Quantitative Gait Analysis in Duplication <scp>15q</scp> Syndrome and Nonsyndromic <scp>ASD</scp>

Wilson, Rujuta B.; Elashoff, David; Gouelle, Arnaud; Smith, Beth A.; Wilson, Andrew; Dickinson, Abigail; Safari, Tabitha; Hyde, Carly; Jeste, Shafali

doi:10.1002/aur.2298

Cited by 15 publications

(13 citation statements)

References 30 publications

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“…With regard to the nature of the first concerns, we found that initial developmental concerns were most often centered around delayed motor milestones. Earliest signs of developmental delay are more likely to present in the motor domain for individuals with an NDD and an associated genetic variant [ 22 , 23 ], suggesting that significant motor delay may increase the likelihood of a positive finding on genetic testing for patients with NDDs. It is important for physicians to be aware of this association, as it will allow for better prioritization of genetic testing and genetic referrals and allow for a more informed and nuanced discussion of the risks and benefit of genetic testing.…”

Section: Discussionmentioning

confidence: 99%

The diagnostic journey of genetically defined neurodevelopmental disorders

Simon

Hyde

Saravanapandian

et al. 2022

J Neurodevelop Disord

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Background The development of advanced genetic technologies has resulted in rapid identification of genetic etiologies of neurodevelopmental disorders (NDDs) and has transformed the classification and diagnosis of various NDDs. However, diagnostic genetics has far outpaced our ability to provide timely medical counseling, guidance, and care for patients with genetically defined NDDs. These patients and their caregivers present with an unmet need for care coordination across multiple domains including medical, developmental, and psychiatric care and for educational resources and guidance from care professionals. After a genetic diagnosis is made, families also face several barriers in access to informed diagnostic evaluations and medical support. Methods As part of Care and Research in Neurogenetics (CARING), a multidisciplinary clinical program for children and adults with neurogenetic disorders, we conducted qualitative clinical interviews about the diagnostic journey of families. This included the overall timeline to receiving diagnoses, experiences before and after diagnosis, barriers to care, and resources that helped them to navigate the diagnostic process. Results A total of 37 interviews were conducted with parents of children ages 16 months to 33 years. Several key themes were identified: (1) delays between initial caregiver observations and formal developmental or genetic diagnoses; (2) practical barriers to clinical evaluation and care, including long wait times for an appointment, lack of insurance coverage, availability of local evaluations, transportation difficulties, and native language differences; (3) the importance of being part of a patient advocacy group to help navigate the diagnostic journey; and (4) unique challenges faced by adults (18 years or older). Conclusions Families of children with complex neurodevelopmental and genetic disabilities face numerous challenges in finding adequate medical care and services for their child. They experience considerable delays in receiving timely diagnoses and face significant barriers that further delay the process of receiving access to services needed for the child’s continued care. The gaps indicated in this study speak to the need for more comprehensive coordination of care for patients with intellectual and developmental disabilities, as well as the development of systematic, disorder-specific resources both for providers and families in order to improve patient outcomes.

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Section: Discussionmentioning

confidence: 99%

The diagnostic journey of genetically defined neurodevelopmental disorders

Simon

Hyde

Saravanapandian

et al. 2022

J Neurodevelop Disord

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“…Although various factors could influence the locomotor activity of mice, reduced time spent for long locomotion in Emx1G6 15q dup mice might result from impaired motor planning and execution due to abnormal M2-related FC. While human dup15q syndrome shows a gait pattern of the slow pace, poor postural control, and large gait variability 40 and patients with paternal duplication in 15q11-13 display clumsy motor skill development 41 , 15q dup mice were also reported to display mild motor impairment such as longer stride length and reduced stride frequency, and deficits in motor learning and cerebellar synaptic plasticity 42 . Since recent studies demonstrate that cerebellar output modulates preparatory activity in the anterolateral motor cortex 43,44 , the abnormal M2-related FC we observed during behavior state transitions may also arise as a consequence of deficiency of a more widespread functional network, potentially including interactions with extracortical brain regions.…”

