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Leptin deficiency may come in another form, in which the body produces a dysfunctional protein that leads to extreme obesity, despite apparently high circulating levels of the hormone, according to German researchers.

, of the University of Ulm in Germany, and colleagues reported a new mutation in LEP -- the gene that encodes leptin -- in a 2-year-old boy who was obese but still had high serum leptin levels.

They found a novel homozygous transversion (c.298G>T) that leads to a change from aspartic acid to tyrosine at amino acid position 100 (p.D100Y), which they published in a .

All cases of congenital leptin deficiency have thus far been characterized by undetectable or very low levels of circulating leptin, with some defects in synthesis or secretion, and several culprit mutations have been found.

But researchers recently developed an animal model in which the animals have the hyperphagia and extreme obesity characteristic of this disease, but they also very high leptin levels -- suggesting that the hormone is biologically inactive.

It hasn't been clear whether this type of leptin dysfunction could also occur in humans.

So Wabitsch and colleagues sequenced the 2-year-old's LEP gene, and did the same in 720 local children for comparison.

The boy definitely had high leptin levels, at 42.6 ng/mL, which were highly immunoreactive.

The researchers found a novel homozygous transversion (c.298G>T) in the LEP gene that led to the change from aspartic acid to tyrosine at amino acid position D100Y.

Overexpression studies showed that the mutant leptin is secreted, but neither binds to nor activates the leptin receptor.

The researchers also assessed leptin-deficient ob/ob mice, which were given either normal leptin or the boy's dysfunctional leptin. Only the mice given the dysfunctional leptin didn't have a reduction in food intake or body weight.

Wabitsch and colleagues treated the boy with recombinant human leptin, metreleptin (Myalept), which led to a rapid reduction in eating behavior, in daily energy intake, and substantial weight loss, they reported.

It's currently recommended to screen for leptin concentrations in children with rapid weight gain and extreme obesity, but the researchers warn that clinicians shouldn't rule out leptin deficiency when high levels are still present.

"Given our findings," they wrote, "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."

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