Annals of Clinical and Translational Neurology最新文献

Objective: Long-read sequencing and optical genome mapping technologies have the ability to detect large and complex structural variants. This has led to the discovery of novel pathogenic variants in neurodegenerative movement disorders. Thus, we aimed to systematically compare the SV detection capabilities of OGM and ONT in Parkinson's disease.

Methods: Ultra-high molecular weight DNA was derived from blood and fibroblast cultures of 19 patients with mostly early-onset Parkinson's disease, and used for Nanopore sequencing and optical genome mapping. The size distributions of deletions and insertions were compared, and variants were filtered for rare or potentially pathogenic variants in 134 known movement disorder genes.

Results: Both methods identified SVs > 50 kb; however, optical mapping identified fewer structural variants (49,677) compared to Nanopore sequencing (94,400), but detected six times more in the range 50-80 kb. In general, it detected significantly larger deletions and insertions (p < 2.2 × 10^-16). Both methods detected a benign intergenic deletion (195 kb) near ITPR1, and optical mapping validated a previously published 7-Mb PRKN inversion. Small heterozygous deletions in ATXN2, SUCLA2, and PNKD detected by optical mapping were identified to be intronic by Nanopore sequencing. No causal variants were identified in movement disorder genes.

Interpretation: Optical mapping can be a powerful first-line method for detecting large structural variants, but it requires a high-resolution method to refine breakpoint positions. Despite certain limitations, Nanopore sequencing was highly capable of detecting large variants independently and allows for a highly complementary assessment and validation of structural variation in combination with optical mapping.

We report a 58-year-old woman with a novel splice-site variant in the TANK-binding kinase 1 (TBK1:c.993-2A>C p.Ala332TyrfsTer39) who sequentially developed primary lateral sclerosis (PLS) followed by right temporal variant frontotemporal dementia (rtvFTD). Neuroimaging demonstrated right anterior temporal atrophy before cognitive symptoms, and prosopagnosia represented the earliest manifestation of rtvFTD. Molecular analysis revealed reduced levels of correctly spliced TBK1 transcripts, consistent with haploinsufficiency. Given the shared involvement of TDP-43 pathology in both PLS and rtvFTD, this case indicates TBK1 dysfunction as a fundamental genetic factor underlying the coexistence of these phenotypes, underscoring the clinical value of early neuroimaging and genetic evaluation.

Pathogenic variants in KIF1C cause Spastic Paraplegia 58 (SPG58), typically presenting with cerebellar ataxia and spastic paraparesis. We report two unrelated patients with spastic paraparesis, cerebellar ataxia, and tremor. Whole-exome sequence analysis identified novel homozygous variants in the motor domain of KIF1C (NM_006612.6): c.921G>A (p.Trp307Ter) and c.607C>T (p.Arg203Trp). In addition to the canonical brain MRI showing leukoencephalopathy with posterior dominance and hyperintensity along the corticospinal tracts, both patients showed symmetric T2 hyperintensity confined to the lateral and dorsal columns of the cervical cord. Given the long disease durations (22 and 51 years), these findings may represent late-emerging or previously overlooked spinal cord involvement and broaden the neuroradiological spectrum of SPG58.

We present the case of a 28-year-old right-handed woman with medically refractory focal epilepsy. Her seizure semiology and electroencephalography (EEG) indicated a seizure onset zone in the right central-parietal area. However, both MRI and PET scans were unremarkable, showing no focal lesions or areas of altered metabolism. Intracranial monitoring, with extensive evaluation of both hemispheres, confirmed the seizure onset zone in the right central-parietal region. This area not only served as the site of seizure onset but also encompassed the primary sensory cortex.

Objective: SNUPN-related muscular dystrophy or LGMDR29 is a new entity that covers from a congenital or childhood onset pure muscular dystrophy to more complex phenotypes combining neurodevelopmental features, cataracts, or spinocerebellar ataxia. So far, 12 different variants have been described. Here we report the first family with SNUPN-related muscular dystrophy presenting an adult-onset myopathy as well as novel ultrastructural findings.

Methods: Clinical evaluation, muscle and brain magnetic resonance imaging (MRI), and muscle histopathological and electron microscopy analysis were conducted. Functional studies including protein modelling and interaction, immunofluorescence and splicing analysis were also performed.

Results: Two siblings carrying two novel deleterious variants in the SNUPN gene (p.Arg27Cys and p.Cys174Tyr) showed adult-onset proximo-distal and axial muscle weakness with early respiratory involvement. One patient presented with asymptomatic cerebellar atrophy. Muscle MRI identified involvement in the paravertebral, triceps brachii, sartorius and gracilis muscles. The histopathology revealed dystrophic changes and an abnormal pattern of cytoskeletal and myofibrillar proteins, while electron microscopy disclosed the proliferation of granules and vesicles associated with features of nuclear envelope and sarcolemma remodelling. Functional studies showed that SNUPN variants impair snurportin-1 function through reduced binding affinity to importin-β and impaired folding, leading to disturbed nuclear import of small nuclear ribonucleoproteins and downstream splicing.

