A Novel Mouse Model for Cerebral Inflammatory Demyelination in X-Linked Adrenoleukodystrophy: Insights into Pathogenesis and Potential Therapeutic Targets.

Objective: X-linked adrenoleukodystrophy (ALD) is caused by mutations in ABCD1, a peroxisomal gene. More than half of males with an ABCD1 mutation develop inflammatory cerebral demyelination (cALD), but underlying mechanisms remain unknown and therapies are limited. We sought to develop and characterize a mouse model of cALD to facilitate study of disease mechanisms and therapy development.

Longitudinal natural history studies based on real-world data in rare diseases: Opportunity and a novel approach.

Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases.

A novel mouse model of cerebral adrenoleukodystrophy highlights NLRP3 activity in lesion pathogenesis.

Objective: We sought to create and characterize a mouse model of the inflammatory, cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD) that would facilitate the study of disease pathogenesis and therapy development. We also sought to cross-validate potential therapeutic targets such as fibrin, oxidative stress, and the NLRP3 inflammasome, in post-mortem human and murine brain tissues.

Background: ALD is caused by mutations in the gene encoding a peroxisomal transporter.

Vitamin D status and latitude predict brain lesions in adrenoleukodystrophy.

Objectives: Approximately 40% of boys with X-linked adrenoleukodystrophy (ALD) develop inflammatory demyelinating brain lesions (cerebral ALD, cALD) and are at risk for death or severe disability. Risk factors for cALD are poorly understood. Our objective was to evaluate whether vitamin D status, which influences immune function, is associated with risk for cALD.

A Phase 1 Study of Oral Vitamin D in Boys and Young Men With X-Linked Adrenoleukodystrophy.

Background And Objectives: There are no therapies for preventing cerebral demyelination in X-linked adrenoleukodystrophy (ALD). Higher plasma vitamin D levels have been linked to lower risk of inflammatory brain lesions. We assessed the safety and pharmacokinetics of oral vitamin D dosing regimens in boys and young men with ALD.

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach.

Pathogenic variants in the gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset.

Presymptomatic Lesion in Childhood Cerebral Adrenoleukodystrophy: Timing and Treatment.

Background And Objectives: We sought to characterize the natural history and standard-of-care practices between the radiologic appearance of brain lesions, the appearance of lesional enhancement, and treatment with hematopoietic stem-cell transplant or gene therapy among boys diagnosed with presymptomatic childhood-onset cerebral adrenoleukodystrophy (CCALD).

Methods: We analyzed a multicenter, mixed retrospective/prospective cohort of patients diagnosed with presymptomatic CCALD (Neurologic Function Score = 0, Loes Score [LS] = 0.5-9.

Pediatric Bickerstaff brainstem encephalitis: a systematic review of literature and case series.

Objective: To characterize the phenotype of pediatric Bickerstaff's brainstem encephalitis (BBE) and evaluate prognostic features in the clinical course, diagnostic studies, and treatment exposures.

Methods: We systematically reviewed PubMed, Web of Science, and SCOPUS databases as well as medical records at the Lucile Packard Children's Hospital to identify cases of pediatric BBE. Inclusion required all of the following criteria: age ≤ 20 years, presence of somnolence or alterations in mental status at the time of presentation or developed within 7 days of presentation, ataxia, and ophthalmoplegia.