In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research ...collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.
Abstract Gracies J-M, Burke K, Clegg NJ, Browne R, Rushing C, Fehlings D, Matthews D, Tilton A, Delgado MR. Reliability of the Tardieu Scale for assessing spasticity in children with cerebral palsy. ...Objective To measure the Tardieu Scale's reliability in children with cerebral palsy (CP) when used by raters with and without experience in using the scale, before and after training. Design Single-center, intrarater and interrater reliability study. Setting Institutional ambulatory care. Participants Referred children with CP in the pretraining phase (n=5), during training (n=3), and in the posttraining phase (n=15). Interventions The Tardieu Scale involves performing passive muscle stretch at 2 velocities, slow and fast. The rater derives 2 parameters; the Spasticity Angle X is the difference between the angles of arrest at slow speed and of catch-and-release or clonus at fast speed; the Spasticity Grade Y is an ordinal variable that grades the intensity (gain) of the muscle reaction to fast stretch. In phase 1, experienced raters without formalized training in the scale graded elbow, knee, and ankle plantar flexors bilaterally, without and with a goniometer. In phase 2, after training, the experienced and nonexperienced raters graded the same muscles unilaterally. Main Outcome Measures Intrarater and interrater reliability of the Tardieu Scale. Results After training, nonexperienced raters had mean ± SD intrarater and interrater agreement rates across all joints and parameters of 80%±14% and 74%±16%, respectively. For experienced raters, intrarater and interrater agreement rates before training were 77%±13% and 66%±15%, respectively, versus 90%±8% and 81%±13%, respectively, after training ( P <.001 for both). Specific angle measurements at the knee were less reliable for the angles of catch measured at fast speed. Across all joints, agreement rates were similar using visual or goniometric measurements. Conclusions Both parameters of the Tardieu Scale have excellent intrarater and interrater reliability when assessed at the elbow and ankle joints of children with CP, with no difference noted between visual and goniometric measurements. Angle measurements were less reliable at the knee joints. Training was associated with a highly significant improvement in reliability.
Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human ...syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.
Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80-90% of ...aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly.
To determine the acceptability and effects of a pediatric constraint induced movement therapy (P-CIMT) camp for children with hemiplegic cerebral palsy (hCP) augmented by use of an exoskeleton to ...play games in virtual reality (VR).
31 children with hCP attended a P-CIMT camp 6 hours per day for 10 days over 2 successive weeks (60 hours) that included 30 minutes of unilateral training with the Hocoma Armeo
®
Spring Pediatric that combines the assistance of an exoskeleton and VR games. The primary outcome measure was the Assisting Hand Assessment (AHA); secondary outcome measures were the Melbourne Assessment of Uni-lateral Hand Function (MUUL), and the Canadian Occupational Performance Measure (COPM). Assessments were completed at pre-intervention, post-intervention, and 6 months following intervention.
Participants demonstrated clinically and statistically significant improvement in bimanual performance (AHA) (p < .001) and COPM Performance (p < .001) and Satisfaction with performance (p < .001). Improvement in unilateral performance (MUUL) was statistically (p < .001) but not clinically significant.
A P-CIMT camp augmented by the Hocoma Armeo
®
Spring Pediatric was feasible and accepted by participants. Bimanual hand function and occupational performance improved immediately following intervention, and the treatment effects persisted 6 months following intervention.
Aim
To assess the neural and non‐neural contributions to spasticity in the impaired ankle of children with cerebral palsy (CP).
Method
Instrumented tapping of the Achilles tendon was done ...isometrically to minimize non‐neural contributions and elicit neural contributions. Robot‐controlled ankle stretching was done at various velocities, including slow stretching, with minimized neural contributions. Spasticity was assessed as having neural (phasic and tonic stretch reflex torque, tendon reflex gain, contraction rate, and half relaxation rate) and non‐neural origin (elastic stiffness and viscous damping) in 17 children with CP (six females and 11 males; mean age SD 10y 8mo 3y 11mo, range 4y–18y) and 17 typically developing children (six females and 11 males; mean age SD 12y 7mo 2y 9mo, range 7y–18y). All torques were normalized to weight×height.