Interpretation: Our work expands the phenotype of SNUPN-related muscular dystrophy and provides more insights into their pathological profile. We advise SNUPN testing in patients with late-onset proximo-distal and axial weakness with early respiratory impairment and features reminding inclusion body myositis (IBM). Granular deposits suggestive of biomolecular condensates perturbed cell organelle traffic and membrane homeostasis, opening new avenues to understand the pathomechanisms involved in this novel disease.

Background: Leucine-rich glioma-inactivated 1 antibody (LGI1-Ab) encephalitis predominantly affected older individuals, but has also been reported in younger patients. However, the demographic, clinical, and prognostic characteristics of early-onset LGI1-Ab encephalitis have yet to be systematically elucidated. This study aims to systematically describe the clinical features and outcomes of early-onset LGI1-Ab encephalitis and compare them with those of later-onset cases.

Methods: A total of 105 patients with LGI1-Ab encephalitis admitted to the Department of Neurology at Beijing Fengtai You'anmen Hospital were enrolled in this study between January 2019 and December 2024. All patients were divided into early-onset (age at onset younger than 50 years) and late-onset (age at onset 50 years or older) groups. Demographic, clinical, paraclinical, and prognostic data were compared between the two groups.

Results: Among the cohort, 30 (28.5%) patients had early-onset LGI1-Ab encephalitis, with a female predominance (17, 56.7%). Epileptic seizures, psychiatric and behavioral symptoms, and memory impairment were the most common symptoms both at disease onset and throughout the disease course. Compared to later-onset patients, early-onset patients exhibited a lower prevalence of faciobrachial dystonic seizures (FBDS) (p = 0.041) and hyponatremia (p = 0.003). Additionally, they had higher serum albumin (p = 0.012), lower CSF protein (p = 0.006), lower age-normalized QAlb (p = 0.001), and fewer epileptic waves (p = 0.041). As for prognosis, memory deficits (11/30, 36.7%) were the most common residual symptom at follow-up, and early-onset patients were less likely to relapse (p = 0.038).

Conclusions: This study provides the first systematic characterization of early-onset LGI1-Ab encephalitis. Compared to late-onset cases, early-onset patients showed a lower incidence of hyponatremia, milder blood-brain barrier disruption, and fewer clinical relapses.

Mutations in myelin regulatory factor (MYRF) are linked to demyelinating disorders. We report a 38-year-old male who developed acute symmetric leukoencephalopathy mimicking a stroke following an influenza A virus infection. While clinical symptoms markedly improved with corticosteroids, MRI revealed persistent white matter lesions, contrasting with the known phenotype of MYRF-related mild encephalopathy with reversible myelin vacuolization (MMERV). Genetic analysis identified a novel MYRF variant (c.2204G>A, p.Gly735Asp) in its C-terminal domain, with familial cosegregation confirming autosomal dominant inheritance. This case demonstrates that viral infections can trigger severe MYRF-related pathology and establishes persistent leukoencephalopathy as a novel clinical phenotype within the MYRF disease spectrum.

The placebo response in clinical trials in ataxias complicates outcome interpretation and potentially obscures genuine treatment effects. We analyzed placebo group data from past trials in Friedreich Ataxia and observed notable responses in appendicular items, in contrast to minimal changes in axial function, as measured by respective subscores of the modified Friedreich Ataxia Rating Scale (mFARS). The effect increased with the number of consecutive tests, shorter testing intervals, and older group ages. This has implications for trial design and endpoint selection, thus strengthening the utility of the Upright Stability Score (USS), a sub-score of mFARS, as an independent measure.

Objective: Spinal Muscular Atrophy (SMA) is a rare genetic disorder marked by progressive muscle weakness and mobility loss. It has a profound physical, emotional and social impact on patients and caregivers, requiring comprehensive medical and supportive care. SMA is classified into Types 1-4, with some individuals identified presymptomatically. This systematic review examined the safety and effectiveness of nusinersen and risdiplam for treating SMA.

Methods: We searched research databases, relevant websites and existing systematic reviews. Screening, data extraction and quality assessment were conducted independently by two authors, with discrepancies resolved by a third. Internal quality appraisal ensured methodological rigour. A total of 131 studies reported in 148 sources were included. The review is registered with PROSPERO (CRD42024512226).

Results: Both treatments showed improvements in motor function and milestones, with high survival rates across most SMA types. Motor function improvements were consistent, but other outcomes-such as bulbar and respiratory function, and ventilation needs-were variable. Adverse events were common across all treatments and SMA types, with some serious cases reported, including deaths in Types 1 and 2.

Interpretation: This comprehensive review highlights the clinical effectiveness and safety of nusinersen and risdiplam across all SMA types. However, variability in outcomes and limited comparative data introduce uncertainty. The findings underscore the need for more high-quality randomised controlled trials to strengthen the evidence base for SMA treatment.