Heterogeneity of comprehensive clinical phenotype and longitudinal adaptive function and correlation with computational predictions of severity of missense genotypes in KIF1A-associated neurological disorder.

PURPOSE: Pathogenic variants in kinesin family member 1A (KIF1A) are associated with KIF1A-associated neurological disorder. We report the clinical phenotypes and correlate genotypes of individuals with KIF1A-associated neurological disorder. METHODS: Medical history and adaptive function were assessed longitudinally. In-person evaluations included neurological, motor, ophthalmologic, and cognitive assessments. RESULTS: We collected online data on 177 individuals. Fifty-seven individuals were also assessed in-person. Most individuals had de novo heterozygous missense likely pathogenic/pathogenic KIF1A variants. The most common characteristics were hypotonia, spasticity, ataxia, seizures, optic nerve atrophy, cerebellar atrophy, and cognitive impairment. Mean Vineland adaptive behavior composite score (VABS-ABC) was low (M = 62.9, SD = 19.1). The mean change in VABS-ABC over time was -3.1 (SD = 7.3). The decline in VABS-ABC was associated with the age at first assessment and abnormal electroencephalogram/seizure. There was a positive correlation between evolutionary scale model (ESM) score for the variants and final VABS-ABC (P = .003). Abnormal electroencephalogram/seizure, neuroimaging result, and ESM explain 34% of the variance in final VABS-ABC (P < .001). CONCLUSION: In-person assessment confirmed caregiver report and identified additional visual deficits. Adaptive function declined over time consistent with both the neurodevelopmental and neurodegenerative nature of the condition. Using ESM score assists in predicting phenotype across a wide range of unique variants.

Clinical phenotypic spectrum of CTNNB1 neurodevelopmental disorder.

Pathogenic heterozygous loss of function variants in CTNNB1 are associated with CTNNB1 neurodevelopmental disorder. We report the clinical phenotype of individuals with CTNNB1 neurodevelopmental disorder using both caregiver-reported data (medical history, adaptive function, quality of life, and behavior issues) and in-person clinical assessments (neurological, motor, and cognitive function) in 32 individuals with likely pathogenic or pathogenic CTNNB1 variants. Most individuals had truncal hypotonia, muscle weakness, hypertonia, dystonia, microcephaly, and many had a history of tethered cord. Visual problems included strabismus, hyperopia, and familial exudative vitreoretinopathy. Half of individuals walked without an assistive device. The mean Gross Motor Functional Measure-66 score was 56.6 (SD = 14.8). Average time to complete Nine-Hole Peg Test was slower than norms. Mean general conceptual ability composite scores from Differential Ability Scales Second Edition were very low (M = 58.3, SD = 11.3). Fifty-five percent of individuals had low adaptive functioning based on the Vineland Adaptive Behavioral Scales. Based upon the Child Behavior Checklist total problems score, the majority (65%) of individuals had behavioral challenges. The mean overall Quality of Life Inventory-Disability score was 81.7 (SD = 11.9). These data provide a detailed characterization of clinical features in individuals with CTNNB1 neurodevelopmental disorder.

Clinical characteristics, longitudinal adaptive functioning, and association with electroencephalogram activity in PPP2R5D-related neurodevelopmental disorder.

Protein phosphatase 2 regulatory subunit B56δ related neurodevelopmental disorder (PPP2R5D-related NDD) is largely caused by de novo heterozygous missense PPP2R5D variants. We report medical characteristics, longitudinal adaptive functioning, and in-person neurological, motor, cognitive, and electroencephalogram (EEG) activity for PPP2R5D-related NDD. Forty-two individuals (median age 6 years, range = 0.8-25.3) with pathogenic/likely pathogenic PPP2R5D variants were assessed, and almost all variants were missense (97.6%) and de novo (85.7%). Common clinical symptoms were developmental delay, hypotonia, macrocephaly, seizures, autism, behavioral challenges, and sleep problems. The mean Gross motor functional measure-66 was 60.2 ± 17.3% and the mean Revised upper limb module score was 25.9 ± 8.8. The Vineland-3 adaptive behavior composite score (VABS-3 ABC) at baseline was low (M = 61.7 ± 16.8). VABS-3 growth scale value scores increased from baseline in all subdomains (range = 0.6-5.9) after a mean follow-up of 1.3 ± 0.3 years. EEG beta and gamma power were negatively correlated with VABS-3 score; p < 0.05. Individuals had a mean Quality-of-life inventory-disability score of 74.7 ± 11.4. Twenty caregivers (80%) had a risk of burnout based on the Caregiver burden inventory. Overall, the most common clinical manifestations of PPP2R5D-related NDD were impaired cognitive, adaptive function, and motor skills; and EEG activity was associated with adaptive functioning. This clinical characterization describes the natural history in preparation for clinical trials.

Clinical phenotypes of individuals with Chung-Jansen syndrome across age groups.

