The Eight and a Half Year Journey of Undiagnosed AD: Gene Sequencing and Funding of Advanced Genetic Testing Has Led to Hope and New Beginnings

Abstract

BackgroundActivity-dependent neuroprotective protein (ADNP) is one of the most prevalent de novo mutated genes in syndromic autism spectrum disorders, driving a general interest in the gene and the syndrome.AimThe aim of this study was to provide a detailed developmental case study of ADNP p.Tyr719* mutation toward improvements in (1) diagnostic procedures, (2) phenotypic scope, and (3) interventions.MethodsLongitudinal clinical and parental reports.ResultsAD (currently 11-year-old) had several rare congenital anomalies including imperforate anus that was surgically repaired at 2 days of age. Her findings were craniofacial asymmetries, global developmental delay, autistic behaviors (loss of smile and inability to make eye contact at the age of 15 months), and slow thriving as she gradually matures. Comprehensive diagnostic procedures at 3 years resulted in no definitive diagnosis. With parental persistence, AD began walking at 3.5 years (skipping crawling). At the age of 8.5 years, AD was subjected to whole exome sequencing, compared to the parents and diagnosed as carrying an ADNP p.Tyr719* mutation, a causal recurring mutation in ADNP (currently ~17/80 worldwide). Brain magnetic resonance imaging demonstrated mild generalized cerebral volume loss with reduced posterior white matter. AD is non-verbal, communicating with signs and word approximations. She continues to make slow but forward developmental progress, and her case teaches newly diagnosed children within the ADNP Kids Research Foundation.ConclusionThis case study emphasizes the importance of diagnosis and describes, for the first time, early motor intervention therapies. Detailed developmental profile of selected cases leads to better treatments.

Developmental Phenotype of the Rare Case of DJ Caused by a Unique ADNP Gene De Novo Mutation

“…The more we research the ADNP protein and gene, in a variety of ways including that of detailed descriptive case reports of patients with mutations of this gene (Gozes et al 1999;Magen and Gozes 2014;Gozes et al 2015a), the better we will gain a valuable understanding of this unique autistic syndrome. While some previous case reports followed ADNP child development (e.g., Gozes et al 2015aGozes et al , 2017a, this is the first longitudinal study evaluating the Vineland-II and the ABC questionnaires' results, paving the path to a better understanding of the disease natural history, toward rational clinical development.…”

Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome

“…Furthermore, premature primary tooth eruption was recently suggested as an early diagnostic biomarker for ADNP syndrome, with ADNP also regulating tooth eruption in mice (17,18). In-depth case studies of ADNP syndrome provide a broad view of the phenotype and identified, among other impairments, global developmental delays, ID, speech impediments, and motor dysfunctions (17,19,20). With more than 160 children diagnosed (http://www.adnpkids-researchfoundation.…”

Specific protein biomarker patterns for Alzheimer’s disease: improved diagnostics in progress

“…In this respect, de novo, mostly truncating mutations in ADNP lead to cognitive impairments and autism in children [23][24][25][26]. Importantly, we have recently shown that serum ADNP content [27] is correlated with premorbid intelligence.…”