副腎白質ジストロフィー

BACKGROUND AND OBJECTIVES: Leukodystrophies are neurogenetic diseases affecting the white matter of the central nervous system. The contributing factors for leukodystrophy mortality are incompletely understood. Our objectives were to characterize inpatient deaths of pediatric leukodystrophies, including demographics and risk factors. METHODS: This retrospective cohort analysis utilized the national Pediatric Health Information System (PHIS) database. Patients under age 19 years with an (ICD-10) diagnosis of leukodystrophy and an inpatient encounter at a PHIS hospital between 2016 and 2024 were included. Analysis included descriptive and multivariate statistics. RESULTS: In all, 613 patients with 15 different leukodystrophies were identified; 32 patients died (5.2%). The most common diagnoses of patients who died were Krabbe disease (KD) (31%), adrenoleukodystrophy (ALD) (28%), metachromatic leukodystrophy (MLD) (28%), and vanishing white matter disease (VWM) (6%). Volume of leukodystrophy admissions at individual hospitals was inversely correlated with mortality. Small numbers limited statistical significance, but mortality rates were higher in females than males (8.3% vs. 3.8%); and Black, Asian, and multiracial patients were more likely to die than White patients, 8.4%, 7.7%, and 8.7%, versus 4.1%. CONCLUSIONS: In this large national administrative database study, we characterized and helped define risks for inpatient mortality of pediatric leukodystrophies. Inpatient mortality was correlated with clinical risk factors, and further, although small numbers precluded statistical significance, mortality disparities by sex and race were identified. The reasons for these differences are not known and warrant further study. Our findings identify directions for new research and underscore the potential impact of specialized institutional experience.

OBJECTIVE: The current clinical nomenclature for individuals with ABCD1 gene dysfunction is often uninformative. The disorder was initially described as a combination of adrenal insufficiency and leukodystrophy, leading to the widespread use of "X-linked adrenoleukodystrophy" (ALD). However, this term is inaccurate for individuals who never develop these features. ABCD1 dysfunction can cause various symptom complexes: adrenal insufficiency, myelopathy, neuropathy, and leukodystrophy, which may occur consecutively, simultaneously, or not at all. METHODS: We developed an intuitive annotation system to precisely convey phenotype status for individuals with ABCD1 dysfunction. The "AMNL score" assesses the presence and severity of [A]drenal insufficiency, [M]yelopathy, [N]europathy, and [L]eukodystrophy, with scores ranging from 0 (no symptoms) to 3 (severe) per domain. RESULTS: Applied to initial clinical encounters with 101 Dutch patients and 30 patients from the California newborn screening (NBS) program, the system identified 33 unique presentations. The most common was isolated mild myelopathy (A0M1N0L0). Including predominantly asymptomatic NBS newborns (mostly A0M0NUL0) broadened the spectrum and highlighted the need for precise classification across ages. Longitudinal use over 2 years in 99 Dutch patients showed progression in one or more domains in 41.4%, most often worsening myelopathy. In the NBS cohort (median follow-up: 3.5 years; range: 0.3-12.2), most patients showed no myelopathy or leukodystrophy, though adrenal involvement was detected in half. Initial inter-rater reliability was high (α = 0.996). INTERPRETATION: The AMNL score's ability to quantify domain-specific changes over time makes it valuable for monitoring disease evolution in clinical practice and research.

