Deficiencies along the MC4R pathway that may cause rare genetic diseases of obesity are likely underdiagnosed. A lack of awareness of these rare diseases exists among healthcare professionals.1

Estimated incidence of MC4R-related rare genetic diseases of obesity in the US population24

Bar chart showing estimated incidence of MC4R-related rare genetic disease of obesity in the US

True prevalence of rare genetic diseases of obesity, including MC4R pathway deficiencies, is unknown. Low awareness results in a lack of suspected cases, and without the suspicion of a potential deficiency, genetic testing is not often pursued.22,25

Affected patients often present with the two hallmark symptoms of early-onset, severe obesity and hyperphagia, and may also demonstrate clinical characteristics including neurological, growth, and endocrine abnormalities as well as a family history of weight differences between family members.1,6

Some MC4R pathway deficiencies include:

Estimated incidence of MC4R-related rare genetic diseases of obesity in the US population24

Bar chart showing estimated incidence of MC4R-related rare genetic disease of obesity in the US

Bardet-Biedl syndrome

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy with a highly variable phenotype that evolves significantly during childhood and/or adolescence.26,27 Individuals with these variants may experience symptoms such as early-onset, severe obesity; hyperphagia; visual impairment; and polydactyly.26,28-29

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Alström syndrome

Alström syndrome is an autosomal recessive inherited disease caused by variants in the ALMS1 gene.30 Individuals with these variants may experience symptoms such as early-onset, severe obesity; rod-cone dystrophy; photophobia; and nystagmus.33

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POMC deficiency

Proopiomelanocortin (POMC) deficiency is an autosomal recessive inherited disease caused by variants in the POMC gene. Individuals with these variants may experience symptoms such as early-onset, severe obesity; hyperphagia; and endocrine abnormalities.6,34-36

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LEPR deficiency

Leptin receptor (LEPR) deficiency is an autosomal recessive disease caused by variants in the LEPR gene. Individuals with these variants may experience symptoms such as hyperphagia; early-onset, severe obesity; and hypogonadotropic hypogonadism.37

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PCSK1 deficiency

Proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency is an autosomal recessive inherited disease caused by variants in the PCSK1 gene, which is also located in the MC4R pathway.11 Individuals with these variants may experience symptoms such as postnatal diarrhea within the first weeks of life, hyperinsulinemia, hypoglycemia, and metabolic acidosis.38,39

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SRC1 deficiency

Steroid receptor coactivator-1 (SRC1) deficiency is an autosomal dominant* inherited disease caused by variants in SRC1 genes.6,42 Individuals with these variants may experience early-onset, severe obesity, hyperphagia, and hyperleptinemia.13,42-43

*Dysfunction/loss of only one copy of the SRC1 gene is sufficient to give rise to obesity and hyperphagia.

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SH2B1 deficiency

SH2B adaptor protein 1 (SH2B1) deficiency is an autosomal dominant* inherited disease caused by variants in SH2B1 genes.6 Individuals with these variants may experience early-onset, severe obesity, hyperphagia, and insulin resistance.40,41

*Dysfunction/loss of only one copy of the SH2B1 gene is sufficient to give rise to obesity and hyperphagia.

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