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Activity-dependent neuroprotective protein (ADNP) is one of the lead genes in autism spectrum disorder/intellectual disability. Heterozygous, de novo ADNP mutations cause the ADNP syndrome. Here, to evaluate natural history of the syndrome, mothers of two ADNP syndrome boys aged 6 and a half and two adults aged 27 years (man and woman) were subjected to Vineland III questionnaire assessing adaptive behavior. The boys were assessed again about 2 years after the first measurements. The skill measures, presented as standard scores (SS) included domains of communication, daily living, socialization, motor skills and a sum of adaptive behavior composite. The age equivalent (AE) and growth scale values (GSV) encompassing 11 subdomains assess the age level at which the subject's raw score is found at a norm sample median and the individual temporal progression, respectively. The norm referenced standard scores age-matched, mean 100 +/- 15 of the two children showed the lowest outcome in communication (SS: 20-30). Daily living skills presented SS of 50-60, with a possible potential loss of some activities as the child ages, especially in interpersonal relationships with people outside of the immediate family (boy A). In contrast, in socialization, both children were at the SS of 38, with some positive increase to SS of similar to 45 (interpersonal relations with family members and coping skills, depending on the particular individual), 2 years later. Interestingly, there was an apparent large difference in motor skills (gross and fine) at the young age, with subject B showing a relatively higher level of skills (SS: 70), decreasing to subject A level (SS: 40) 2 years later. Together, the adaptive behavior composite suggested a level of SS: 39-48 with B showing a potential increase (SS: 41-44) and A, a substantial decrease (SS: 48-39), suggesting a strong impact of daily living skills. Adults were at SS: 20, which is the lowest possible score. AE showed minor improvements for subject A and B, with all AE values being below 3 years. GSVs for subject A showed some improvement with age, especially in interpersonal, play and leisure, and gross motor subdomains. GSV for subject B showed minor improvements in the various subdomains. Notably, all subjects showed a percentile rank < 1 compared with age-matched norms except for subject B as to motor domain (2nd percentile) at the age of 6 years. In summary, the results, especially comparing SS and AEs between childhood and adulthood, implied a continuous deterioration of activities compared to the general population, encompassing a slower developmental process coupled to possible neurodegeneration, strongly supporting a great need for disease modifying medicinal procedures.

Encompassing live cell imaging and morphometrics at the microscopical level, we showed here, for the first time, protection of neuronal-like cells by the novel drug candidate, SKIP, against the Parkinson's disease-related neurotoxin, rotenone. Mechanistically, rotenone disrupted microtubule dynamics, which SKIP partially repaired through microtubule end-binding proteins, coupled with increasing neurite branch length. Given the previous association of rotenone toxicity with increased dopaminergic cell death hallmarking Parkinson's disease, we chose an established rat model of 6-hydroxydopamine (6-OHDA) toxicity to initially evaluate SKIP in vivo. SKIP pretreatment showed protection against nigral dopaminergic cell degeneration and improved motor behavior in the forelimb asymmetry test. With Parkinson's disease being a major neurodegenerative disorder, afflicting millions of people globally, and with disease modification challenges, SKIP may hold promise for future therapeutic development.

Studies point to an increased hereditary risk of cluster headache. HCRTR2 gene rs2653349 and ADH4 gene rs1800759 polymorphisms have been associated with cluster headache susceptibility. Also, GNB3 rs5443 polymorphism, associated with increased signal transduction via GPCRs, seems to influence triptan treatment response. DNA from 114 cluster headache patients and 570 non-related controls, representing a general Southeastern European Caucasian (SEC) population, was extracted from buccal swabs and genotyped using real-time PCR. Gene distribution for the rs2653349 was GG = 79.8%, GA = 18.4%, and AA = 1.8% for patients and GG = 79.1%, GA = 19.1%, and AA = 1.8% for controls. The frequency of the mutated A allele was 11.0% for patients and 11.3% for controls. The frequencies for rs5443 were CC = 44.7%, CT = 44.7%, and TT = 10.5% for patients and CC = 43.9%, CT = 42.6%, and TT = 13.5% for controls. The frequency of the mutated T allele was 32.9% for patients and 34.8% for controls. A 2.7-fold more frequent appearance of the mutated T allele was observed in patients with better triptan treatment response, although not statistically significant. For rs1800759, the frequencies were CC = 36.0%, CA = 43.0%, and AA = 21.0% for patients and CC = 34.0%, CA = 50.2%, and AA = 15.8% for controls. The frequency of the mutated A allele was 42.5% and 40.9% for patients and controls, respectively. The mutated T allele of GNB3 rs5443 polymorphism was more prevalent in patients with better triptan treatment response, indicating a possible trend of association between this polymorphism and triptan treatment response in SEC population. According to our observation, no association of HCRTR2 rs2653349 and ADH4 rs1800759 polymorphisms and cluster headache in SEC population could be documented.