Section: Discussionmentioning

confidence: 99%

VR-based real-time imaging reveals abnormal cortical dynamics during behavioral transitions in a mouse model of autism

Nakai

Sato

Yamashita

et al. 2022

Preprint

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Functional connectivity (FC) can provide insight into cortical circuit dysfunction in neuropsychiatric disorders. However, dynamic changes in FC related to locomotion with sensory feedback remain unexplored. To investigate FC dynamics in locomoting mice, we developed mesoscopic Ca2+ imaging with a virtual reality (VR) environment. We find rapid reorganization of cortical FC in response to changing behavioral states. Using machine learning classification, behavioral states are accurately decoded. We then use our VR-based imaging system to study cortical FC in a mouse model of autism and find that locomotion states are associated with altered FC dynamics. Furthermore, we identify FC patterns involving the motor area as the most distinguishing features of the autism mice from wild-type mice during behavioral transitions, which might correlate with motor clumsiness in patients with autism. Our VR-based real-time imaging system provides invaluable information to understand FC dynamics linked to a behavioral abnormality of neuropsychiatric disorders.

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“…Our study showcases translational and longitudinal use of quantitative motor metrics for a genetic NDD. Clinically, quantitative gait research has gained traction across many NDDs and the idea to tailor attention on gait in preclinical studies is now also gaining momentum (IDDRC working group, AGENDA working group, personal communications) for Rett syndrome, neurofibromatosis, Down syndrome, and other NDDs (Hampton et al, 2004;Jequier Gygax et al, 2020;Kennedy et al, 2020;Layne et al 2018;Rahn et al, 2020;Summers et al, 2015;Wilson et al, 2020). Data from our work showed analogous measures of gait phenotypes in rodents that are being quantified currently in AS clinics (Jessica Duis MD, personal communication).…”

Section: Discussionmentioning

confidence: 99%

Gait as a Quantitative Translational Outcome Measure in Angelman Syndrome

Petkova

Duis

Silverman

2021

Preprint

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Angelman Syndrome (AS) is a genetic neurodevelopmental disorder characterized by developmental delay, lack of speech, seizures, intellectual disability, and walking and balance disorders. Recently, motor ability became an interesting outcome measure in AS, as it is broad including ataxia, hypotonia, delayed and abnormal walking and postural movements and affects nearly every individual with AS. We predict that gait presents a strong opportunity for rigorous, reliable, and quantitative metrics with direct translation to evaluate pharmacological, dietary, and genetic therapies. Numerous motoric deficits have been identified clinically. In this study, we used an innovative, automated gait analysis as well as gold standard motor behavioral assays to further delineate components of motor, coordination, balance, and gait impairments in an AS mouse model across development. Our study demonstrated marked global motoric deficits in AS mice, corroborating many previous reports. Uniquely, this is the first report of nuanced and pertinent aberrations in quantitative spatial and temporal components of gait between AS and wildtype littermate controls, that are analogous in AS individuals. These metrics were followed longitudinally to observe the progression of maladaptive gait in AS, a clinical phenotype. This has not been reported previously and contributes a substantial novel metric for therapeutic development. Taken together, these findings demonstrate the robust translational value in the study of nuanced motor outcomes, i.e., gait, for AS, as well as similar genetic syndromes, in the endeavor of therapeutic screening.

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Quantitative Gait Analysis in Duplication 15q Syndrome and Nonsyndromic ASD

Cited by 15 publications

References 30 publications

The diagnostic journey of genetically defined neurodevelopmental disorders

The diagnostic journey of genetically defined neurodevelopmental disorders

VR-based real-time imaging reveals abnormal cortical dynamics during behavioral transitions in a mouse model of autism

Gait as a Quantitative Translational Outcome Measure in Angelman Syndrome

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