syndrome may include9:

  • Severe obesity beginning early in life
  • Mental disabilities
  • Polydactyly
  • Renal dysfunction
  • Hypogonadism
  • Visual impairment (retinal disorders and blindness)
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Alström syndrome is a genetic disorder caused by mutations in the ALMS1 gene.1

Features of Alström syndrome may include1,10:

  • Severe obesity beginning early in life
  • Short stature in adulthood
  • Progressive visual impairment
  • Progressive auditory impairment
  • Insulin resistance and type 2 diabetes mellitus
  • Hyperlipidemia
  • Progressive kidney dysfunction

Research into these disorders is ongoing and helps gain a better understanding of disease-causing mutations. Clinical studies of investigational therapies specifically for rare genetic disorders of obesity are also underway.1,3,4

SCREENING FOR RARE GENETIC DISORDERS OF OBESITY

If you suspect that one of your patients might have a rare genetic disorder of obesity, consider genetic screening. Advancements in screening for confirming suspected cases have only recently become available to clinicians.1,3 Conducting screening sooner rather than later will ensure that your patients are well-positioned if and when treatment specifically for rare genetic disorders of obesity becomes available.

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Symptoms of genetic disorders include early-onset obesity

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  1. Huvenne H, Duberne B, Clément K, Poitou C. Rare genetic forms of obesity: clinical approach and current treatments in 2016. Obes Facts. 2016;9(3):158-173.
  2. Kolsdorf K, Nunziata A, Funcke JB, et al. Early childhood BMI trajectories in monogenic obesity due to leptin, leptin receptor, and melanocortin 4 receptor deficiency. Int J Obes. [epub ahead of print 1 June 2017]. doi:10.1038/s41366-018-0049-6.
  3. da Fonseca ACP, Mastronardi C, Johar A, Arcos-Burgos M, Paz-Filho G. Genetics of non-syndromic childhood obesity and the use of high-throughput DNA sequencing technologies. J Diabetes Complications. 2017;102(3):709-757.
  4. ClinicalTrials.gov. Setmelanotide. Clinicaltrials.gov/ct2/results?cond=&term=setmelanotide. Accessed Sept 6, 2018.
  5. Coll A, Farooqi IS, Challis B, Yeo GSH, O’Rahilly S. Proopiomelanocortin and energy balance: insights from human and murine genetics. J Clin Endocrinol Metab. 2004;89(6):2557-2562.
  6. Styne D, Arslanian S, Connor E, et al. Pediatric obesity—assessment, treatment, and prevention: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2007;102(3);709-757.
  7. Farooqi IS, Wangensteen T, Collins S, Kimber W, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356(3):237-247,
  8. Angulo MA, Butler MG, Cataletto ME. Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings. J Endocrinol Invest. 2015;38:1249-1263.
  9. Zagloul N, Katsanis N. Mechanistic insights into Bardet-Biedl syndrome, a model ciliopathy. J Clin Invest. 2009;119(3):428-437.
  10. Joy T, Cao H, Black G, et al. Alstrom syndrome (OMIM 203800): a case report and literature review. Orphanet J Rare Dis. 2007;2(49).
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