Results
Children with CP showed increased phasic and tonic stretch reflex torque (p=0.004 and p=0.001 respectively), tendon reflex gain (p=0.02), contraction rate (p=0.038), half relaxation rate (p=0.02), elastic stiffness (p=0.01), and viscous damping (p=0.01) compared to typically developing children.
Interpretation
Controlled stretching and instrumented tendon tapping allow the systematic quantification of various neural and non‐neural changes in CP, which can be used to guide impairment‐specific treatment.
What this paper adds
Ankle spasticity is associated with increased phasic and tonic stretch reflexes, tendon reflex gain, and contraction and half relaxation rates.
Ankle spasticity is also associated with increased elastic stiffness and viscous damping.
Resumen
Contribuciones neuronales y no neuronales a la espasticidad del tobillo en niños con parálisis cerebral
Objetivo
Evaluar las contribuciones neurales y no neurales a la espasticidad en el tobillo comprometido de niños con parálisis cerebral (PC).
Método
La percusión instrumentada en el tendón de Aquiles se realizó de forma isométrica para minimizar las contribuciones no neurales y un tirón del tendón exagerado, para obtener contribuciones neurales. El estiramiento del tobillo controlado por robot se realizó a varias velocidades, incluido el estiramiento lento, con contribuciones neurales minimizadas. Se evaluó la espasticidad como neural (torque reflejo de estiramiento fásico y tónico, ganancia del reflejo tendinoso, tasa de contracción y media tasa de relajación) y origen no neural (rigidez elástica y amortiguación viscosa) en 17 niños con PC (seis mujeres y 11 varones; edad media DE 10a 8m 3a 11m, rango 4a‐18a) y 17 niños con desarrollo típico (seis mujeres y 11 hombres; edad media SD 12a 7m 2a 9m, rango 7a‐18a). Todos los pares de torsion se normalizaron al peso × altura.
Resultados
Los niños con PC mostraron un aumento del torque reflejo de estiramiento fásico y tónico (p = 0,004 y p = 0,001 respectivamente), ganancia refleja del tendón (p = 0,02), tasa de contracción (p = 0,038), tasa de relajación media (p = 0,02), rigidez elastica (p = 0,01) y amortiguación viscosa (p = 0,01) en comparación con los niños con desarrollo normal.
Interpretación
El estiramiento controlado y la percusión instrumentada del tendón, permiten la cuantificación sistemática de varios cambios neuronales y no neuronales en la PC, que pueden usarse para guiar el tratamiento específico de la discapacidad.
Resumo
Contribuições neurais e não neurais para a espasticidade do tornozelo em crianças com paralisia cerebral
Objetivo
Avaliar as contribuições neurais e não‐neurais para a espasticidade no tornozelo comprometido de crianças com paralisia cerebral (PC).
Método
O golpeamento instrumentalizado do tendão de Aquiles foi realizado isometricamente para minimizar as contribuições não‐neurais e um desvio exagerado do tendão, e assim eliciar as contribuições neurais. O alongamento do tornozelo controlado por um robô foi realizado em várias velocidades, incluindo alongamento lento, com contribuições neurais limitadas. A espasticidade foi avaliada como tendo origem neural (torque do reflexo fásico e tônico, ganho do reflexo tendinoso, taxa de contração, e taxa de meio relaxamento) e não‐neural (rigidez elástica e amortecimento viscoso) em 17 crianças com PC (seis do sexo feminino e 11 do sexo masculino; média de idade DP 10a 8m 3 11m, variação 4a–18a) e 17 crianças com desenvolvimento típico (seis do sexo feminino e 11 do sexo masculino; média de idade DP 12a 7m 2a 9m, variação 7a–18a). Todos os torques foram normalizados para peso x altura.
Resultados
Crianças com PC mostraram aumento do torque do reflexo tônico e fásico e (p=0,004 e p=0,001 respectivamente), ganho do reflexo tendinoso (p=0,02), taxa de contração (p=0,038), taxa de meio relaxamento (p=0,02), rigidez elástica (p=0,01), e amortecimento viscoso (p=0,01) em comparação com as crianças com desenvolvimento típico.
