LMNB1 関連大脳白質脳症

We present a family of five siblings who came to our attention with a clinical and radiological diagnosis of familial hypomyelinating leukodystrophy. Despite brain white matter abnormalities being present in all siblings, the clinical phenotype was variable: the three brothers presented with a clear-cut late-onset spastic paraplegia, whereas the two sisters displayed only mild pyramidal signs. Molecular analysis revealed a single relevant variant shared by all affected siblings, namely the likely pathogenic variant c.659C>T (p.Ser220Phe) in the GJA1 gene. Variants in this gene are generally associated with oculodentodigital dysplasia (ODDD), an autosomal dominant condition characterized by distinctive facial features and anomalies of the eyes, teeth, and digits. Neurological features are reported in about 30% of cases. In this family, ODDD manifested as a predominantly neurological phenotype. Although a clear explanation for this uncommon presentation is lacking, shared genetic modifiers, the effect of the specific variant, and a possible patient-population bias may have contributed. This case highlights the wide phenotypic spectrum of CX43-related disorders and suggests the importance of testing the GJA1 gene in individuals with atypical presentations, including predominant or isolated neurological phenotypes such as late-onset spastic paraplegia. MRI findings may also provide a useful diagnostic clue when ODDD is suspected.

Autosomal dominant leukodystrophy (ADLD) is a fatal-adult-onset CNS demyelinating disorder for which no treatment exists. The majority of ADLD cases are caused by duplications of the lamin B1 (LMNB1) gene, resulting in increased LMNB1 expression. While reducing LMNB1 levels represents a logical therapeutic strategy, its efficacy has not been previously demonstrated in any in vivo model. Mouse models with oligodendrocyte-specific human LMNB1 (hLMNB1) overexpression recapitulate salient features of ADLD. Using a modified version of this model, where hLMNB1 can be inducibly downregulated, we demonstrated that hLMNB1 reduction can prevent or substantially ameliorate disease progression. Therapeutic effects were maximized when hLMNB1 reduction was induced before expected symptom onset, resulting in improvements in behavioral, biochemical, histopathological, and survival measures relative to untreated animals. Reducing hLMNB1 levels after symptom onset led to improved survival, but mixed results for other disease phenotypes. In addition, we identified potential biomarkers that track disease progression. Furthermore, we demonstrated that near-complete knockdown of murine LMNB1 expression in adulthood did not result in any overt CNS phenotype. Together, these results provide a proof of concept supporting LMNB1 reduction as a therapeutic strategy and offer a rationale for treatments aimed at lowering levels of this protein in ADLD.

Colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) is a rare, fatal, autosomal-dominant neurodegenerative disorder caused by pathogenic CSF1R variants and characterized by progressive cognitive, neuropsychiatric, and motor dysfunction, white matter lesions on brain imaging, and white matter demyelination, swollen axons, and pigmented glial cells on pathology. Limited data regarding clinical, biofluid or radiological biomarkers of disease severity are available, and no clinical trial endpoints have yet been validated. The objectives of this first-of-its-kind, prospective, observational natural history study were to characterize the clinical trajectory of CSF1R-ALSP and to identify and evaluate key biomarkers and clinical endpoints indicative of disease severity and progression. ILLUMINATE (NCT05020743) was a multicentre, noninterventional natural history study of adults with CSF1R-ALSP and prodromal carriers of CSF1R variants. Participants were followed for up to 36 months, with clinical assessments, fluid biomarkers and volumetric MRI assessments of brain atrophy collected at screening and every 6 months. This study was terminated early (4 June 2025). The analyses reported here include data collected through 19 February 2025. Of 53 participants, 19 were prodromal and 34 were symptomatic (11 of whom had a history of haematopoietic stem cell transplant and 23 who did not). Mean participant age was 47.8 (standard deviation, 4.5) years, and 36.4% were female. Prodromal participants remained relatively stable over 36 months, with little change in neurological function, neurodegeneration biomarkers or radiological disease burden. Impaired neurological function, MRI characteristics of CSF1R-ALSP, and elevated NfL (neurofilament light chain; neurodegeneration biomarker) and GFAP (glial fibrillary acidic protein; astrogliosis biomarker) levels were more pronounced at baseline and often showed progression over time among symptomatic participants who had not previously received haematopoietic stem cell transplant compared with participants who had previously received haematopoietic stem cell transplant. Significant correlations were observed at baseline and longitudinally between MRI measures of brain atrophy and clinical outcome measures. Based on the fluid biomarkers, MRI measures, and clinical outcome assessments evaluated here, active neurodegeneration, widespread changes visualized on brain MRI, and impaired cognitive and motor function were observed in symptomatic patients with CSF1R-ALSP. The neurological impairment can be assessed using the Montreal Cognitive Assessment and Cortical Basal ganglia Functional Scale. Our data suggest that quantification of brain atrophy using MRI volumetry is a potential biomarker of disease severity and progression in CSF1R-ALSP. It is hoped that this report will contribute to the understanding of disease progression in CSF1R-ALSP and inform future drug development.

