Multicenter appraisal of comorbid TANGO2 deficiency disorder in patients with 22q11.2 deletion syndrome.

TANGO2 deficiency disorder (TDD) is a rare, autosomal recessive condition caused by pathogenic variants in TANGO2, a gene residing within the region commonly deleted in 22q11.2 deletion syndrome (22q11.2DS). Although patients with 22q11.2DS are at substantially higher risk for comorbid TDD, it remains underdiagnosed within 22q11.2DS, likely due to overlapping symptomatology and a lack of knowledge about TDD. Initiation of B-vitamin supplementation may provide therapeutic benefit in TDD, highlighting the need for effective screening methods to improve diagnosis rates in this at-risk group. In this retrospective, multicenter study, we evaluated two cohorts of patients with 22q11.2DS (total N = 435) for possible comorbid TDD using two different symptom-based screening methods (free text-mining and manual chart review versus manual chart review alone). The methodology of the cohort 1 screening method successfully identified a known 22q11.2DS patient with TDD. Combined, these two cohorts identified 21 living patients meeting the consensus recommendation for TANGO2 testing for suspected comorbid TDD. Of the nine patients undergoing TANGO2 sequencing with del/dup analysis, none were ultimately diagnosed with TDD. Of the 12 deaths in the suspected comorbid TDD cohort, some of these patients exhibited symptoms (rhabdomyolysis, cardiac arrhythmia, or metabolic crisis) suspicious of comorbid TDD contributing to their death. Collectively, these findings highlight the need for robust prospective screening tools for diagnosing comorbid TDD in patients with 22q11.2DS.

Haem's relevance genuine? Re-visiting the roles of TANGO2 homologues including HRG-9 and HRG-10 in C. elegans.

Mutations in the TANGO2 gene cause severe illness in humans, including life-threatening metabolic crises; however, the function of TANGO2 protein remains unknown. In a recent publication in Nature, Sun et al. proposed that TANGO2 helps transport haem within and between cells, from areas with high haem concentrations to those with lower concentrations. Caenorhabditis elegans has two versions of TANGO2 that Sun et al. called HRG-9 and HRG-10. They demonstrated that worms deficient in these proteins show increased survival upon exposure to a toxic haem analog, which Sun et al. interpreted as evidence of decreased haem uptake from intestinal cells into the rest of the organism. We repeated several experiments using the same C. elegans strain as Sun et al. and believe that their findings are better explained by reduced feeding behavior in these worms. We demonstrate that hrg-9 in particular is highly responsive to oxidative stress, independent of haem status. Our group also performed several experiments in yeast and zebrafish models of TANGO2 deficiency and was unable to replicate key findings from these models reported in Sun et al.'s original study. Overall, we believe there is insufficient evidence to support haem transport as the primary function for TANGO2.

Early initiation of B-vitamin supplementation may reduce symptoms and explain intrafamilial variability: Insights from two sibling pairs from the TANGO2 natural history study.

TANGO2-deficiency disorder (TDD) is an autosomal recessive condition arising from pathogenic biallelic variants in the TANGO2 gene. TDD is characterized by symptoms typically beginning in late infancy including delayed developmental milestones, cognitive impairment, dysarthria, expressive language deficits, and gait abnormalities. There is wide phenotypic variability where some are severely affected while others have mild symptoms. This variability has been documented even among sibling pairs who share the same genotype, but reasons for this variability have not been well understood. Emerging data suggest a potential link between B-complex or multivitamin supplementation and decreased metabolic crises in TDD. In this report, we describe two sibling pairs from unreladiagnosed with TDD with marked differences in symptoms. In both families, the older siblings suffered multiple metabolic crises and are clinically more affected than their younger siblings who have very mild to no symptoms; they are the least impaired among 70 other patients in our ongoing international natural history study. Unlike their older siblings, the two younger siblings started taking B-complex vitamins early between 9 and 16 months. This report delineates the mildest presentation of TDD in two families. These data may support a role for early diagnosis and initiation of vitamin supplementation to not only prevent metabolic crises but also improve neurologic outcomes in this life-threatening disorder.

