TY - JOUR
T1 - Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males
AU - Levine, Jospeh
AU - Lobyntseva, Alexandra
AU - Shazman, Shula
AU - Hakim, Fahed
AU - Gozes, Illana
N1 - Publisher Copyright:
© 2024, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2024/3
Y1 - 2024/3
N2 - Activity-dependent neuroprotective protein (ADNP) is essential for neurodevelopment and de novo mutations in ADNP cause the ADNP syndrome. From brain pathologies point of view, tauopathy has been demonstrated at a young age, implying stunted development coupled with early/accelerated neurodegeneration. Given potential genotype–phenotype differences and age-dependency, we have assessed here a cohort of 15 individuals (1–27-year-old), using 1–3 longitudinal parent (caretaker) interview/s (Vineland 3 questionnaire) over several years. Our results indicated developmental delays, or even developmental arrests, coupled with potential spurts of development at early ages. Severe outcomes correlated with the truncating high impact mutation, in other words, the remaining mutated protein length as well as with the tested individual age, corroborating the hypothesis of developmental delays coupled with accelerated aging. A significant correlation was noted between mutated protein length and communication, implying a high impact of ADNP on communicative skills. Additionally, correlations were discovered between the two previously described epi-genetic signatures in ADNP emphasizing aberrant acquisition of motor behaviors, with truncating mutations around the nuclear localization signal being mostly affected. Finally, all individuals seem to acquire an age equivalent of 1–6 years, requiring disease modification treatment, such as the ADNP-derived drug candidate, NAP (davunetide), which has recently shown efficacy in women suffering from the neurodegenerative disorder, progressive supranuclear palsy (PSP), a late-onset tauopathy.
AB - Activity-dependent neuroprotective protein (ADNP) is essential for neurodevelopment and de novo mutations in ADNP cause the ADNP syndrome. From brain pathologies point of view, tauopathy has been demonstrated at a young age, implying stunted development coupled with early/accelerated neurodegeneration. Given potential genotype–phenotype differences and age-dependency, we have assessed here a cohort of 15 individuals (1–27-year-old), using 1–3 longitudinal parent (caretaker) interview/s (Vineland 3 questionnaire) over several years. Our results indicated developmental delays, or even developmental arrests, coupled with potential spurts of development at early ages. Severe outcomes correlated with the truncating high impact mutation, in other words, the remaining mutated protein length as well as with the tested individual age, corroborating the hypothesis of developmental delays coupled with accelerated aging. A significant correlation was noted between mutated protein length and communication, implying a high impact of ADNP on communicative skills. Additionally, correlations were discovered between the two previously described epi-genetic signatures in ADNP emphasizing aberrant acquisition of motor behaviors, with truncating mutations around the nuclear localization signal being mostly affected. Finally, all individuals seem to acquire an age equivalent of 1–6 years, requiring disease modification treatment, such as the ADNP-derived drug candidate, NAP (davunetide), which has recently shown efficacy in women suffering from the neurodegenerative disorder, progressive supranuclear palsy (PSP), a late-onset tauopathy.
KW - ADNP syndrome
KW - Activity-dependent neuroprotective protein (ADNP)
KW - Helsmoortel-van der Aa syndrome (HVDAS)
KW - Vineland 3 questionnaire
UR - http://www.scopus.com/inward/record.url?scp=85183379863&partnerID=8YFLogxK
U2 - 10.1007/s12031-024-02189-4
DO - 10.1007/s12031-024-02189-4
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 38282129
AN - SCOPUS:85183379863
SN - 0895-8696
VL - 74
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
IS - 1
M1 - 15
ER -