Hormonal
Haploinsufficiency of the SIM1 gene causes severe early-onset obesity by disrupting the development of hypothalamic nuclei (specifically the PVN) that regulate energy balance and food intake.
This paper identifies a specific genetic cause for severe obesity. For patients with early-onset, profound obesity and normal metabolic rates, genetic testing for SIM1 mutations or translocations may be warranted. Standard lifestyle interventions may be insufficient due to the biological drive for intake; medical management targeting the melanocortin pathway may be necessary.
We hypothesize that haploinsufficiency of SIM1, possibly acting upstream or downstream of the melanocortin 4 receptor in the PVN, is responsible for severe obesity in our subject.
Why this rating
Based on a single case study (n=1) with a de novo translocation; strong mechanistic plausibility from mouse models but limited human generalizability.
Source
Profound obesity associated with a balanced translocation that disrupts the SIM1 gene
J. L. · Human Molecular Genetics · 2000
DOI 10.1093/hmg/9.1.101
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