脳内鉄沈着神経変性症

BACKGROUND: Cognitive impairment is a relatively prevalent comorbidity in chronic obstructive pulmonary disease (COPD), yet its neuropathological mechanism remains poorly understood. METHODS: We enrolled 48 stable COPD patients, categorized into cognitively normal (CogN, n = 22) and impaired (Cog, n = 26) groups based on Montreal Cognitive Assessment (MoCA) scores, along with 34 matched healthy controls. All participants underwent 3T MRI with quantitative susceptibility mapping (QSM) to quantify regional brain iron content. Group comparisons of whole-brain and region-of-interest susceptibility were performed. Mediation analysis was then used to test whether specific brain iron deposition mediates the relationship of both COPD status and peripheral inflammatory markers with cognitive performance. RESULTS: Cog patients showed increased total iron in the right cerebellum crus I, while CogN patients exhibited higher paramagnetic susceptibility (χpara) in the left orbitofrontal cortex (OFC), right precentral gyrus, and right brainstem. χpara in the left OFC and right brainstem were positively correlated with total MoCA, abstraction, and orientation scores. Mediation analysis demonstrated that χpara of the left OFC mediated the effects of both COPD status and systemic neutrophil counts on impaired abstraction. Additionally, right brainstem χpara mediated the relationship between COPD and deficits in orientation. CONCLUSIONS: COPD patients with cognitive impairment exhibited distinct patterns of brain iron deposition. Importantly, deposition in several key regions served as a potential mediator, linking both COPD and systemic inflammation to specific cognitive deficits. These preliminary findings suggest a possible association between brain iron accumulation and cognitive impairment in COPD, offering candidate neuroimaging markers for early identification. .

BACKGROUND: Infantile neuroaxonal dystrophy is a rare autosomal recessive neurodegenerative disorder within the spectrum of PLA2G6-associated neurodegeneration. It is typically characterized by early psychomotor regression, progressive motor impairment, bulbar dysfunction, and characteristic neuroimaging abnormalities, including cerebellar atrophy and, in some cases, brain iron accumulation. CASE REPORT: We report the case of a 4-year-11-month-old girl with progressive neurodevelopmental regression beginning at approximately 18 months of age. The patient presented with loss of previously acquired motor abilities, absence of verbal language, marked hypotonia, preserved deep tendon reflexes, and progressive feeding difficulties. Laboratory evaluation was largely unremarkable, except for persistent isolated elevation of aspartate aminotransferase (AST). Brain MRI showed no overt structural or signal abnormalities despite advanced neurological impairment. Electroencephalography (EEG) did not reveal epileptiform activity. Given the progressive course and suspicion of an underlying neurodegenerative disorder, whole-exome sequencing was performed and identified a homozygous PLA2G6 variant, supporting the diagnosis of PLA2G6-associated neurodegeneration. During follow-up, the patient developed dysphagia and grade II gastroesophageal reflux, requiring gastrostomy placement and Nissen fundoplication. CONCLUSION: This case highlights the importance of early molecular diagnosis in pediatric regression syndromes and emphasizes that normal neuroimaging does not exclude PLA2G6-associated neurodegeneration, particularly in atypical presentations. Early recognition enables timely multidisciplinary management, prognostic assessment, and appropriate genetic counseling for the family.

BACKGROUND: Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous group of heritable, mostly recessive, progressive neurodegenerative diseases characterized by iron deposition in the basal ganglia and brainstem. There are no solid global epidemiological data on prevalence and incidence of NBIA subtypes, but registry data and expert opinion suggest PKAN, BPAN, PLAN, and MPAN are the most common subtypes. NBIA disorders present with a wide spectrum of clinical symptoms, including movement disorders (dystonia, parkinsonism, chorea), pyramidal involvement (eg, spasticity), speech and cognitive deficits, motor and cognitive slowing, and ocular abnormalities. Treatment remains symptomatic, though several new drugs are in development. OBJECTIVES AND METHODS: Following our review published in 2021, this article provides an updated summary of recent developments. We discuss the rationale of new compounds, summarize clinical trials or-in their absence-preclinical studies for NBIA subtypes. The article is divided into two sections: one section on general approaches based on the shared feature of increased iron in the brain; and the second section on tailor-made, mechanistic treatments for the various NBIA subtypes targeting the specific molecular and cellular pathways of the affected enzyme including gene therapy. RESULTS AND CONCLUSIONS: In summary, randomized controlled trials in NBIA have not yet demonstrated substantial benefit, neither for iron removal, in general, which appears to be clinically ineffective in most subtypes, except aceruloplasminemia; nor for subtype-specific approaches. Several ongoing studies are exploring more dedicated compounds in this exciting field.

BACKGROUND: Long-read sequencing and multi-omic analytical frameworks are increasingly being adopted in rare disease diagnostics. However, clinical workflows comprehensively integrating these methodologies remain uncommon. OBJECTIVE: This study aimed to assess the potential and limitations of integrating long-read genomic, transcriptomic, and proteomic analyses to characterize complex structural variants. METHODS: Two unrelated patients presenting with dystonia and comorbid neurological features underwent nanopore-based long-read DNA sequencing. In patient 1, complementary transcriptomic and proteomic analyses were performed. RESULTS: The workflow enabled the identification and characterization of two pathogenic complex structural variants: a homozygous AluY-mediated inversion disrupting PANK2, underlying neurodegeneration with brain iron accumulation (patient 1), and a heterozygous de novo 16p13.3 duplication-triplication event associated with an atypical dystonia-parkinsonism phenotype (patient 2). CONCLUSIONS: Our findings underscore the diagnostic potential of integrated long-read and multi-omic approaches for complex structural variant characterization, while illustrating persistent limitations of automated pipelines and highlighting unpredictable relationships between genomic, transcriptomic, and proteomic findings. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND: Early-onset Parkinson's disease (EOPD) differs from late-onset PD in clinical progression and neurodegenerative patterns. DJ-1 mutations are a known genetic cause of EOPD. Despite the recognized role of iron dyshomeostasis in PD pathogenesis, its spatial distribution and associated tissue alterations in EOPD remain unclear. This study investigated whole-brain iron distribution and related pathological changes in 9-month-old DJ-1-/- mice. METHODS: In vivo quantitative susceptibility mapping (QSM) was performed to characterize whole-brain iron distribution, complemented by ex vivo laser ablation inductively coupled plasma mass spectrometry imaging (LA-ICP-MSI) to validate abnormal iron deposition in secondary motor cortex (M2) and ventral orbital cortex (VO). Anatomical magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), Western blotting, and immunohistochemistry were used to assess brain morphology, microstructural alterations, iron-related proteins, myelination, oxidative stress, and dopaminergic integrity. RESULTS: DJ-1-/- mice exhibited motor deficits without significant nigrostriatal dopaminergic degeneration. QSM revealed significantly increased magnetic susceptibility in the M2, VO, the core of nucleus accumbens (NAc), and ventral pallidum (VP). Elevated iron content in M2 and VO was further verified by LA-ICP-MSI. Regions with increased iron deposition were also shown to exhibit altered ferritin composition, increased fractional anisotropy and myelin basic protein expression, and elevated oxidative stress. CONCLUSION: 9-month-old DJ-1-/- mice show region-specific iron dyshomeostasis in parts of the prefrontal cortex and ventral basal ganglia, which precedes overt nigrostriatal dopaminergic degeneration. Iron accumulation, myelin remodeling, and oxidative stress occur in parallel in the affected brain regions, and may increase metabolic and redox demands, thereby contributing to early functional impairment independent of dopaminergic neurodegeneration.