Adrenoleukodystrophy (ALD) is an X-linked recessive disease caused by defects in the ABCD1 gene, leading to the accumulation of very long-chain fatty acids in the nervous system, adrenal glands, blood and other tissues. Male ALD patients may present with either the severe neurological phenotype of cerebral ALD, characterized by inflammatory demyelination in the white matter and rapid neurological deterioration, or milder forms, such as adrenomyeloneuropathy. We aimed to identify early brain changes in asymptomatic ALD patients prior to the clinical onset of cerebral ALD or adrenomyeloneuropathy by exploratory analysis of multimodal MRI data. Multimodal MRI data-including structural images, diffusion tensor imaging, magnetization transfer imaging and MR spectroscopy-were obtained from asymptomatic ALD patients during regular follow-up MRIs. Longitudinal MRI data were analysed from 12 asymptomatic ALD patients aged 10-18 years who did not develop a cerebral ALD phenotype during our surveillance and from 12 healthy age-matched male controls. Volumetric analyses of brain structures were performed using structural MRI data, as well as region-of-interest measurements on diffusion tensor imaging, magnetization transfer imaging and MR spectroscopy data. Statistical analysis was performed using linear mixed-effects models. Volumetry indicated increased white matter volume in asymptomatic ALD patients. Diffusion tensor imaging analysis revealed increased values of radial and mean diffusivity in the supratentorial white matter. Magnetization transfer saturation values derived from magnetization transfer imaging metrics were increased in the cortical and subcortical grey matter, but not in the white matter. MR spectroscopy showed increased inositol levels in the frontal white matter. Our diffusion tensor imaging and MR spectroscopy data indicate early white matter pathology in adolescent asymptomatic ALD patients. Among these findings, increased white matter volume and, in addition, elevated magnetization transfer saturation values in the grey matter are novel MRI phenotypes associated with asymptomatic ALD. These results suggest that not only white matter but also grey matter can be pathologically altered even before the onset of neurological phenotypes. Multimodal MRI parameters therefore constitute promising biomarkers for the assessment of pre-symptomatic brain tissue alterations in ALD and may be useful in future clinical studies targeting early therapeutic intervention.

Cerebral adrenoleukodystrophy (CALD) is a progressive immune-inflammatory neurologic disease that can be arrested with autologous hematopoietic cell transplant-based gene therapy (GT) or allogeneic hematopoietic cell transplantation (Allo-HCT). We compared transplant types by evaluating changes in two biomarkers, C26:0-lysophosphatidylcholine (C26:0-lysoPC) and neurofilament light chain (NfL), before and 12 months after therapy. Disease severity was quantified by Loes score on MRI. Baseline C26:0-lysoPC was 489 nmol/L for GT recipients and 487 nmol/L for Allo-HCT recipients; it decreased by 6.7% after GT and 48.4% after Allo-HCT (p < 0.0001). Baseline NfL was 17.3 for GT recipients and 35.9 pg/mL for Allo-HCT recipients; it increased by 143% after GT and decreased by 43% after Allo-HCT (p = 0.0006). Loes score progression was greater with GT (+3.0 vs. +1.0 points, p = 0.0134). Multivariate analyses to understand which pre-HCT variable was best associated with disease progression indicated that modality of transplant, GT, was the only significant factor (p = 0.0302).

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder and is associated with serious clinical consequences. While newborn screening (NBS) could facilitate early identification and timely intervention, its implementation for X-ALD remains controversial due to ethical concerns arising from its X-linked recessive inheritance pattern, particularly regarding female newborns. This study aims to explore the perspectives of healthcare professionals and the general public on NBS for X-ALD in Hong Kong. An online survey with 20 quantitative questions on ethical considerations was conducted from May to August 2024. Among a total of 259 responses, most respondents (99.2%) supported NBS for their male newborns, primarily because it facilitates early diagnosis and effective management. The majority of the respondents were in favor of offering NBS to female newborns, citing potential benefits for the management of adult-onset disease, enhanced family planning and support, and opportunities for extended family screening. However, some respondents expressed concerns regarding (1) psychological stress and anxiety from uncertain disease onset and frequent monitoring; (2) potential genetic discrimination and adverse impact on insurance premiums/coverage; (3) affordability and accessibility of expensive treatments, such as gene therapy; and (4) ethical issues regarding children's "right to an open future", particularly for late-onset female X-ALD. To address these concerns while respecting family autonomy, we propose an opt-in system with clear, balanced information for parents, combined with a three-tier screening algorithm. In summary, while inclusion of X-ALD in Hong Kong's NBS program receives strong community support, targeted measures are needed to mitigate the identified ethical and practical barriers.