Pathogenic variants in pleckstrin homology domain interacting protein (PHIP) are associated with Chung-Jansen syndrome characterized by developmental delay, intellectual disability, behavioral challenges, hypotonia, obesity, and dysmorphic features. We report phenotypes and genotypes of 47 individuals with likely pathogenic/pathogenic PHIP variants. Variants were de novo in 61.7%, unknown inheritance in 29.8%, and inherited in 8.5%. The median age of the individuals was 10.9 years, approximately equally divided by sex. Individuals in this cohort frequently had a history of developmental delay (85.1%), attention-deficit/hyperactivity disorder (51.1%), anxiety (46.8%), depression (27.7%), and sleep difficulties (42.6%). Depression was significantly higher in the older age group (>12 years old). Most individuals had moderately low adaptive functioning based on the Vineland-3 (mean = 76.8, standard deviation = 12.0). Overall, 55.8% of individuals were obese/overweight. The percentage of obese individuals was greater in the older age group (>12 years old) and evolves over time. Other common symptoms were hypotonia (78.7%), constipation (48.9%), visual problems (66%), and cryptorchidism (39.1% of males). Our findings provide additional natural history data for Chung-Jansen syndrome and provide opportunities for early intervention of healthy eating habits and awareness of developing mood and behavioral challenges over the life course.

Characterizing ambulatory function in children with PPP2R5D-related neurodevelopmental disorder.

BACKGROUND: Individuals with PPP2R5D-related neurodevelopmental disorder have an atypical gait pattern characterized by ataxia and incoordination. Structured, quantitative assessments are needed to further understand the impact of these impairments on function. RESEARCH QUESTION: How do gait parameters and ambulatory function of individuals with PPP2R5D-related neurodevelopmental disorder compare to age and sex matched healthy norms? METHODS: Twenty-six individuals with PPP2R5D pathogenic genetic variants participated in this observational, single visit study. Participants completed at least one of the following gait assessments: quantitative gait analysis at three different speeds (preferred pace walking (PPW), fast paced walking (FPW) and running, six-minute walk test (6MWT), 10-meter walk run (10MWR), and timed up and go (TUG). Descriptive statistics were used to summarize gait variables. Percent of predicted values were calculated using published norms. Paired t-tests and regression analyses were used to compare gait variables. RESULTS: The median age of the participants was 8 years (range 4-27) and eighteen (69.2 %) were female. Individuals with PPP2R5D-related neurodevelopmental disorder walked slower and with a wider base of support than predicted for their age and sex. Stride velocity ranged from 48.9 % to 70.1 % and stride distance from 58.5 % to 81.9 % of predicted during PPW. Percent of predicted distance walked on the 6MWT ranged from 30.6 % to 71.1 % representing varied walking impairment. Increases in stride distance, not cadence, were associated with changes in stride velocity in FPW (R2 = 0.675, p =< 0.001) and running conditions (R2 = 0.918, p =< 0.001). SIGNIFICANCE: We quantitatively assessed the abnormal gait in individuals with PPP2R5D-related neurodevelopmental disorder. These impairments may affect ability to adapt to environmental changes and participation in daily life. Rehabilitative interventions targeting gait speed and balance may improve function and safety for individuals with PPP2R5D-related neurodevelopmental disorder.

Validation of a modified version of the gross motor function measure in PPPR5D related neurodevelopmental disorder.

BACKGROUND: Protein phosphatase 2 regulatory subunit B' Delta (PPP2R5D)-related neurodevelopmental disorder is a rare genetic condition caused by pathogenic variants in the PPP2R5D gene. Clinical signs include hypotonia, gross motor delay, intellectual disability (ID), epilepsy, speech delays, and abnormal gait among other impairments. As this disorder was recognized within the last decade, there are only 103 people published diagnoses to date. A thorough understanding of the motor manifestations of this disorder has not yet been established. Knowledge of the natural history of PPP2R5D related neurodevelopmental disorder will lead to improved standard of care treatments as well as serve as a baseline foundation for future clinical trials. Appropriate outcome measures are necessary for use in clinical trials to uniformly measure function and monitor potential for change. The aim of this study was to validate the gross motor function measure (GMFM) in children and adults with PPP2R5D-related neurodevelopmental disorder in order to better characterize the disorder. RESULTS: Thirty-eight individuals with PPP2R5D pathogenic variants, median age 8.0 years (range 1-27) were evaluated. Gross motor, upper limb and ambulatory function were assessed using the GMFM-66, six-minute walk test (6MWT), 10-meter walk run (10MWR), timed up and go (TUG), and revised upper limb module (RULM). The pediatric disability inventory computer adapted test (PEDI-CAT) captured caregiver reported assessment. Median GMFM-66 score was 60.6 (SD = 17.3, range 21.1-96.0). There were strong associations between the GMFM-66 and related mobility measures, 10MWR (rs = -0.733; p < 0.001), TUG (rs= -0.747; p = 0.003), 6MWT (r = 0.633; p = 0.006), RULM (r = 0.763; p < 0.001), PEDICAT-mobility (r = 0.855; p < 0.001), and daily activities (r = 0.822; p < 0.001) domains. CONCLUSIONS: The GMFM is a valid measure for characterizing motor function in individuals with PPP2R5D related neurodevelopmental disorder. The GMFM-66 had strong associations with the RULM and timed function tests which characterized gross motor, upper limb and ambulatory function demonstrating concurrent validity. The GMFM-66 was also able to differentiate between functional levels in PPP2R5D related neurodevelopmental disorder demonstrating discriminant validity. Future studies should examine its sensitivity to change over time, ability to identify sub-phenotypes, and suitability as an outcome measure in future clinical trials in individuals with PPP2R5D variants.