Natural history of TANGO2 deficiency disorder: Baseline assessment of 73 patients.

PURPOSE: TANGO2 deficiency disorder (TDD), an autosomal recessive disease first reported in 2016, is characterized by neurodevelopmental delay, seizures, intermittent ataxia, hypothyroidism, and life-threatening metabolic and cardiac crises. The purpose of this study was to define the natural history of TDD. METHODS: Data were collected from an ongoing natural history study of patients with TDD enrolled between February 2019 and May 2022. Data were obtained through phone or video based parent interviews and medical record review. RESULTS: Data were collected from 73 patients (59% male) from 57 unrelated families living in 16 different countries. The median age of participants at the time of data collection was 9.0 years (interquartile range = 5.3-15.9 years, range = fetal to 31.8 years). A total of 24 different TANGO2 alleles were observed. Patients showed normal development in early infancy, with progressive delay in developmental milestones thereafter. Symptoms included ataxia, dystonia, and speech difficulties, typically starting between the ages of 1 to 3 years. A total of 46/71 (65%) patients suffered metabolic crises, and of those, 30 (65%) developed cardiac crises. Metabolic crises were significantly decreased after the initiation of B-complex or multivitamin supplementation. CONCLUSION: We provide the most comprehensive review of natural history of TDD and important observational data suggesting that B-complex or multivitamins may prevent metabolic crises.

Benefits of aerobic exercise in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is a multisystem trinucleotide repeat expansion disorder characterized by the misregulated alternative splicing of critical mRNAs. Previous work in a transgenic mouse model indicated that aerobic exercise effectively improves splicing regulation and function in skeletal muscle. In this issue of the JCI, Mikhail et al. describe the safety and benefits of applying this approach in individuals affected by DM1. A 12-week aerobic exercise program improved aerobic capacity and mobility, but not by the mechanism observed in transgenic mice. Here, we consider the possible reasons for this disparity and review other salient findings of the study in the context of evolving DM1 research.

Symptom Prevalence and Genotype-Phenotype Correlations in Patients With TANGO2-Related Metabolic Encephalopathy and Arrhythmias (TRMEA).

BACKGROUND: TANGO2-related metabolic encephalopathy and arrhythmias (TRMEA) is a rare, phenotypically heterogeneous, neurological disease affecting children. METHODS: We conducted a chart review of five children with molecularly confirmed TRMEA diagnosed at our institution and compiled pathogenic variant frequency and symptom prevalence from cases previously reported in the literature. RESULTS: Including those patients in our case series, 76 patients with TRMEA have been described. Developmental delay (93%) and/or regression (71%), spasticity (78%), and seizures (57%) are common in TRMEA and frequently precede life-threatening symptoms such as metabolic decompensation with lactic acidosis (83%), cardiomyopathy (38%), and cardiac arrhythmias (68%). Deletion of exons 3 to 9 is the most common pathogenic variant (39% of alleles). The majority of reported intragenic variants (17 of 27) result in disruption of the reading frame, and no clear genotype-phenotype correlations could be identified for those variants wherein the reading frame is maintained, highlighting instead the variable expressivity of the disease. CONCLUSIONS: Patients with TRMEA frequently experience life-threatening complications that are preceded by common neurological symptoms underscoring the need for pediatric neurologists to be familiar with this condition. Additional work pertaining to disease pathophysiology and potential therapeutics is needed.

Therapeutic Approaches for Duchenne Muscular Dystrophy: Old and New.

Duchenne muscular dystrophy (DMD) is marked by pathogenic variants in the DMD gene, leading to reduced or absent dystrophin translation, muscle fiber destruction, loss of ambulation, cardiomyopathy, respiratory failure, and eventually death. Disease progression is slowed with use of prednisone or other corticosteroid agents. Gene replacement therapy, which is one of the focus points of this review, has emerged as the most promising potential treatment for DMD, though alternative RNA-based strategies have been employed for patients with specific pathogenic variants. While challenges remain, many of these novel therapeutic approaches hold promise for treating this devastating disease.

