Rare Mutation Renders Leptin Present but Inactive

Miriam E Tucker

December 31, 2014

A newly identified mutation in the leptin gene causes early-onset extreme obesity by rendering the protein biologically inactive rather than absent.

The case of a child born to consanguineous parents was reported December 31, 2014 in the New England Journal of Medicine by Dr Martin Wabitsch (University of Ulm, Germany) and colleagues.

The finding is clinically important because current recommendations advise measurement of serum leptin concentrations in children who have rapid weight gain in the first months of life in order to identify congenital leptin deficiency. But this child, with the same clinical picture, instead had high serum levels of biologically inactive mutant leptin.

"Given our findings, circulating levels of the hormone that appear to be normal in relation to body mass index and fat mass do not rule out disease-causing mutations in the gene encoding leptin and might obscure the correct diagnosis," Dr Wabitsch and colleagues write.

Leptin expert Dr Elif A Oral (University of Michigan, Ann Arbor) told Medscape Medical News, "As far as I know, this is the first report of biologically inactive leptin seen in humans per se, but there have been reports of most of the other peptide hormones having inactive mutants. Mutant insulin is well-known, but rare."

She said the findings suggest that "high leptin will not totally exclude congenital leptin deficiency as we previously assumed....This may force us to develop assays or tests for assessing leptin responsiveness. I truly believe that there were quite a few reasons to develop these assays even before knowing about this patient, but knowing about this patient [makes me want] to see these kinds of tests find their place in clinical medicine."

The child, whose parents are first cousins, was 2 years and 6 months at presentation and weighed 33.7 kg (> 99th percentile). His body mass index was 38.6 kg/m2. Hyperphagia was confirmed when he was given an unlimited breakfast and rapidly consumed 680 kcal. He also had recurrent ear and pulmonary infections and a history of severe pneumonia.

His serum leptin level was high (42.6 ng/mL), in the range of levels found in children with extreme obesity not related to leptin deficiency, the authors note.

Sequencing ruled out a mutation in the gene encoding the leptin receptor but identified a novel homozygous transversion in the gene encoding leptin. Subsequent testing demonstrated that the mutant protein encoded by the gene was unable to bind to the leptin receptor. Both parents were heterozygous carriers of the mutation.

The child was treated with subcutaneous metreleptin (Myalept, acquired in November 2014 by Aegerion), a drug approved by the US Food and Drug Administration in February 2014 as replacement therapy to treat the complications of leptin deficiency in patients with congenital generalized or acquired generalized lipodystrophy. The boy's excessive eating diminished dramatically and his weight fell, with concurrent metabolic and hormonal changes, Dr Wabitsch and colleagues report.

Dr Oral told Medscape Medical News, "Giving an active analog worked, suggesting that the receptors and postreceptor signals of the patient are working just fine....These findings suggest that leptin could potentially be used to treat extreme obesity even when circulating leptin is not absent. However, this must still be a rare occurrence."

She added, "We now will have to think about this in the differential of extreme childhood obesity. This also shows once again that nature sometimes bestows humanity with gifts that are very insightful to teach us lessons. Seeing just one of a rare situation teaches us that this presentation is possible. Thinking about potential mechanisms of disease in rare presentations of common conditions or rare, unusual diseases will continue to teach us novel possibilities and insights if we are willing to find and uncover them."

Dr Wabitsch reports grant support from the German Federal Ministry of Education and Research during the conduct of the study and personal fees from the Bristol-Myers Squibb/AstraZeneca Diabetes Alliance outside the submitted work. Disclosures for the coauthors are listed here. Dr Oral has received grant, drug, and/or scientific writing support from Amylin, Bristol-Myers Squibb, and AstraZeneca, has worked on scientific advisory boards of Bristol-Myers Squibb and AstraZeneca, and has an active grant from GI Dynamics.

N Engl J Med. Published online December 31, 2014. Article


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