Gross Motor Function in Pediatric Onset TUBB4A-Related Leukodystrophy: GMFM-88 Performance and Validation of GMFC-MLD in TUBB4A.

TUBB4A pathogenic variants are associated with a spectrum of neurologic impairments including movement disorders and leukodystrophy. With the development of targeted therapies, there is an urgent unmet need for validated tools to measure mobility impairment. Our aim is to explore gross motor function in a pediatric-onset TUBB4A-related leukodystrophy cohort with existing gross motor outcome tools. Gross Motor Function Measure-88 (GMFM-88), Gross Motor Function Classification System (GMFCS-ER), and Gross Motor Function Classification-Metachromatic Leukodystrophy (GMFC-MLD) were selected through face validity. Subjects with a confirmed clinical and molecular diagnosis of TUBB4A-related leukodystrophy were enrolled. Participants' sex, age, genotype, and age at disease onset were collected, together with GMFM-88 and concurrent GMFCS-ER and GMFC-MLD. Performances on each measure were compared. GMFM-88 floor effect was defined as total score below 20%. A total of 35 subjects participated. Median performance by GMFM-88 was 16.24% (range 0-97.31), with 42.9% (n = 15) of individuals performing above the floor. GMFM-88 Dimension A (Lying and Rolling) was the best-performing dimension in the GMFM-88 (n = 29 above the floor). All levels of the Classification Scales were represented, with the exception of the GMFC-MLD level 0. Evaluation by GMFM-88 was strongly correlated with the Classification Scales (Spearman correlations: GMFCS-ER:GMFM-88 r = 0.90; GMFC-MLD:GMFM-88 r = 0.88; GMFCS-ER:GMFC-MLD: r = 0.92). Despite overall observation of a floor effect, the GMFM-88 is able to accurately capture the performance of individuals with attenuated phenotypes. GMFM-88 Dimension A shows no floor effect. GMFC-MLD shows a strong correlation with GMFCS-ER and GMFM-88, supporting its use as an age-independent functional score in TUBB4A-related leukodystrophy.

Exploration of Gross Motor Function in Aicardi-Goutières Syndrome.

Background: Aicardi-Goutières syndrome (AGS) is a rare genetic disorder characterized by a spectrum of motor abilities. While the Aicardi-Goutières syndrome severity score favors severely impacted individuals, there is an unmet need to define tools measuring function across the Aicardi-Goutières syndrome spectrum as potential outcome assessments for future clinical trials. Methods: Gross Motor Function Measure-88 (GMFM-88) and AGS Severity Scale were administered in individuals affected by Aicardi-Goutières syndrome (n = 71). We characterized the performance variability by genotype. Derived versions of the GMFM-88, including the GMFM-66, GMFM-66 item set (GMFM-66IS), and GMFM-66 Basal&Ceiling (GMFM-66BC) were calculated. The Aicardi-Goutières syndrome cohort was divided into severe (AGS Severity Scale score <4) or attenuated (≥4). Performance on the AGS Severity Scale highly correlated with total GMFM-88 scores (Spearman Correlation: R = 0.91). To assess variability of the GMFM-88 within genotypic subcohorts, interquartile ranges (IQRs) were compared. Results: GMFM-88 performance in the TREX1 cohort had least variability while the SAMHD1 cohort had the largest IQR (4.23 vs 81.8). Floor effect was prominent, with most evaluations scoring below 20% (n = 46, 64.79%), particularly in TREX1- and RNASEH2-cohorts. Performance by the GMFM-66, GMFM-66IS, and GMFM-66BC highly correlated with the full GMFM-88. The Aicardi-Goutières syndrome population represents a broad range of gross motor skills. Conclusions: This work identified the GMFM-88 as a potential clinical outcome assessment in subsets of the Aicardi-Goutières syndrome population but underscores the need for additional validation of outcome measures reflective of the diverse gross motor function observed in this population, including low motor function. When time is limited by resources or patient endurance, shorter versions of the GMFM-88 may be a reasonable alternative.

Unweighting infants reveals hidden motor skills.

We investigated the role of rate limiting factors in development using walking as a model system. The achievement of bipedal posture and locomotion are among the most significant achievements in an infant's first year, with poor balance and weak muscles long proposed as the rate limiting factors. Compensating for either may reveal upright motor skill that has not yet emerged in the infant's natural repertoire. To probe this question, we unweighted prewalking infants and measured their performance in various standing and walking behaviors while unweighted compared to baseline. Our secondary objective was to determine if the influence of unweighting was related to infants' locomotor experience. Infants stood unsupported for longer durations with 20% or 40% unweighting. Infants took more independent steps and more steps with one hand held with 40% unweighting. No differences in transition to/from standing were observed. Locomotor experience was related to the influence of unweighting during cruising and walking with a push toy. This is the first report of more advanced motor skills-longer periods of unsupported standing and the emergence of independent walking-revealed by unweighting infants. We interpret our observations to suggest that the refinement of motor control needed to support bipedal posture and locomotion precedes the functional emergence of these skills in infants. In other words, the musculoskeletal components required for walking are slower to develop than the neurological factors - and consequently may be the rate limiters. We further suggest that training regimens including unweighting should be explored in infants with motor delays.