Genetic testing utilization for patients with neurologic disease and the limitations of claims data.

OBJECTIVE: To determine the utilization of genetic testing in patients seen by a neurologist within a large private insurance population. METHODS: Using the Optum health care claims database, we identified a cross-sectional cohort of patients who had been evaluated by a neurologist no more than 30 days before initial genetic testing. Within this group, we then categorized genetic testing between 2014 and 2016 on the basis of the Current Procedural Terminology (CPT) codes related to molecular and genetic testing. We also evaluated the International Classification of Disease Version 9 Clinical Code Classifications (ICD-9 CCS) associated with testing. RESULTS: From 2014 to 2016, a total of 45,014 claims were placed for 29,951 patients who had been evaluated by a neurologist within the preceding 30 days. Of these, 29,926 (66.5%) were associated with codes that were too nonspecific to infer what test was actually performed. Among those claims where the test was clearly identifiable, 7,307 (16.2%) were likely obtained for purposes of neurologic diagnosis, whereas the remainder (17.2%) was obtained for non-neurological purposes. An additional 3,793 claims (8.4%) wherein the test ordered could not be clearly identified were associated with a neurology-related ICD-9 CCS. CONCLUSIONS: Accurate assessment of genetic testing utilization using claims data is not possible given the high prevalence of nonspecific codes. Reducing the ambiguity surrounding the CPT codes and the actual testing performed will become even more important as more genetic tests become available.

Cauda equina repair in the rat: Part 3. Axonal regeneration across Schwann cell-Seeded collagen foam.

INTRODUCTION: Treatments for patients with cauda equina injury are limited. METHODS: In this study, we first used retrograde labeling to determine the relative contributions of cauda equina motor neurons to intrinsic and extrinsic rat tail muscles. Next, we transected cauda equina ventral roots and proceeded to bridge the proximal and distal stumps with either a type I collagen scaffold coated in laminin (CL) or a collagen-laminin scaffold that was also seeded with Schwann cells (CLSC). Regeneration was assessed by way of serial retrograde labeling. RESULTS: After accounting for the axonal contributions to intrinsic vs. extrinsic tail muscles, we noted a higher degree of double labeling in the CLSC group (58.0 ± 39.6%) as compared with the CL group (27.8 ± 16.0%; P = 0.02), but not the control group (33.5 ± 18.2%; P = 0.10). DISCUSSION: Our findings demonstrate the feasibility of using CLSCs in cauda equina injury repair. Muscle Nerve 57: E78-E84, 2018.

Innervation and function of rat tail muscles for modeling cauda equina injury and repair.

INTRODUCTION: The rat tail exhibits functional impairment after cauda equina injury. Our goal was to better understand the innervation and roles of muscles that control the tail. METHODS: Adult rats received either: (1) ventral root injury; (2) caudales nerve injury; or (3) mapping of sacrococcygeal myotomes. Activation of small muscles within the tail itself (intrinsics) was compared with that of larger lumbosacral muscles acting on the tail (extrinsics). Behavioral testing of tail movement was done 1 week later. RESULTS: Rats that received ventral root injury exhibited multiple behavioral deficits, whereas rats with injury to caudales nerves maintained more fully preserved tail movement. Mapping studies revealed much broader overlap of myotomes for extrinsic muscles. CONCLUSIONS: Extrinsic tail muscles play a greater role in tail movement in the rat than their intrinsic counterparts and are innervated by multiple neurological segments. These findings have major implications for future research on cauda equina injury.

Cauda equina repair in the rat: part 2. Time course of ventral root conduction failure.