Interpretação
O alongamento controlado e o golpeamento instrumentalizado do tendão permitem quantificação sistemática de várias mudanças neurais e não‐neurais em PC, as quais podem ser usadas para guiar tratamento específico para a deficiência observada.
What this paper adds
Ankle spasticity is associated with increased phasic and tonic stretch reflexes, tendon reflex gain, and contraction and half relaxation rates.
Ankle spasticity is also associated with increased elastic stiffness and viscous damping.
This article is commented on by Meskers and Kwakkel on page 1008 of this issue.
This article's has been translated into Spanish and Portuguese.
Follow the links from the to view the translations.
Management of children with holoprosencephaly Levey, Eric B.; Stashinko, Elaine; Clegg, Nancy J. ...
American journal of medical genetics. Part C, Seminars in medical genetics,
15 February 2010, Letnik:
154C, Številka:
1
Journal Article
To pilot Therapy Together, an 8-week parent-led pediatric constraint induced movementtherapy (P-CIMT) program for preschool aged children with unilateral cerebral palsy (UCP). Five children with UCP ...and their caregivers participated in eight, 1 hour group sessions structured by the TEAM approach (topic, encourage, activity, and motivate). Three of the sessions were in person and 5 of the sessions were online due to COVID 19. Parent coaching and therapeutic activities for each weekly session aimed to improve a specific upper limb domain. The caregivers were asked to implement therapeutic activities 1 hour each day at home. The primary outcome measure was the Assisting Hand Assessment (AHA), scored by a blinded rater. The secondary outcome measure was the Canadian Occupational Performance Measure (COPM). Caregivers kept a log of hours completed at home, comments about implementing the program, and rated their child's unilateral and bilateral hand performance weekly. Participants demonstrated clinically significant changes in bimanual performance (AHA) with a large effect size, but statistical significance was not reached. Improvements in occupational performance and satisfaction (COPM) were clinically and statistically significant. Therapy Together is a promising P-CIMT intervention program for preschooler with UCP. The program incorporates caregiver education and coaching with caregiver-led home therapeutic activities to improve children's bimanual hand skills and occupational performance while addressing barriers to intervention access such as caregiver hesitancy in order to reduce health disparities in children with UCP.
Sensorimotor cortex plasticity induced by constraint-induced movement therapy (CIMT) in six children (10.2±2.1 years old) with hemiplegic cerebral palsy was assessed by functional near-infrared ...spectroscopy (fNIRS). The activation laterality index and time-to-peak/duration during a finger-tapping task and the resting-state functional connectivity were quantified before, immediately after, and 6 months after CIMT. These fNIRS-based metrics were used to help explain changes in clinical scores of manual performance obtained concurrently with imaging time points. Five age-matched healthy children (9.8±1.3 years old) were also imaged to provide comparative activation metrics for normal controls. Interestingly, the activation time-to-peak/duration for all sensorimotor centers displayed significant normalization immediately after CIMT that persisted 6 months later. In contrast to this improved localized activation response, the laterality index and resting-state connectivity metrics that depended on communication between sensorimotor centers improved immediately after CIMT, but relapsed 6 months later. In addition, for the subjects measured in this work, there was either a trade-off between improving unimanual versus bimanual performance when sensorimotor activation patterns normalized after CIMT, or an improvement occurred in both unimanual and bimanual performance but at the cost of very abnormal plastic changes in sensorimotor activity.
With improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the ...underlying molecular causes.
Participants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.
Semilobar HPE was the most common subtype of HPE, seen in 50% of the participants. Neurodevelopmental disabilities were found to correlate with HPE subtype. Factors associated with long-term survival included HPE subtype not alobar, female gender, and nontypical facial features. Four participants had de novo pathogenic variants in ZIC2. WES analysis of 11 participants did not reveal plausible candidate genes, suggesting complex inheritance in these cases. Indeed, in two probands there was a history of uncontrolled maternal type 1 diabetes.
Individuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Based on the facial characteristics and molecular evaluations, we suggest that classic genetic causes of HPE may play a smaller role in this cohort.
PDF
