👤 J Franc

Individuals with obesity caused by biallelic pathogenic LEPR (leptin receptor) variants can benefit from setmelanotide, the novel MC4R agonist. An ongoing phase 3 clinical trial (NCT05093634) includes individuals with obesity who carry a heterozygous LEPR variant, although the obesogenic impact of these variants remains incompletely evaluated. The aim of this study was to functionally assess heterozygous variants in LEPR and to evaluate their effect on obesity. We sequenced LEPR in ∼10,000 participants from the French RaDiO study. We found 86 rare heterozygous variants. Each identified variant was then investigated in vitro using luciferase and western blot assays. Using the criteria of the American College of Medical Genetics and Genomics (ACMG), including the strong criterion related to functional assays, we found 12 pathogenic LEPR variants. Most heterozygotes did not present with obesity, and we found no association between these pathogenic variants and body mass index (BMI). This lack of association between pathogenic LEPR variants and obesity risk or BMI was confirmed using exome data from 200,000 individuals in the UK Biobank. In the literature, among 55 reported heterozygotes for of a rare pathogenic LEPR variant, only 27% had obesity. In conclusion, monoallelic pathogenic LEPR variants were functionally tested, and they do not elevate the risk of obesity or BMI levels. This raises questions about the use of setmelanotide, a costly drug with potential side effects, based solely on the presence of a heterozygous LEPR variant. Show less

A series of 57 patients (from 51 families) with neuronal ceroid lipofuscinosis (NCL) has been diagnosed during the last 25 years. Using clinical and electrophysiological criteria together with results of ultrastructural, histochemical, immunohistochemical and neuropathological analyses it has been possible to classify the following NCL types. Two cases were of the infantile type (CLN1), one case of the juvenile (CLN3) type and one case of the adult (CLN4) type. The bulk of the series was represented by 26 cases of the late infantile (CLN2) type and by 27 cases of the early juvenile (CLN6) type (also called non-Finnish variant late infantile, or Lake-Cavanagh). Besides the infantile form, microcephaly was a relatively frequent finding (nine cases) in the late infantile and early juvenile NCLs. In more than half of the late infantile and early juvenile cases there was a significant reduction of the nerve conduction velocity. The early juvenile CLN6 type was found to have a relatively high incidence in the Romany population (12 cases in nine families). Incidence of NCL in the Czech republic is estimated to be 1.3:100,000. Show less