Premature primary tooth eruption in cognitive/motor-delayed ADNP-mutated children

Abstract

A major flaw in autism spectrum disorder (ASD) management is late diagnosis. Activity-dependent neuroprotective protein (ADNP) is a most frequent de novo mutated ASD-related gene. Functionally, ADNP protects nerve cells against electrical blockade. In mice, complete Adnp deficiency results in dysregulation of over 400 genes and failure to form a brain. Adnp haploinsufficiency results in cognitive and social deficiencies coupled to sex- and age-dependent deficits in the key microtubule and ion channel pathways. Here, collaborating with parents/caregivers globally, we discovered premature tooth eruption as a potential early diagnostic biomarker for ADNP mutation. The parents of 44/54 ADNP-mutated children reported an almost full erupted dentition by 1 year of age, including molars and only 10 of the children had teeth within the normal developmental time range. Looking at Adnp-deficient mice, by computed tomography, showed significantly smaller dental sacs and tooth buds at 5 days of age in the deficient mice compared to littermate controls. There was only trending at 2 days, implicating age-dependent dysregulation of teething in Adnp-deficient mice. Allen Atlas analysis showed Adnp expression in the jaw area. RNA sequencing (RNAseq) and gene array analysis of human ADNP-mutated lymphoblastoids, whole-mouse embryos and mouse brains identified dysregulation of bone/nervous system-controlling genes resulting from ADNP mutation/deficiency (for example, BMP1 and BMP4). AKAP6, discovered here as a major gene regulated by ADNP, also links cognition and bone maintenance. To the best of our knowledge, this is the first time that early primary (deciduous) teething is related to the ADNP syndrome, providing for early/simple diagnosis and paving the path to early intervention/specialized treatment plan.

Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study

“…Tauclearance therapies [15] are also being developed, however, Tau monotherapy may not suffice [44,45]. Importantly, it is apparent that the various tauopathies constitute different diseases, which may require versatile treatment modalities [15].…”

“…Soluble tau damages the morphology and connectivity of newborn granule cells [54] and NAP/ADNP enhance Tau-MT association and dendritic spine formation in an EB1/EB3dependent manner [23,25]. Furthermore, Tau aggregation is inhibited by augmented autophagy [55], and ADNP/ NAP accelerate autophagy [14,15,19,[56][57][58][59]. As tauopathy is suggested to propagate in a prion-like manner [60][61][62], it is hypothesized that even rare occurrences of cellular tauopathy will propagate, making prevention therapy with NAP treatment prior to disease onset a desired possibility.…”

Synaptic metabolism: a new approach to inborn errors of neurotransmission

“…Besides classic neurotransmitters (biogenic amines and amino acids), there are other signaling molecules involved in neuronal communication. Some of the most relevant include ADNP (activity-dependent neuroprotective protein) that regulates axonal transport (Gozes et al 2017), Spermine (Spermine synthase deficiencies produce intellectual disability), X-linked Synder-Robinson type (Pegg 2014), and BDNF (brain-derived neurotrophic factor). BDNF is the most known neurotrophin in the brain which plays an important role in synaptogenesis and synaptic plasticity mechanisms.…”

ADNP Plays a Key Role in Autophagy: From Autism to Schizophrenia and Alzheimer's Disease

“…Together with additional point/frameshift truncating mutations identified in autistic patients, all of whom suffered from intellectual deficiencies, delayed developmental milestones including motor function development and shared characteristic facial features, it was concluded that mutations in ADNP cause a syndromic form of autism. A short summary of the clinical phenotype was recently published including the observation that most ADNP syndrome children also exhibit early primary tooth eruption . Importantly, a systematic variant annotation approach for ranking genes associated with ASDs classified ADNP as one of three most prevalent autism‐causing genes (including SHANK3 and CHD8 ) …”

“…Future clinical studies are planned for the ADNP syndrome by Coronis Neurosciences (http://www.coronisns.com/). The syndrome mimics our Adnp‐deficient (heterozygote) mouse model, displaying cognitive and social deficits, which are reversed, in part by the ADNP 8‐amino‐acid snippet NAP (NAPVSIPQ) − Coronis lead compound (CP201), as well as by SKIP (CP102), which reversed BECN1 reduced expression in the female Adnp‐deficient mouse hippocampus …”