Reliability of the Telemedicine Application of the Gross Motor Function Measure-88 in Patients With Leukodystrophy.

BACKGROUND: Leukodystrophies are a rare class of disorders characterized by severe neuromotor disability. There is a strong need for research regarding the functional status of people with leukodystrophy which is limited by the need for in-person assessments of mobility. The purpose of this study is to assess the reliability of the Gross Motor Function Measure-88 (GMFM-88) using telemedicine compared with standard in-person assessments in patients with leukodystrophy. METHODS: A total of 21 subjects with a diagnosis of leukodystrophy (age range = 1.79-52.82 years) were evaluated by in-person and by telemedicine evaluations with the GMFM-88 by physical therapists. Inter-rater reliability was assessed through evaluation of the same subject by two independent raters within a three-week period (n = 10 encounters), and intrarater reliability was assessed through blinded rescoring of video-recorded assessments after a one-week time interval (n = 6 encounters). RESULTS: Remote assessments were performed by caregivers in all 21 subjects using resources found in the home with remote guidance. There was agreement between all paired in-person and remote measurements (Lin's concordance correlation ≥0.995). The Bland-Altman analysis indicated that the paired differences were within ±5%. Intrarater and inter-rater reliability demonstrated an intraclass correlation coefficient of >0.90. CONCLUSIONS: These results support that remote application of the GMFM-88 is a feasible and reliable approach to assess individuals with leukodystrophy. Telemedicine application of outcome measures may be of particular value in rare diseases and those with severe neurologic disability that impacts the ability to travel.

Diagnostic journey and impact of enzyme replacement therapy for mucopolysaccharidosis IVA: a sibling control study.

BACKGROUND: Mucopolysaccharidosis (MPS) IVA, also known as Morquio A syndrome, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency in the enzyme N-acetylgalactosamine-6-sulfatase. Early recognition, diagnosis, and treatment of this progressive, multisystem disease by enzyme replacement therapy (ERT) can lead to improved outcomes and reduced mortality. METHODS: This report documents the diagnostic journey and treatment with ERT of three siblings with MPS IVA. Clinical outcome measures included growth, endurance, imaging, cardiac, respiratory, ophthalmology, and laboratory evaluations. RESULTS: Three siblings, diagnosed at 14.7, 10.1, and 3.2 years of age, demonstrated clinical improvement with weekly infusions of 2.0 mg/kg elosulfase alfa (Vimizim®, BioMarin Pharmaceutical, Novato, CA, USA). Patient 1 (oldest sibling) and Patient 2 (middle sibling) experienced a diagnostic delay of 8 years 7 months and 4 years after symptom onset, respectively. All three patients demonstrated improvements in growth, 6-min walk distance, joint range of motion, and respiratory function after 30 months of ERT. The treatment was well tolerated without any adverse events. CONCLUSIONS: This case series highlights the importance of early recognition of the clinical and imaging findings that are initially subtle in MPS IVA. Early treatment with ERT is necessary to slow irreversible disease progression and improve patient outcomes. The oldest sibling experienced improvements in mobility despite severe symptoms resulting from a late diagnosis. When evaluating patients with skeletal anomalies, imaging multiple body regions is recommended. When findings such as anterior beaking of vertebrae or bilateral femoral head dysplasia are present, MPS IVA should be included in the differential diagnosis. Newborn screening must be considered for early detection, accurate diagnosis, and initiation of treatment to reduce morbidity.

Construct Validity of the Early Clinical Assessment of Balance in Toddlers with Cerebral Palsy: Brief Report.

Purpose: The purpose of this research was to investigate differences in Early Clinical Assessment of Balance (ECAB) scores within children with cerebral palsy (CP) with different Gross Motor Function Classification System (GMFCS) levels and between children with CP and typical development (TD) who are under three years of age.Methods: The ECAB was administered to fifty children (13 with TD, 16 with GMFCS level II, 11 with GMFCS level III, 10 with GMFCS level III).Results: The group of children of TD had significantly higher scores than all groups of children with CP. There were significant differences in ECAB within the groups of children with CP with different GMFCS levels.Conclusion: The results of this study support the construct validity of the ECAB as a measure of postural control in children under three years of age with CP.

Physical and Occupational Therapy for a Teenager with Acute Flaccid Myelitis: A Case Report.

AIMS: The purpose of this case report is to describe the inpatient rehabilitation program of a 13-year-old boy with acute flaccid myelitis (AFM), specific to physical and occupational therapy examination, treatment, and outcomes. CASE DESCRIPTION: AFM is a rare, acute neurologic illness in children and young adults who present with weakness and/or paralysis of unknown etiology. The teenager was admitted to the program, dependent for all mobility and self-care. Interventions focused on range of motion, transfer training, self-care, power wheelchair mobility, and environmental adaptations. OUTCOMES: Weekly re-evaluations and the WeeFIM were used at admission and discharge to measure the teenager's progress. At discharge, the teenager had made small gains in his passive and active range of motion. He was independent in directing his care and able to drive his power wheelchair with supervision. DISCUSSION: Due to the scarcity of published data describing AFM, this report describes an individual's response to a rehabilitation program and will hopefully add to future research in order to provide patients and families with expectations for their recovery and ultimate level of function.