LMNB1 関連大脳白質脳症

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.

Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset, autosomal dominant disorder caused by heterozygous C-terminal frameshift mutations in TREX1, leading to mislocalization of its normally perinuclear exonuclease. Patients typically present with progressive visual impairment and neurological decline, while brain magnetic resonance imaging (MRI) commonly demonstrates punctate white matter lesions or tumor-like rim-enhancing masses. We report the case of a 53-year-old woman who initially presented with progressive headaches, followed by visual loss, cognitive impairment, and focal neurological deficits. Brain MRI revealed a left frontal white matter rim-enhancing lesion highly suggestive of a high-grade glioma. Histopathological evaluation demonstrated ischemic white matter injury, marked vascular hyalinization with fibrinoid necrosis, and prominent dystrophic calcifications. Ultrastructural analysis revealed multilaminated basement membranes and granular osmophilic deposits. Genetic testing, which had been performed previously, later demonstrated a pathogenic TREX1 mutation, establishing the diagnosis of RVCL. This case highlights the importance of considering RVCL in the differential diagnosis of tumor-like white matter lesions and underscores the clinical value of detailed histopathological and ultrastructural characterization, which is seldom available in reported cases.

BACKGROUND AND OBJECTIVES: Genetic small vessel diseases (SVDs) are associated with early onset of stroke and dementia. Cathepsin A-related arteriopathy with strokes and leukoencephalopathy (CARASAL) is an extremely rare genetic SVD caused by a single heterozygous CTSA variant, which can mimic cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common genetic SVD. In this study, we describe a series of patients with CARASAL and compare stroke subtypes and radiologic features with those of patients with CADASIL. METHODS: Twenty-one patients with CARASAL were included from 3 pedigrees; 7 participated in a prospective genetic SVD cohort study, and for 14, data were collected retrospectively. Clinical characteristics were assessed, and 2 analyses of neuroimaging outcomes were performed: (1) a comparison between patients with CARASAL (n = 7) and age- and sex-matched patients with CADASIL (n = 28) and (2) a comparison between patients with CARASAL and normalized white matter hyperintensity volume (nWMHv)-matched patients with CADASIL (n = 28). Enophthalmos in patients with CARASAL was investigated and quantified on MRI. RESULTS: Stroke patients with CARASAL (n = 9) had variable stroke subtypes, including subcortical stroke (n = 3/9), cortical stroke (n = 4/9), and (fatal) intracerebral hemorrhage (n = 4/9). Total nWMHv was higher in patients with CARASAL than in those with CADASIL (mean difference: 5.0% of intracranial volume, 95% CI [2.0-8.0], p = 0.0007). Compared with nWMHv-matched patients with CADASIL, patients with CARASAL had higher pontine nWMHv (mean rank difference: 25.5, p = 0.0019), but fewer lacunes and a higher brain parenchymal fraction (both p < 0.05). Overall, 13 of 14 patients with CARASAL had an enophthalmos, with reduced volumes of the extraocular rectus muscles and intraorbital fat, and an "orbital check-mark sign" on MRI. DISCUSSION: Stroke in CARASAL is heterogeneous, suggesting that CARASAL-specific guidelines for stroke management are warranted. The high white matter hyperintensity lesion load, including the pons, in combination with the orbital check-mark sign, can serve as radiologic clues for the diagnosis of CARASAL.