Background
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is a rare leukodystrophy with motor impairment due to biallelic mutations in DARS2, which encodes mitochondrial aspartyl tRNA synthetase. Progressive ataxia is the primary feature.
Objective
The study objective is to determine the feasibility of remotely collecting quantitative gait and balance measures in LBSL.
Methods
The study design uses wearable accelerometers and the scale for the assessment and rating of ataxia (SARA) scale to assess gait and postural sway in LBSL and control participants' homes through video conferencing.
Results
Lateral step variability (LSV), which indicates stride variability, and elevation of the step at mid‐swing are increased for LBSL patients during brief walking tests. During stance with the eyes closed, LBSL participants show rapid accelerations and decelerations of body movement covering a large sway area and path. Both the LSV and sway area during stance with the feet together and eyes closed correlate strongly with the SARA.
Conclusions
Wearable accelerometers are valid and sensitive for detecting ataxia in LBSL patients during remote assessments. The finding of large increases in the sway area during stance with the eyes closed is intriguing since dorsal column dysfunction is universally seen in LBSL. This approach can be applied to related rare diseases that feature ataxia.
Adrenomyeloneuropathy (AMN), the slow progressive phenotype of adrenoleukodystrophy (ALD), has no clinical plasma biomarker for disease progression. This feasibility study aimed to determine whether metabolomics and micro‐RNA in blood plasma provide a potential source of biomarkers for AMN disease severity. Metabolomics and RNA‐seq were performed on AMN and healthy human blood plasma. Biomarker discovery and pathway analyses were performed using clustering, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and regression against patient's clinical Expanded Disability Status Score (EDSS). Fourteen AMN and six healthy control samples were analyzed. AMN showed strong disease‐severity‐specific metabolic and miRNA clustering signatures. Strong, significant clinical correlations were shown for 7‐alpha‐hydroxy‐3‐oxo‐4‐cholestenoate (7‐HOCA) (r2 = 0.83, p < 0.00001), dehydroepiandrosterone sulfate (DHEA‐S; r2 = 0.82, p < 0.00001), hypoxanthine (r2 = 0.82, p < 0.00001), as well as miRNA‐432‐5p (r2 = 0.68, p < 0.00001). KEGG pathway comparison of mild versus severe disease identified affected downstream systems: GAREM, IGF‐1, CALCRL, SMAD2&3, glutathione peroxidase, LDH, and NOS. This feasibility study demonstrates that miRNA and metabolomics are a source of potential plasma biomarkers for disease severity in AMN, providing both a disease signature and individual markers with strong clinical correlations. Network analyses of affected systems implicate differentially altered vascular, inflammatory, and oxidative stress pathways, suggesting disease‐severity‐specific mechanisms as a function of disease severity.
Objective: Vitamin D status has been linked to risk of inflammatory brain lesions. We sought to assess the safety and pharmacokinetics of oral vitamin D dosing regimens in boys with X-linked adrenoleukodystrophy (ALD).
Methods: In this open-label, multi-center, phase I study, we enrolled 21 ALD males without brain lesions, aged 1.5 to 25 years to oral vitamin D supplementation for 12 months. Our primary outcome was attainment of plasma 25-hydroxyvitamin D levels in target range (40-80ng/ml) at 6 and 12 months. Secondary outcomes included safety and glutathione levels in brain and blood. Participants were initially assigned to a fixed dosing regimen starting at 2,000 IU daily, regardless of weight. Following a mid-study safety assessment, we modified the dosing regimen so all subsequent participants were assigned to a weight-stratified dosing regimen starting as low as 1,000 IU daily. Results: Between October 2016 and June 2019, we recruited 21 participants (n=12 fixed dose; n=9 weight-stratified) with a median age and weight of 6.7 years and 20 kilograms. Most participants achieved target plasma vitamin D levels at 6 and 12 months regardless of dosing regimen. In the fixed dose regimen, 6 of 12 participants had asymptomatic elevation in urine calcium:creatinine or plasma 25-hydroxyvitamin D; no laboratory deviations occurred with the weight-stratified regimen. Glutathione levels increased between baseline and 12 months in the brain but not in the blood. Conclusions: Our weight-stratified vitamin D dosing regimen was well-tolerated and achieved target 25-hydroxyvitamin D levels in most participants. Brain glutathione levels increased over the 12-month trial period.
Classification of Evidence: This study provides Class II evidence that a weight-stratified dosing regimen of vitamin D supplementation is safe, well-tolerated, and effective at achieving moderately high vitamin D levels in boys with ALD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.