OR47-2 Loss of function of DMXL2 causes a complex neuroendocrine disorder with peripheral polyneuropathy and mental disability

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR47-Hypothalamus-Pituitary Development & Biology
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:30 AM
Room 130 (Moscone Center)
Juliane Leger1, Melanie Amouyal2, Sofia Leka2, Alexandra Durr3, Didier Chevenne4, Emmanuelle Genin5, Jean-Claude Carel6 and Nicolas de Roux*2
1Hosp Robert Debre, Paris, France, 2Inserm U676 Hosp Robert Debre, Paris, France, 3Genetic department and Inserm US975. Hosp Pitie Salpetriere, Paris, France, 4AP-HP, Biochemistry Laboratory, Hosp Robert Debre, Paris, France, 5Inserm U1078, Brest, France, 6Paediatric Endocrinology, Hosp Robert Debre, Paris, France
Progressive neuroendocrine disorders with multisystemic manifestations are rare and difficult to diagnose. Here, we studied the clinical and genetic characteristics of a new syndrome, including dysregulation of glucose metabolism, hypogonadotropic hypogonadism, central hypothyroidism, demyelinating neuropathy, cognitive impairment and alopecia in three brothers born from first cousins of Senegalese origin.

Disease onset began in early childhood with growth retardation and profound asymptomatic hypoglycemia diagnosed between two and five years of age. Extensive laboratory analyses revealed normal metabolic and hormonal parameters but spontaneous hypoglycemia (up to 1.6mmol/l), corresponding with incomplete suppression of insulin levels. Between 14 and 16 years of age, subjects started to develop a slowly progressing non-autoimmune insulin deficient diabetes mellitus, central hypothyroidism and partial hypogonadotropic hypogonadism. In addition, they exhibited movement disorders with ataxia and dystonia due to progressive peripheral sensitive-motor demyelinating polyneuropathy, which mainly affected the lower limbs, along with pyramidal manifestations. Brain MRI exposed moderate sub-cortical temporal white matter disease in the older patient. Optic and audio nerve conductions were mildly decreased. All three subjects presented a moderately low intelligence quotient (IQ 70), dysarthria, difficulties swallowing and frontal alopecia to different degrees.

After several candidate genes were unsuccessfully tested, genome mapping followed by high throughput sequencing of two candidate regions revealed an un-described homozygous in-frame deletion of 15 nucleotides in exon 24 of DMXL2 (c.5827_5841del, p.1942_1946del) in the three brothers. The c.5827_5841del deletion was associated with a significant decrease in DMXL2 mRNA levels in blood lymphocytes of the patients. The screening of DMXL2 in 10 additional cases with a similar phenotype did not reveal any new mutation.

DMXL2 encodes for the rabconnectin-3α which is a synaptic protein interacting with regulators of the Rab3a “on-off” activity, a vesicle associated protein involved in the regulatory secretion. The phenotyping of Dmxl2-deleted mice is currently on-going. This will confirm the link between Dmxl2 inactivation and the observed phenotype. It will also lead to understand how a synaptic protein controls pubertal onset through the activation of the gonadotropic axis.

Nothing to Disclose: JL, MA, SL, AD, DC, EG, JCC, ND

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm