Reliability of the Test of Gross Motor Development Third Edition Among Children with Developmental Coordination Disorder.

AIM: The Test of Gross Motor Development Third Edition (TGMD-3) is used to assess the development of fundamental movement skills in children from 3 to 10 years old. This study aimed to evaluate the intra-rater, inter-rater, and test-retest reliability and to determine the minimal detectable change (MDC) value of the TGMD-3 in children with developmental coordination disorder (DCD). METHODS: The TGMD-3 was administered to 20 children with DCD. The child's fundamental movement skills were recorded using a digital video camera. Reliability was assessed at two occasions by three raters using the generalizability theory. RESULTS: The TGMD-3 demonstrates good inter-rater reliability for the locomotor skills subscale, the ball skills subscale, and the total score (φ = 0.77 - 0.91), while the intra-rater reliability was even higher (φ = 0.94 - 0.97). Test-retest reliability was also shown to be good (φ = 0.79-0.93). The MDC95 was determined to be 10 points. CONCLUSION: This study provides evidence that the TGMD-3 is a reliable test when used to evaluate fundamental movement skills in children with DCD and suggests that an increase of 10 points represents a significant change in the motor function of a child with DCD.

A position statement on the post gene-therapy rehabilitation of aromatic I-amino acid decarboxylase deficiency patients.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder of monoamine neurotransmitter synthesis that presents with a range of symptoms, including motor dysfunction and limited attainment of developmental motor milestones. The approval of eladocagene exuparvovec, a gene therapy for AADC deficiency with demonstrated efficacy for motor improvements, now expands the range of motor outcomes possible for patients with this disorder. However, recommendations and guidelines for therapy following treatment with gene therapy are lacking. To ensure patients can reach their full potential following treatment with gene therapy, it is essential they receive rehabilitation therapies designed specifically with their impairments and goals in mind. Therefore, we highlight specific rehabilitative needs of patients following gene therapy and propose a set of recommendations for the post-treatment period based on collective experiences of therapists, physicians, and caregivers treating and caring for patients with AADC deficiency who have been treated with gene therapy. These recommendations include a focus on periods of intensive therapy, facilitating active movements, training for functional abilities, cognitive and communication training, parent/caregiver empowerment, collaboration between therapists and caregivers to develop in-home programs, and the incorporation of supplemental forms of therapy that patients and their families may find more enjoyable and engaging. Many of these rehabilitative strategies may be employed prior to gene therapy. However, these recommendations will be valuable for therapists, caregivers, and wider treatment teams as they prepare for the post-treatment journey with these patients. Furthermore, the considerations and recommendations presented here may prove beneficial outside the AADC deficiency community as gene therapies and other treatments are developed and approved for other rare diseases.

The first three years: The association of early postpartum depressive symptoms with infant and toddler development.

BACKGROUND: The influence of postpartum depression (PPD) on child development has been a source of professional interest and practical relevance. OBJECTIVE: This study investigated the association of early PPD symptoms with developmental domains. DESIGN AND METHOD: This historical cohort study included 574,282 children attending Mother Child Healthcare Centers in Israel from January 1, 2014 to July 31, 2020, who underwent at least one developmental screening examination by public health nurses up to age 36 months, and whose mothers completed the Edinburgh Postnatal Depression Scale (EPDS) postnatally. Developmental milestone tasks included four domains: fine and gross motor, language/communication, and social/behavioral. RESULTS: The rate of failure to complete age-appropriate tasks was higher among children whose mothers had scored ≥ 10 on the EPDS on the majority of tasks in every domain. DISCUSSION: This large population-based study has demonstrated the association between early maternal postnatal depressive symptoms and failure to meet developmental milestones across domains, until three years. Recommendations for practice focus on the mother, the child, and health policy.

Health supervision for children and adolescents with 16p11.2 deletion syndrome.

Rare genetic conditions are challenging for the primary care provider to manage without proper guidelines. This clinical review is designed to assist the pediatrician, family physician, or internist in the primary care setting to manage the complexities of 16p11.2 deletion syndrome. A multidisciplinary medical home with the primary care provider leading the care and armed with up-to-date guidelines will prove most helpful to the rare genetic patient population. A special focus on technology to fill gaps in deficits, review of case studies on novel medical treatments, and involvement with the educational system for advocacy with an emphasis on celebrating diversity will serve the rare genetic syndrome population well.

Comprehensive Evaluation of Fundamental Motor Skills: Insights From the Test of Gross Motor Development-3.

BACKGROUND: A comprehensive evaluation of basic motor abilities is provided by the Test of Gross Motor Development-3 (TGMD-3), which assesses 13 basic motor skills. These skills are categorized into locomotor and ball skill subsets. OBJECTIVE: An assessment of gross motor skills in diverse populations with the TGMD-3 is the goal of this study. METHODS: From control and intervention groups, locomotor subset scores were collected. In addition to identifying developmental delays, the study highlights the TGMD-3's ability to detect deficits in motor skills. Depending on whether a skill meets the criteria, it is scored as either a 1 or a 0. A locomotor score of 46, a ball skill score of 54, and an overall gross motor score of 100 are the maximum scores. RESULTS: The control group's baseline scores increased from 34.3±0.9 to 37.3±0.7 by the sixth week (p = 0.03), while the intervention group's scores rose from 36.5±1.1 to 40.9±0.6 (p = 0.0007). Both groups also showed similar trends in gross motor coordination scores. CONCLUSION: Gross motor skill assessment is robust across different populations, making the TGMD-3 an effective tool for improving motor development and performance.

¡Miranos! An 8-Month Comprehensive Preschool Obesity Prevention Program in Low-Income Latino Children: Effects on Children's Gross Motor Development.

Organized childcare is an ideal setting to promote gross motor development in young children from low-income minority families. A three-group clustered randomized controlled trial was conducted in Head Start centers serving low-income Latino children to evaluate the impact of an 8-month comprehensive obesity-prevention intervention on children's percentile scores for locomotive skills (LS pctl) and ball skills (BS pctl), and general motor quotient (GMQ). Trained Head Start staff delivered the center-based intervention (CBI) to modify center physical activity and nutrition policies, staff practices, and child behaviors, while the home-based intervention (HBI) offered training and support to parents for obesity prevention at home. Participants were 3-year-old children (n = 310; 87% Latino; 58% female) enrolled in Head Start centers in South Texas. Twelve centers were randomized (1:1:1 ratio) to receive CBI, CBI and HBI (CBI + HBI), or control treatment. Posttest data were collected from 79.1% of participants. All gross motor development measures improved significantly for children in CBI compared to the control, while children in CBI + HBI only showed improvement for GMQ (p = 0.09) and LS pctl (p < 0.001) compared to the control. A comprehensive and culturally competent intervention targeting childcare centers and children's homes was effective at improving children's gross motor development and reducing disparities in child development.

A 6-Week Badminton-Based Movement Intervention Enhances Fundamental Movement Skills and Physical Fitness in Saudi Boys and Girls.

This study examined the short (pre-post) and longer-term (post to 10 weeks post) effects of the Badminton World Federation (BWF) Shuttle Time program on fundamental movement skills (FMS) and physical fitness in Saudi boys and girls. Seventy-six children aged 9-11 years (44 boys, 32 girls; mean ± SD = 10.2 ± 0.9 years) undertook twice weekly Shuttle Time sessions for 6 weeks. Pre, post, and 10 weeks post, FMS was measured using the test of gross motor development 3 and physical fitness was measured via 10 m sprint speed, standing long jump, seated medicine ball throw, and a 6 min walk test (6MWT). There were significant improvements in FMS from pre to post (p = 0.0001) and post to 10-weeks post (p = 0.0001) for both boys and girls. Girls demonstrated a significantly greater magnitude of change in FMS. For 10 m sprint time, seated medicine ball throw, standing long jump, and 6MWT performance, both boys and girls significantly improved from pre-10 weeks post (all p = 0.001). The magnitude of change was greater pre to 10-weeks post for girls for the seated medicine ball throw, but was greater for boys for the standing long jump and 6MWT. In terms of practical applications, the BWF Shuttle Time program is feasible for administration in the Saudi context and is beneficial in developing FMS and fitness for Saudi children aged 8-12 years.

Clinical features of PPP2 syndrome type R5D (Jordan's syndrome) to support standardization of care.

PPP2 syndrome type R5D, or Jordan's syndrome, is a neurodevelopmental disorder caused by pathogenic missense variants in PPP2R5D, a ß-subunit of the Protein Phosphatase 2A (PP2A). The condition is characterized by global developmental delays, seizures, macrocephaly, ophthalmological abnormalities, hypotonia, attention disorder, social and sensory challenges often associated with autism, disordered sleep, and feeding difficulties. Among affected individuals, there is a broad spectrum of severity, and each person only has a subset of all associated symptoms. Some, but not all, of the clinical variability is due to differences in the PPP2R5D genotype. These suggested clinical care guidelines for the evaluation and treatment of individuals with PPP2 syndrome type R5D are based on data from 100 individuals reported in the literature and from an ongoing natural history study. As more data are available, particularly for adults and regarding treatment response, we anticipate that revisions to these guidelines will be made.

Fundamental motor skill proficiency among 7- to 10-year-old children with Down syndrome.

[Purpose] The purposes of this study were to assess the fundamental motor skill (FMS) of children with Down syndrome (DS) and to compare their FMS proficiencies to those of chronological age-matched and gender-matched typically developing children (TDC). [Participants and Methods] This cross-sectional study involved a total of 60 participants (30 children with DS and 30 TDC). The FMS proficiency of participants was assessed by using the test of gross motor development, second edition (TGMD-2). The data were analyzed using independent samples t-tests to verify the differences between the two groups and gender. The effect size of Cohen's d was also determined for comparing the two groups. [Results] The results showed that there were significant differences between children with DS and the TDC on locomotor and object control standard scores, and the gross motor quotient (GMQ). However, there were no significant gender-based differences in the locomotor and object control standard scores and the GMQ in both groups. [Conclusion] Based on the current results, the FMS proficiency of children with DS is lower than the TDC. Therefore, a therapeutic intervention program is necessary for children with DS to improve their FMS proficiency.

Does earlier acquisition of motor competence promote pubertal physical activity in Japanese elementary school children: A 4-year follow-up study.

This 4-year follow-up study investigated which profile of motor competence (MC) in early childhood more strongly correlated with moderate-to-vigorous physical activity (MVPA) in early pubescence. A total of 247 first-grade children (152 boys) aged 6 to 7 years old participated in the baseline measurement. MVPA was measured using an accelerometer annually until the fifth grade. Body fat percentage was assessed using dual-energy X-ray absorptiometry at baseline. MC included fundamental movement skills (FMS) and motor performance, which were assessed in terms of locomotor and object control. FMS was assessed by the Test of Gross Motor Development-2, while motor performance (locomotor: run, hop, jump, and side-step, object control: throw, kick, and hand dribble) was assessed by Japanese Physical Fitness and Motor Abilities Test at baseline. Multiple regression analysis showed that locomotor and object control performance were significant predictors of MVPA in later grades in boys but not in girls. These associations between locomotor performance and MVPA mainly remained significant after controlling for body fat and MVPA at baseline. FMS in both genders was not a significant predictor of MVPA in early pubescence. This study suggests that appropriate strategies for increasing MVPA from prepubescence to early pubescence may differ between boys and girls.

Comparison of vestibular ocular reflex and gross motor development in children with semicircular canal aplasia and hypoplasia.

OBJECTIVE: To examine the effect of vestibular ocular reflex on gross motor development in children with semicircular canal aplasia and hypoplasia. STUDY DESIGN: Case series. MATERIALS AND METHODS: Children with congenital hearing loss underwent temporal bone computed tomography to assess their inner ear morphology. In this study, we examined eight children with bilateral complete aplasia of semicircular canals and seven children with bilateral hypoplasia of semicircular canals. Their vestibular ocular reflex was assessed using a damped rotational chair test. Their gross motor development was assessed by examining their ages of acquisition of head control and independent walking. RESULTS: All eight children with semicircular canal aplasia were diagnosed as having CHARGE syndrome and five children were found to have CHD7 mutations. Cochlear morphological examination showed that cochlear hypoplasia type III was the most common in eight of 16 ears in children with semicircular canal aplasia. In semicircular canal hypoplasia, incomplete partition type II was found in seven of 14 ears. All eight children with semicircular canal aplasia showed no response in the damped rotational chair test. Even the three children followed up were unresponsive in all tests. In the group with semicircular canal hypoplasia, three children showed normal responses, one child showed no response, and three children showed poor responses. The mean age of acquisition of head control was 9.1 ± 6.3 months and that of independent walking was 31 ± 8.1 months in children with semicircular canal aplasia. The mean age of acquisition of head control was 6.0 ± 2.8 months and that of independent walking was 19.9 ± 4.9 months in children with semicircular canal hypoplasia. CONCLUSIONS: We found that children with semicircular canal aplasia have severe dysfunction of the vestibular ocular reflex, and vestibular sensory cells derived from the semicircular canal may not be present. Semicircular canal hypoplasia is associated with dysfunction of the vestibular ocular reflex, but vestibular sensory cells may be present, and rotary nystagmus develops with growth similar to that observed in normal children previously reported. Semicircular canal aplasia is associated with CHARGE syndrome, and affected children tended to have a slower gross motor development. It was suggested that the combination of visual impairment and mental retardation may delay the development of central-level integrated functions and may further delay motor development.

Effects of Play in an Upright Position on Intra-Individual Variability of Gross Motor and Language Development in Institutionalized Infants.

(1) Objective: To investigate the effects of play in an upright position on intra-individual variability and to examine the relationship between the variability of gross motor and language development in institutionalized infants aged six to ten months. (2) Methods: Thirty infants were conveniently enrolled in either the experimental or control groups. The Alberta Infant Motor Scale (AIMS) and the Communication and Symbolic Behavior Scales Developmental Profile (CSBS-DP) Infant/Toddler Checklist were tested pre and post each monthly intervention for three months. Sixteen infants in the experimental group received an additional program of 45 min play in an upright position three times a week for a 3-month period. (3) Results: There were significant between-group differences in intra-individual variability of the AIMS percentiles (p-value = 0.042). In addition, there was a significant difference in the intra-individual variability of the language percentile between groups (p-value = 0.009). The intra-individual variability of gross motor development was significantly correlated (rs = 0.541; p = 0.03) with language development. (4) Conclusions: Play in an upright position could be applied to improve intra-individual variability in gross motor and language development percentiles in institutionalized infants.

Gender Differences in Fundamental Motor Skills Proficiency in Children Aged 3-6 Years: A Systematic Review and Meta-Analysis.

The age range of 3−6 years is considered as a critical period in developing and learning fundamental motor skills (FMS). To make the formulation of future FMS guidance programs more targeted, we examined gender differences in children's FMS proficiency using a meta-analysis. Structured electronic databases including PubMed, Scopus and Web of Science were systematically searched using key terms, and the Joanna Briggs Institute (JBI) was used to assess the quality of included literature. Finally, 38 articles (39 studies) met the pre-specified inclusion criteria. The results showed that boys had higher proficiency in total FMS and object control skills than girls (SMD = 0.17 (95% CI 0.03, 0.31), p = 0.02; SMD = 0.48 (95% CI 0.38, 0.58), p < 0.00001), and gender differences in locomotor skill proficiency approached significance, trending in favor of girls (SMD = −0.07 (95 % CI −0.15, 0.01), p = 0.09, I2 = 66%). Meta-regression shows that age is associated with gender differences in object control skills (p < 0.05). In addition, through subgroup analysis, we found that boys' advantage in object control skills increased with age (3 years: SMD = 0.27 (95% CI 0.00, 0.54), p < 0.00001; 4 years: SMD = 0.58 (95% CI 0.38, 0.77), p < 0.00001; 5 years: SMD = 0.59 (95% CI 0.31, 0.88), p < 0.00001; 6 years: SMD = 0.81 (95% CI 0.61, 1.01), p < 0.00001). In this meta-analysis, we found gender differences in FMS levels in children aged 3−6 years. Notably, gender differences in skill proficiency in object control were influenced by age. We recommend focusing on and developing girls' object control skills starting at age 3.

Bi-Directionality between Physical Activity within School and Fundamental Movement Skills in School-Aged Students: A Cross-Lagged Study.

Background: Evidence has indicated the health importance of fundamental movement skills (FMS) and physical activity (PA) in children and their relationships seems bidirectional. However, their bidirectional relationship has not yet been fully answered in the literature. Aim: This study sought to determine bidirectional relationship between FMS and PA in children using cross-lagged study design. Methods: A total of 183 second-level students (8.8 ± 1.1 years old) from three primary schools in Henan Province, China were selected as subjects. The average number of steps per school day was used as the amount of PA in the school environment; the third edition of the test of gross motor development was used for FMS testing. The baseline data (T1) and tracking data (T2) were collected at the beginning and end of the fall semester, respectively. The two tests were separated by 3 months (11 weeks), and a cross-lag model analysis was performed. Based on the hypothetical model, we tested the cross-lag effect of children's PA and FMS. Results: The model fit index was χ2/df = 2.861 (p < 0.001, n = 183); goodness of fit index GFI = 0.900; NFI = 0.909; CFI = 0.931 and the 95%CI was between 0.071−0.192. The RMSEA = 0.063, and the standardized residual root mean square SRMR = 0.029. The T1 FMS can be used to predict the number of steps in the T2 teaching days with statistical significance (ß = 0.22, 95% CI: 0.07−0.38, p = 0.003). However, the T1 steps cannot be used to predict the T2 FMS (ß = 0.05, 95% CI: 0.07−0.13, p = 0.475). Further analysis shows that the main contributor to these relationships are ball skills in the FMS. Conclusions: The relationship between children's fundamental movement skills and PA is not two-way. Students with higher FMS are expected to reach higher levels of PA after undergoing school PA in a teaching cycle. The PA of the students can be improved by improving their motor skills, which further improves their physical and mental health.