INTRODUCTION: Adult-onset autosomal dominant leukodystrophy (ADLD) is an ultra-rare inherited white matter disorder caused by variants in the LMNB1 gene. Here, we report a case of ADLD and characterize its typical magnetic resonance imaging (MRI) features, with the aim of facilitating its clinical recognition and differential diagnosis. CASE DESCRIPTION: The patient was a 55-year-old male who had experienced incomplete voiding, dysuria, and constipation for 10 years. One year prior to presentation, he developed lower limb weakness and unsteady gait, which progressively worsened over time. Brain MRI revealed extensive white matter abnormalities, including a symmetric hyperintensity pattern in the brainstem corticospinal tract and bilateral middle cerebellar peduncles on T2-weighted/FLAIR images, which resembled the facial profile of a Beagle dog. Subsequent genetic testing identified a pathogenic duplication of the LMNB1 gene, a typical variant associated with ADLD. CONCLUSION: We report a case of ADLD caused by LMNB1 duplication with a typical clinical course and characteristic MRI features. Its characteristic MRI features, including the "Beagle sign" as an illustrative imaging analogy in the brainstem, may facilitate the clinical recognition and differential diagnosis of this disorder.

BACKGROUND: CSF1R-related disorder (CSF1R-RD) is a severe autosomal dominant leukoencephalopathy characterized by progressive cognitive, neuropsychiatric, and motor decline. Although genetic testing is widely available, numerous likely pathogenic variants in CSF1R frequently remain classified as variants of uncertain significance (VUS), limiting the option of pre-symptomatic genetic testing or prenatal options for at-risk family members. METHODS: We report a male in his early 50s with progressive leukoencephalopathy and a strong multigenerational family history supported by neuropathological findings consistent with CSF1R-RD. Genetic testing identified a heterozygous CSF1R splice-region variant (c.2763 + 4_2763 + 7del) classified as a VUS. Targeted long-read RNA sequencing of peripheral blood was performed to assess transcript-level consequences. RESULTS: Long-read transcriptomic analysis identified a novel exon 20-skipping isoform absent in pooled controls, accounting for approximately 63% of detected transcripts, with a corresponding reduction in the canonical transcript. Exon skipping (109 bp) results in a frameshift and a premature termination codon in the final exon, predicted to escape nonsense-mediated decay and disrupt the tyrosine kinase domain. These findings establish a direct molecular mechanism of pathogenicity. Functional evidence allowed reclassification of the variant using American College of Medical Genetics and Genomics (ACMG) and Association for Clinical Genomic Science (ACGS) guidelines from VUS to likely pathogenic, enabling definitive molecular diagnosis. CONCLUSIONS: This case demonstrates that targeted long-read transcriptomic sequencing can provide decisive functional evidence to resolve non-canonical splice variants in CSF1R-RD. Focused transcript-level assessment represents a practical adjunct to genomic testing in clinically compelling cases where DNA-based interpretation alone is insufficient. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.