Annals of Neurology最新文献

Objectives

Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene has recently been recognized as a common cause of late-onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4-aminopyridine in a cohort of 102 patients bearing GAA repeat expansions.

Methods

We compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post-mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B.

Results

In our cohort of 102 patients with SCA27B, we found that SCA27B was a late-onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post-mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4-aminopyridine.

Interpretation

Our study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024;96:1092–1103

Objective

Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes.

Methods

Whole exome sequencing of the probands was performed to identify pathogenic variants. We validated the mitochondrial defect by analyzing mtDNA, mitochondrial dNTP pools, respiratory chain activities, and GUK1 activity. To confirm pathogenicity of GUK1 deficiency, we expressed 2 GUK1 isoforms in patient cells.

Results

We identified biallelic GUK1 pathogenic variants in all 4 probands who presented with ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy and altered T-lymphocyte profiles. Muscle biopsies from all probands showed mtDNA depletion, deletions, or both, as well as reduced activities of mitochondrial respiratory chain enzymes. GUK1 encodes guanylate kinase, originally identified as a cytosolic enzyme. Long and short isoforms of GUK1 exist. We observed that the long isoform is intramitochondrial and the short is cytosolic. In probands’ fibroblasts, we noted decreased GUK1 activity causing unbalanced mitochondrial dNTP pools and mtDNA depletion in both replicating and quiescent fibroblasts indicating that GUK1 deficiency impairs de novo and salvage nucleotide pathways. Proband fibroblasts treated with deoxyguanosine and/or forodesine, a purine phosphatase inhibitor, ameliorated mtDNA depletion, indicating potential pharmacological therapies.

Interpretation

Primary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T-lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024;96:1209–1224

The no-reflow phenomenon is a potential contributor to poor outcome despite successful thrombectomy. There are multiple proposed imaging-based definitions of no-reflow leading to wide variations in reported prevalence. We investigated the agreement between existing imaging definitions and compared the characteristics and outcomes of patients identified as having no-reflow.

Methods

We performed an external validation of 4 existing published definitions of no-reflow in thrombectomy patients with extended Thrombolysis in Cerebral Infarction scale 2c to 3 (eTICI2c-3) angiographic reperfusion who underwent 24-hour perfusion imaging from 2 international randomized controlled trials (EXTEND-IA TNK part-1 and 2) and a multicenter prospective observational study. Receiver-operating-characteristic and Bayesian-information-criterion (BIC) analyses were performed with the outcome variable being dependent-or-dead at 90-days (modified Rankin Score [mRS] ≥3).

Results

Of 131 patients analyzed, the prevalence of no-reflow significantly varied between definitions (0.8–22.1%; p < 0.001). There was poor agreement between definitions (kappa 5/6 comparisons <0.212). Among patients with no-reflow according to at least 1 definition, there were significant differences between definitions in the intralesional interside differences in cerebral blood flow (CBF) (p = 0.006), cerebral blood volume (CBV) (p < 0.001), and mean-transit-time (MTT) (p = 0.005). No-reflow defined by 3 definitions was associated with mRS ≥3 at 90 days. The definition of >15% CBV or CBF asymmetry was the only definition that improved model fit on BIC analysis (ΔBIC = −8.105) and demonstrated an association between no-reflow and clinical outcome among patients with eTICI3 reperfusion.

Conclusions

Existing imaging definitions of no-reflow varied significantly in prevalence and post-treatment perfusion imaging profile, potentially explaining the variable prevalence of no-reflow reported in literature. The definition of >15% CBV or CBF asymmetry best discriminated for functional outcome at 90 days, including patients with eTICI3 reperfusion. ANN NEUROL 2024;96:1104–1114

Objective

Hexanucleotide repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A large body of evidence implicates dipeptide repeats (DPRs) proteins as one of the main drivers of neuronal injury in cell and animal models.

Methods

A pure repeat-associated non-AUG (RAN) translation zebrafish model of C9orf72-ALS/FTD was generated. Embryonic and adult transgenic zebrafish lysates were investigated for the presence of RAN-translated DPR species and adult-onset motor deficits. Using C9orf72 cell models as well as embryonic C9orf72-ALS/FTD zebrafish, hypothermic-therapeutic temperature management (TTM) was explored as a potential therapeutic option for C9orf72-ALS/FTD.

Results

Here, we describe a pure RAN translation zebrafish model of C9orf72-ALS/FTD that exhibits significant RAN-translated DPR pathology and progressive motor decline. We further demonstrate that hypothermic-TTM results in a profound reduction in DPR species in C9orf72-ALS/FTD cell models as well as embryonic C9orf72-ALS/FTD zebrafish.

Interpretation

The transgenic model detailed in this paper provides a medium throughput in vivo research tool to further investigate the role of RAN-translation in C9orf72-ALS/FTD and further understand the mechanisms that underpin neuroprotective strategies. Hypothermic-TTM presents a viable therapeutic avenue to explore in the context of C9orf72-ALS/FTD. ANN NEUROL 2024;96:1058–1069