Severity of GNAO1-Related Disorder Correlates with Changes in G-Protein Function.

OBJECTIVE: GNAO1-related disorders (OMIM #615473 and #617493), caused by variants in the GNAO1 gene, are characterized by developmental delay or intellectual disability, hypotonia, movement disorders, and epilepsy. Neither a genotype-phenotype correlation nor a clear severity score have been established for this disorder. The objective of this prospective and retrospective observational study was to develop a severity score for GNAO1-related disorders, and to delineate the correlation between the underlying molecular mechanisms and clinical severity. METHODS: A total of 16 individuals with GNAO1-related disorders harboring 12 distinct missense variants, including four novel variants (p.K46R, p.T48I, p.R209P, and p.L235P), were examined with repeated clinical assessments, video-electroencephalogram monitoring, and brain magnetic resonance imaging. The molecular pathology of each variant was delineated using a molecular deconvoluting platform. RESULTS: The patients displayed a wide variability in the severity of their symptoms. This heterogeneity was well represented in the GNAO1-related disorders severity score, with a broad range of results. Patients with the same variant had comparable severity scores, indicating that differences in disease profiles are not due to interpatient variability, but rather, to unique disease mechanisms. Moreover, we found a significant correlation between clinical severity scores and molecular mechanisms. INTERPRETATION: The clinical score proposed here provides further insight into the correlation between pathophysiology and phenotypic severity in GNAO1-related disorders. We found that each variant has a unique profile of clinical phenotypes and pathological molecular mechanisms. These findings will contribute to better understanding GNAO1-related disorders. Additionally, the severity score will facilitate standardization of patients categorization and assessment of response to therapies in development. ANN NEUROL 2023;94:987-1004.

Early Physiotherapy Intervention Program for Preterm Infants and Parents: A Randomized, Single-Blind Clinical Trial.

BACKGROUND: The early developmental interventions might be designed with a preventative approach to improving the development of at-risk preterm infants. The present study aimed to evaluate the effectiveness of an early physiotherapy intervention on preterm infants' motor and global development, and on parents' stress index. METHODS: 48 infants were enrolled and randomized into two groups. Infants allocated to the intervention group received an early physiotherapy intervention, based on parental education sessions and tactile and kinesthetic stimulation during the NICU period, as well as a home-based activity program. The intervention commenced after 32 weeks post-menstrual age and ended at 2 months corrected age. Infants allocated to the control group received the usual care based on the NIDCAP-care. RESULTS: No differences were found between groups on the Alberta Infant Motor Scale at 2- or 8-months corrected age. Infants in the intervention group showed more optimal fine motor, problem-solving, personal-social, and communication development at 1 month corrected age. CONCLUSIONS: The results showed no effect on the early physiotherapy intervention. Results might be related to the dose or intensity of the intervention, but also to the poor parental compliance. CLINICALTRIALS: gov NCT03313427.

The Spanish version of the Alberta Infant Motor Scale: Validity and reliability analysis.

OBJECTIVES: Validity and reliability of the cross-cultural adaptive translation of the Alberta Infant Motor Scale (AIMS), to monitor gross motor development in infants from 0 to 18 months of age, were evaluated. METHODS: A cross-cultural translation was used to generate a Spanish version of the AIMS. Fifty infants at risk or with diagnosis of motor delay, 0-18 months of age, participated in this study. Two independent physical therapists scored infants on the AIMS. Concurrent validity was tested using the AIMS and the Bayley Scales of Infant and Toddler Development - III (Bayley - III). RESULTS: Reliability and the internal consistency were high (ICCs ranged from 0.94 to 1.00 and KR-20 ranged from 0.90 to 0.98, respectively). AIMS and Bayley - III scores correlated strongly (r = 0.97). CONCLUSION: The Spanish version of the AIMS presented excellent validity and reliability. Further studies are suggested in order to assess the AIMS in preterm babies.