Congenital Leptin Deficiency Due to Homozygosity for the Δ133G Mutation: Report of Another Case and Evaluation of Response to Four Years of Leptin Therapy
Abstract
Congenital leptin deficiency is a rare, but treatable, cause of severe early-onset obesity. To date, two United Kingdom families of Pakistani origin carrying a frameshift/premature stop mutation, c.398delG (Delta133G), and one Turkish family carrying a missense mutation, c.313C>T (Arg(105)Trp), have been described. Affected subjects are homozygotes and manifest severe obesity and hyperphagia accompanied by metabolic, neuroendocrine, and immune dysfunction. The effects of recombinant leptin therapy have been reported in three children with the Delta133G mutation, and in all cases this has led to a dramatic resolution of clinical and biochemical abnormalities. We now report a Canadian child, of Pakistani origin but unrelated to the previously reported subjects, presenting with severe hyperphagia and obesity, who was found to be homozygous for the Delta133G mutation. In this child, 4 yr of therapy with sc injections of recombinant leptin provided additional evidence for the sustained beneficial effects of leptin replacement on fat mass, hyperinsulinemia, and hyperlipidemia. In addition, leptin administration corrected abnormal thyroid biochemistry and allowed the withdrawal of T(4) treatment, providing additional support for the role of leptin in the regulation of the human hypothalamic-pituitary-thyroid axis.
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Congenital leptin deficiency is characterized by obesity, excessive adipose tissue, moderate storage of ectopic fat, and moderate insulin resistance.
“The second example is congenital leptin deficiency (18 -20), which is characterized by obesity, excessive adipose tissue, moderate storage of ectopic fat, and moderate insulin resistance.”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [20]
In congenital leptin deficiency, metabolic abnormalities of dyslipidemia, glucose intolerance, and steatosis, which are only mildly abnormal, are corrected by leptin therapy.
“Metabolic abnormalities of dyslipidemia, glucose intolerance, and steatosis, which are only mildly abnormal, are also corrected by leptin therapy.”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [20]
In congenital leptin deficiency, leptin replacement therapy is highly effective in controlling appetite, reducing food intake, and reducing overall fat mass.
“Here, leptin replacement therapy is highly effective in controlling appetite, reducing food intake, and reducing overall fat mass.”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [20]
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- Authors
- Gibson, W. T., Farooqi, I. S., Moreau, M., DePaoli, A. M., Lawrence, E., O’Rahilly, S., & Trussell, R. A.
- Affiliations
- University of Cambridge (GB)
- Alberta Children's Hospital (CA)
- Amgen (United States) (US)
- Corresponding author
- Gibson, William T.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2004-10
- Volume
- 89
- Issue
- 10
- Pages
- 4821-4826
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2082181174
- Semantic Scholar
- ba155a16f73b8ee90e965d2ec74ca1c483c957db
- Cited by
- 275
- References
- 17
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 11 · 2023: 8 · 2022: 5 · 2021: 7 · 2020: 4 · 2019: 9 · 2018: 14 · 2017: 16 · 2016: 11 · 2015: 14 · 2014: 20 · 2013: 15 · 2012: 26
- FWCI
- 4.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (068086)
- Health Research Board
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- congenital leptin deficiency, homozygosity, early-onset obesity, hyperphagia, leptin replacement, hyperinsulinemia, hyperlipidemia, thyroid dysfunction, hypothalamic-pituitary-thyroid axis, Pakistani children
- MeSH terms
- Body Composition, Body Weight, Bone Development, Child, Child, Preschool, Female, Follicle Stimulating Hormone, Homozygote, Humans, Hypothyroidism, Insulin, Leukocyte Count, Luteinizing Hormone, Lipids, Obesity, Point Mutation, Leptin
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