Activity-dependent neuroprotective protein (ADNP)-related intellectual disability and autism spectrum disorders: A literature review

Background: Recently described in 2014, the activity-dependent neuroprotective protein (ADNP) syndrome combines a neurodevelopmental delay (intellectual disability and/or autism) with multiple body organ involvements. ADNP syndrome is a prevalent syndromic autism spectrum disorder caused by a single de novo mutation, leading to an increasing interest in the ADNP gene as well in clinical and behavioral manifestations of the syndrome. However, the full extent of ADNP syndrome is unknown and a comprehensive clinical overview is needed. Aim: We report the current state of knowledge about ADNP syndrome, five years after its discovery. This literature review offers a clinical description and specifies the diagnostic tools and the management of this rare syndrome. Methods: We conducted a literature review on the ADNP syndrome from April 2014 to July 2019, based on Medline bibliographic data, via the PubMed server. We completed our search with a manual search. Results: Eighteen articles provide clinical descriptions of patients with ADNP syndrome. Six articles describe a series of cases or a descriptive cohort study. Twelve articles report isolated clinical cases. The literature review emphasizes the importance of whole-exome sequencing, in order to establish an early diagnosis of the ADNP syndrome, in cases of polymalformative syndrome associated with intellectual disability and/or autism spectrum disorder. An early primary tooth eruption (almost fully erupted dentition by 1 year of age), a coloboma and/or a blepharophimosis are suggestive features, knowing that many organs may be involved (cerebro-cranio-facial malformations, gastrointestinal, cardiac, urogenital, musculoskeletal in particular). Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. Management requires close collaboration between somaticians and psychiatrists. Improvements may be achieved over time when intensive multidimensional and integrative care is provided. It is worth noting that clinical research is underway to offer ADNP children a target-specific therapeutic strategy, using novel biologically active ADNP peptides. Conclusion: Extensive knowledge concerning the ADNP syndrome is very recent. Early recognition of ADNP syndrome is required to improve the multidisciplinary management and quality of life of affected patients and their families. Genetic testing with next generation sequencing strategies such as whole exome sequencing is compulsory for patients with autism spectrum disorder, intellectual disability and multiple congenital anomalies.