Vitamin D supplementation and gross motor development: A 3-year follow-up of a randomized trial.

BACKGROUND: Vitamin D status during pregnancy, early childhood and season-at-birth are implicated in gross motor development (GMD). AIM: To test whether vitamin D intake in infancy and season-at-birth affect GMD in early childhood. STUDY DESIGN: 3-year follow up study of a single-center trial. SUBJECTS: Healthy infants (n = 116) were allocated to 400 (standard-of-care), 800 or 1200 IU/day of vitamin D3 supplementation from 1 to 12 months; n = 70 returned for follow-up at 3-years. OUTCOME MEASURES: The main outcome was GMD using the Peabody Developmental Motor Scales-2 which includes gross motor quotient (GMQ) and stationary, locomotion and object manipulation subtests. RESULTS: GMQ scores were normal (≥85) in 94 %. An interaction between dosage group and season-at-birth (p = 0.01) was observed for GMQ and stationary standardized score; among winter/spring born children, the 1200 IU/d scored higher vs. 400 and 800 IU/d groups. Object manipulation standardized score was higher (p = 0.04) in children in the 1200 vs. 400 IU/d group, without interaction with season-at-birth. CONCLUSIONS: GMD in young children who received 400 IU/d of supplemental vitamin D in infancy is not influenced by season-at-birth. This dose of vitamin D of 400 IU/d as recommended in North America adequately supports GMD. The modest enhancement in GMD with 1200 IU/d in winter/spring born children requires further study.

Intra-Individual Variability in Gross Motor Development in Healthy Full-Term Infants Aged 0-13 Months and Associated Factors during Child Rearing.

The gross motor development of a typically developing infant is a dynamic process, the intra-individual variability of which can be investigated through longitudinal assessments. Changes in gross motor development vary, according to the interaction of multiple sub-systems within the child, environment, task setting, and experience or practice of movement. At present, studies on environmental factors that influence gross motor development in full-term infants over time are limited. The main aim of this study was to investigate environmental factors affecting intra-individual variability from birth to 13 months. The gross motor development of 41 full-term infants was longitudinally assessed every month from the age of 15 days using the Alberta Infant Motor Scale. Parents were interviewed monthly about environmental factors during childcare. Infants showed fluctuations in the percentile of gross motor development, and no systematic pattern was detected. The total mean range of gross motor percentile was 65.95 (SD = 15.74; SEM = 2.28). The percentiles of gross motor skills over the 14 assessments ranged from 36 to 93 percentile points. Factors that were significantly associated with the gross motor development percentile were the use of a baby walker (Coef. = -8.83, p ≤ 0.0001) and a baby hammock (Coef. = 7.33, p = 0.04). The use of baby hammocks could increase the gross motor percentile by 7.33 points. Although the usage of a baby walker is common practice in childcare, it may cause a decrease in the gross motor percentile by 8.83 points according to this study. In conclusion, healthy full-term infants exhibited a natural variability in gross motor development. Placing infants in a baby walker during the first year of age should be approached with caution due to the risk of delayed gross motor development.

Canadian and Brazilian Percentile Ranks for the Alberta Infant Motor Scale.

Aim: To verify if there is a difference between the percentile ranks for Brazilian infants compared with norms for Canadian infants on the Alberta Infant Motor Scale (AIMS). Method: A cross-sectional study in which 322 Brazilian infants, 2 to 15 months old, were administered the AIMS. Percentile ranks were calculated using norms for Canadian infants and norms from two studies of Brazilian infants. The Friedman test compared the AIMS percentile ranks for the entire sample. For reliability analysis, the interclass correlation coefficient (ICC) was used. Bland Altman's analysis was applied to compare percentile ranks. Results: Of the 322 evaluations analyzed, there were significant differences (p<.001) between the three percentile ranks compared. The Canadian norms presented the lowest average rating. There was good reliability between the percentile ranks (ICC > 0.75) but low agreement (Bland Altman; p<.001). Conclusion: There are differences between the Brazilian and Canadian percentile ranks and between the Brazilian percentile ranks of 2014 and 2016, and these differences may influence identification of motor development.

Ethylmalonic encephalopathy masquerading as meningococcemia.

Ethylmalonic encephalopathy (MIM #602473) is a rare autosomal recessive metabolic condition caused by biallelic variants in ETHE1 (MIM #608451), characterized by global developmental delay, infantile hypotonia, seizures, and microvascular damage. The microvascular changes result in a pattern of relapsing spontaneous diffuse petechiae and purpura, positional acrocyanosis, and pedal edema, hemorrhagic suffusions of mucous membranes, and chronic diarrhea. Here, we describe an instructive case in which ethylmalonic encephalopathy masqueraded as meningococcal septicemia and shock. Ultrarapid whole-genome testing (time to result 60 h) and prompt biochemical analysis facilitated accurate diagnosis and counseling with rapid implementation of precision treatment for the metabolic crisis related to this condition. This case provides a timely reminder to consider rare genetic diagnoses when atypical features of more common conditions are present, with an early referral to ensure prompt biochemical and genomic diagnosis.

Relationship of Quantitative Measures of Jumping Performance with Gross Motor Development in Typically Developed Preschool Children.

Jumping is a key movement developing in the preschool period, but limited studies have reported the determinants of jumping performance and its relationship with gross motor development. This study aimed to determine the correlations among jumping performance, quantitative parameters of jumping, and gross motor development in preschool children. Twenty-one preschool children were recruited from one kindergarten, and fifteen of them with complete data were further analyzed. The quantitative parameters of standing long jump (SLJ) and standing vertical jump (SVJ) were measured using a video-based motion capture system. The gross motor development was measured using the Preschooler Gross Motor Quality Scale (PGMQ). The Spearman's rho value and a linear regression model were used to determine the relationships among the jumping performance, the quantitative measures, and the total PGMQ scores. The results indicate that the jumping performances were significantly correlated with the takeoff velocity, which was predicted by trunk inclination before takeoff in SLJ and by the ranges of trunk inclination during jumping in SVJ. Regression analysis showed that the preschool children with higher normalized jump height had better gross motor development, and that the jump performance and the gross motor development were directly or indirectly predicted by the slope of the hip-to-ankle angle plot during pre-takeoff. In conclusion, this study identifies key components of jumping in jumping performance and gross motor development in preschool children for physical education.

Biallelic SEPSECS variants in two siblings with pontocerebellar hypoplasia type 2D underscore the relevance of splice-disrupting synonymous variants in disease.

Noncoding and synonymous coding variants that exert their effects via alternative splicing are increasingly recognized as an important category of disease-causing variants. In this report, we describe two siblings who presented with hypotonia, profound developmental delays, and seizures. Brain magnetic resonance imaging (MRI) in the proband at 5 yr showed diffuse cerebral and cerebellar white matter volume loss. Both siblings later developed ventilator-dependent respiratory insufficiency and scoliosis and are currently nonverbal and nonambulatory. Extensive molecular testing including oligo array and clinical exome sequencing was nondiagnostic. Research genome sequencing under an institutional review board (IRB)-approved study protocol revealed that both affected children were compound-heterozygous for variants in the SEPSECS gene. One variant was an initiator codon change (c.1A > T) that disrupted protein translation, consistent with the observation that most disease-causing variants are loss-of-function changes. The other variant was a coding change (c.846G > A) that was predicted to be synonymous but had been demonstrated to disrupt mRNA splicing in a minigene assay. The SEPSECS gene encodes O-phosphoseryl-tRNA(Sec) selenium transferase, an enzyme that participates in the biosynthesis and transport of selenoproteins in the body. Variations in SEPSECS cause autosomal recessive pontocerebellar hypoplasia type 2D (PCHT 2D; OMIM #613811), a neurodegenerative condition characterized by progressive cerebrocerebellar atrophy, microcephaly, and epileptic encephalopathy. The identification of biallelic pathogenic variants in this family-one of which was a synonymous change not identified by prior clinical testing-not only ended the diagnostic odyssey for this family but also highlights the contribution of occult pathogenic variants that may not be recognized by standard genetic testing methodologies.