Other symptoms include seizures, hypotonia, feeding difficulties, gastroesophageal reflux disease, constipation, vomiting, heart defects (atrial septal defects and mitral valve prolapse), brain abnormalities (anxiety, aggressiveness, obsessive compulsive disorder), delayed milestones, severe cognitive delays, language disorder, motor skill disorder, undescended testicles, bilateral cryptorchidism, congenital hernia, and visual disturbances (hypermetropia, strabismus, and ptosis) ( 1, 5, 26). Dysmorphic facial features are common, including a prominent forehead, high hairline, widely spaced and down-sloping eyes, posteriorly rotated ears, large head, long flat philtrum, thin upper lip, and a flat/broad nasal bridge (( 4) ). SymptomsĬhildren are delivered on time (normal length and weight) ( 1, 26). Most recent data showed direct protection of CP201 against deleterious effects of ADNP pathogenic sequence variants spanning the ADNP protein ( 24, 25) as detailed below. Mice with both Adnp genes deleted ( Adnp −/−) do not survive, as Adnp is critical for neural tube closure and further brain formation ( 4, 23). Data have shown the resolution of these symptoms with the administration of CP201, which also reduces neurodegeneration ( 20, 22). In this respect, Adnp +/− mice suffer from learning and memory deficiencies, muscle weakness, and communication problems. The mutation is most often a de novo ( 4). The syndrome occurs when one of the two copies of the ADNP gene is mutated and loses its normal function ( 4). This causes a negative impact on brain formation leading to decreased learning skills and memory ( 5). When there is a mutation and one of the ADNP alleles is lost (or dysfunctional), there is a disruption in the MT–EB protein interaction ( 6). Importantly, ADNP interacts directly with the MT end-binding proteins (EB1 and EB3). Tau hyperphosphorylation has been associated with neurodegeneration along with cognitive decline ( 6, 20, 21). In the cytoplasm, ADNP has been shown to correlate with the microtubule (MT)–associated protein Tau, leading to dynamic Tau expression and protection against Tau pathology (hyperphosphorylation) ( 20). In the nucleus, ADNP is a member of a chromatin remodeling complex that is responsible for RNA transcription and splicing ( 13, 17– 19). More than 400 genes are regulated by ADNP, which are critical for brain formation, organ development, cognition, and motor function ( 6, 13– 16). According to the original description, the ADNP syndrome is estimated to account for 0.17% of all cases of ASD ( 4, 12). The ADNP gene is one of the most prevalent single mutated genes within the autism spectrum disorders (ASDs) ( 5, 6, 10, 11). NAP is referred here to as CP201 ( 1, 4, 7, 8). The protein comprises 1,102 amino acids including asparagine–alanine–proline–valine–serine–isoleucine–proline–glutamine (NAPVSIPQ), which is an 8-amino-acid neuroprotective peptide called NAP (also discovered by the Gozes Laboratory). The gene is located on the q13.13 band of chromosome 20 ( 8, 9). The human ADNP gene is ~40 kilobases long and contains five exons and four introns ( 5). as reviewed in the laboratory of Illana Gozes, the discoverer of the ADNP gene ( 2– 8). ADNP de novo mutations (pathogenic sequence variants) causing syndromic autism were first described by O'Roak et al. The ADNP syndrome ( ) traits include limitations of social interactions and communication along with stereotypic, repetitive behavior, and restricted interest ( 1). With a clean toxicology and positive human adult experience, CP201 is planned for future clinical trials in the ADNP syndrome. Further studies showed that the ADNP microtubule-interacting fragment NAP (called here CP201) resolves, in part, Adnp deficiencies and protects against ADNP pathogenic sequence variant abnormalities. Original data showed that Adnp +/− mice suffer from learning and memory deficiencies, muscle weakness, and communication problems. The syndrome occurs when one of the two copies of the ADNP gene carries a pathogenic sequence variant, mostly a de novo mutation resulting in loss of normal functions. Specifically, the disease is suspected when a child is suffering from developmental delay and/or intellectual disability. The Elton Laboratory for Molecular Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv, IsraelĪctivity-dependent neuroprotective protein ( ADNP) syndrome, also known as Helsmoortel-Van Der Aa syndrome, is a rare condition, which is diagnosed in children exhibiting signs of autism.
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