Treatment for cauda equina (CE) ventral root injury is currently limited. Furthermore, relatively little is known about the time course of nerve root functional degeneration after such injury has occurred. Using a previously developed method for identifying spinal nerve roots that innervate the rat tail, we transected S2, S3, and S4 ventral roots and measured their ability to activate tail muscles out to 72 h post-injury by way of stimulus-evoked electromyography (EMG) recording. Immediately following transection, all distal ventral root stumps successfully activated muscles in the tail upon stimulation with no change in stimulus threshold (0.07±0.04 to 0.07±0.06 V using 0.1-msec pulse duration; 0.04±0.02 to 0.04±0.02 V using 1.0-msec pulse duration). Thresholds increased incrementally at each later time point (24 h: 0.27±0.33 V using 0.1-msec pulse duration; 0.09±0.07 V using 1-msec pulse duration; 48 h: 0.57±1.00 V using 0.1-msec pulse duration; 0.56±1.09 V using 1-msec pulse duration), with the first complete absence of EMG noted at 48 h post-transection in a subset of nerve roots (4/12). We were not able to elicit EMG at 72 h post-transection without moving distally along the nerve root stump. Based on neurofilament staining, only 51% of axons were identifiably intact nearest the site of injury at 24 h post-injury. This percentage dropped to 39% at 48 h, and just 18% at 72 h. Moving 5 mm from the site of injury, we identified 83% intact axons at 24 h post-transection, 77% at 48 h, and 68% at 72 h. Regenerative implications aside, if electrophysiological mapping of injured nerve roots is to be carried out for repair purposes, the rapid nature of conduction failure needs to be considered.

Short term auditory pacing changes dual motor task coordination in children with and without dyslexia.

This study examined the effect of short-term auditory pacing practice on dual motor task performance in children with and without dyslexia. Groups included dyslexic with Movement Assessment Battery for Children (MABC) scores > 15th percentile (D_HIGH, n = 18; mean age 9.89 +/- 2.0 years), dyslexic with MABC < or = 15th percentile (D_LOW, n = 15; mean age 10.43 +/- 1.8 years), and typically developing (TD, n = 18; mean age 10.64 +/- 1.8 years). Participants clapped and walked simultaneously for 3 pretest trials, completed 16 trials with auditory pacing, and 3 posttest trials without pacing. D_LOW differed significantly from D_HIGH and TD in mean relative phase (MRP) of the clap relative to the step, and variability (VRP) of the MRP. Significant differences also existed between pretest blocks and all other blocks in MRP. The results suggest that a short-term auditory pacing may be effective in improving MRP in all children. Further, there may be subtypes of dyslexia wherein children have more profound coordination difficulties and may preferentially change dual motor task performance with auditory pacing.

Using grasping tasks to evaluate hand force coordination in children with hemiplegic cerebral palsy.

UNLABELLED: Mackenzie SJ, Getchell N, Modlesky CM, Miller F, Jaric S. Using grasping tasks to evaluate hand force coordination in children with hemiplegic cerebral palsy. OBJECTIVE: To assess force coordination in children with hemiplegic cerebral palsy (CP) using a device that allows for testing both unimanual and bimanual manipulation tasks performed under static and dynamic conditions. DESIGN: Nonequivalent groups design. SETTING: University research laboratory for motor control. PARTICIPANTS: Six children with hemiplegic CP (age, mean +/- SD, 11.6+/-1.8 y) and 6 typically developing controls (11.6+/-1.6 y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Children performed simple lifting and force-matching static ramp tasks by way of both unimanual and bimanual pulling using a device that measures grip force (force acting perpendicularly at the digits-device contact area) and load force (tangential force). Main outcome measures were grip/load force ratios (grip force scaling) and correlation coefficients (force coupling). RESULTS: CP subjects showed significantly higher grip/load force ratios (P<.05) and slightly lower correlation coefficients than the control group, with more pronounced differences for most tasks when using their involved hand. For subjects with CP, switching from unimanual to bimanual conditions did not bring changes in scaling or coupling for the involved hand (P>.05). CONCLUSIONS: Compared with healthy children, the impaired hand function in the hemiplegic CP pediatric population could be reflected in excessive grip force that is also decoupled from ongoing changes in load force. Therefore, the bimanual grip load device used in this study could provide a sensitive measure of grip force coordination in CP, although nonmotor deficits should be taken into account when asking children to perform more complex tasks.