davunetide and Intellectual-Disability

Mutations in ADNP were recently identified as a frequent cause of syndromic autism, characterized by deficits in social communication and interaction and restricted, repetitive behavioral patterns. Based on its functional domains, ADNP is a presumed transcription factor. The gene interacts closely with the SWI/SNF complex by direct and experimentally verified binding of its C-terminus to three of its core components. A detailed and systematic clinical assessment of the symptoms observed in our patients allows a detailed comparison with the symptoms observed in other SWI/SNF disorders. While the mutational mechanism of the first 10 patients identified suggested a gain of function mechanism, an 11th patient reported here is predicted haploinsufficient. The latter observation may raise hope for therapy, as addition of NAP, a neuroprotective octapeptide named after the first three amino acids of the sequence NAPVSPIQ, has been reported by others to ameliorate some of the cognitive abnormalities observed in a knockout mouse model. It is concluded that detailed clinical and molecular studies on larger cohorts of patients are necessary to establish a better insight in the genotype phenotype correlation and in the mutational mechanism.

Topics: Abnormalities, Multiple; Animals; Autistic Disorder; Child, Preschool; DNA Helicases; Face; Hand Deformities, Congenital; Haploinsufficiency; Homeodomain Proteins; Humans; Infant; Intellectual Disability; Mice, Knockout; Micrognathism; Mutation; Neck; Nerve Tissue Proteins; Nuclear Proteins; Oligopeptides; Transcription Factors

Down syndrome (DS) affects 1/800 infants. Prenatal NAPVSIPQ (NAP) and SALLRSIPA (SAL) (NAP+SAL) prevent developmental delay in Ts65Dn mice, a mouse model of DS. We investigated whether this finding involves N-methyl-D-aspartic acid and gamma-aminobutyric acid (GABA) receptor subunits.. Pregnant Ts65Dn mice were treated with placebo or NAP+SAL on gestational days 8-12. After developmental delay prevention was shown, 4 trisomic (Ts), 4 control, and 3 Ts+NAP+SAL adult offspring brains (from 3 litters) were collected. Calibrator-normalized real-time polymerase chain reaction was performed using primers for N-methyl-D-aspartic acid subunits NR2A and NR2B, and for GABA subunits GABA(A)alpha5 and GABA(A)beta3 with glyceraldehyde-3-phosphate dehydrogenase standardization. Statistics included analysis of variance and Fisher PLSD with P < .05 as significant.. NR2A, NR2B, and GABA(A)beta3 levels were decreased in Ts vs control (all P < .05). Prenatal NAP+SAL increased NR2A, NR2B, and GABA(A)beta3 to levels similar to control (all P < .05). A significant difference in GABA(A)alpha5 levels was not found.. Prenatal NAP+SAL increases NR2A, NR2B, and GABA(A)beta3 expression in adult DS mice to levels similar to controls. This may explain how NAP+SAL improve developmental milestone achievement.

Topics: Animals; Animals, Newborn; Brain Diseases; Central Nervous System; Disease Models, Animal; Down Syndrome; Female; Intellectual Disability; Mice; Mice, Mutant Strains; Nerve Tissue Proteins; Oligopeptides; Peptide Fragments; Pregnancy; Prenatal Exposure Delayed Effects; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate