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Endocrine Abstracts (2024) 99 P358 | DOI: 10.1530/endoabs.99.P358

ECE2024 Poster Presentations Reproductive and Developmental Endocrinology (45 abstracts)

Congenital hypogonadotropic hypogonadism by PNPLA6 mutations: identification of a wide phenotypic spectrum and functional correlations with the NTE in vitro activity

Luigi Maione 1 , Jerome Bouligand 2 , Antoine Rousseau 3 , Salome Prevost 4 , Lydie Naule 5 , Sylvie Salenave 1 , Philippe Chanson 1 , Ursula Kaiser 6 & Jacques young 7


1Saclay University, Endocrinology and Reproductive Diseases, Le Kremlin-Bicêtre, France; 2Saclay University, Genetics, Le Kremlin-Bicêtre, France; 3Saclay University, Ophtalmology, Le Kremlin-Bicêtre, France; 4Kremlin-Bicètre, Genetics, Le Kremlin-Bicêtre, France; 5Paris, Sorbonne University, Paris, France; 6Brigham and Women’s Hospital, Boston, United States; 7Saclay University, Endocrinology and Reproductive Diseases, Le Kremlin-Bicêtre, France


Background: PNPLA6 mutations are associated with complex autosomal recessive disorders including congenital hypogonadotropic hypogonadism (CHH): Gordon-Holmes syndrome, Boucher-Neuhauser syndrome and hereditary spastic paraplegia, which include ophthalmologic and neurologic disorders in addition to CHH. PNPLA6 gene encodes the neuropathy target esterase (NTE), an endoplasmic reticulum-associated enzyme intervening in the metabolism of membrane phospholipids.

Aim: Analysis of prevalence of PNPLA6 mutations within a large cohort of CHH patients. Clinical, biological, neuroendocrine and molecular characterization of six patients from three unrelated families, carrying five PNPLA6 biallelic mutations.

Patients and Methods: Neuroendocrine profile: measurement of 4 hours-spontaneous LH pulsatility and response to bolus and repeated GnRH (by pump), neurological and ophthalmological examinations of affected patients. Assessment of the enzymatic activity on cell lysates expressing wild-type (WT) and mutant NTE.

Results: Biallelic PNPLA6 mutations are very rare (<1% among 800 exomes in CHH patients). Two brothers harbored a homozygous, four patients a composite heterozygous mutation. Phenotypic spectrum was wide, ranging from severe neurological and ophthalmological manifestations (spastic paraplegia, cerebellar ataxia and chorioretinitis) to a very mild phenotype. Neuroendocrine profile showed apulsatile and unresponsive LH to bolus and repeated GnRH exposure. Molecular analyses showed a variable degree of loss of activity of NTE function according to various mutations. A phenotype-genotype correlation was observed, with a low impact NTE disruption seen in patients with the mildest phenotype.

Conclusion: PNPLA6 mutations are associated with a more diverse phenotype than that previously known. PNPLA6 mutations cause a pituitary deficiency at the level of gonadotropes. Following our results, we recommend to include the sequencing of PNPLA6 gene in all patients with CHH.

Volume 99

26th European Congress of Endocrinology

Stockholm, Sweden
11 May 2024 - 14 May 2024

European Society of Endocrinology 

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