Background: Phospholipase A2 group VI (PLA2G6) mutations associated with neurodegeneration (PLAN) manifest as heterogeneous neurodegenerative disorders with variable ages of onset. The genotype-phenotype correlation is not well-established. We aim to describe three adult patients with PLAN and combined these data with results from previous studies to elucidate adult-onset PLA2G6 phenotype-genotype correlations. Case presentations: The first index patient presented with dystonia-parkinsonism starting at age 31 years, accompanied by major depression and cognitive decline. Genetic analysis using targeted next generation sequencing (NGS) panel, Sanger sequencing, and segregation analyses revealed a compound heterozygous mutation, c.991G > T (p.D331Y)/c.1077G > A (M358IfsX), in PLA2G6. The other two patients had levodopa-responsive, early-onset parkinsonism, starting in their late twenties. Both patients had homozygous c.991G > T (p.D331Y) mutations in PLA2G6. Patient characteristics of our reported 3 cases were compared to those of 32 previously described (2008 to 2019) patients with adult-onset PLAN. Among the combined cohort of 35 patients with adult-onset PLAN, 14 had dystonia-parkinsonism, 17 had early-onset Parkinson's disease, 3 had hereditary spastic paraparesis, and one had ataxia. The c.991G > T (p. D331Y) mutation was almost exclusively found in Chinese patients, suggesting a common founder effect. All patients with homozygous p.D331Y mutations had levodopa-responsive, early-onset PD (100%); while other mutations mostly led to dystonia-parkinsonism, ataxia, spasticity, and combine psychiatric comorbidities. Conclusions: We showed that adult-onset PLAN could present as purely parkinsonism features, without brain iron accumulation, particularly patients with homozygous p.D331Y mutations. Compound heterozygous mutations, including heterozygous p.D331Y, produced heterogeneous phenotypes, without obvious levodopa responsiveness.

Background and purpose:The NOTCH3 mutation is a common cause of hereditary cerebral small vessel disease (CSVD) and may be a cause of spontaneous intracerebral haemorrhage (ICH). The aim was to investigate the clinical/imaging features for identifying the NOTCH3-mutation-related ICH. Methods:The study was based on a cohort of 749 CSVD patients in Taiwan who received next-generation sequencing of CSVD genes including NOTCH3. Patients with a history of ICH (n = 206) were included for analysis. The CSVD neuroimaging markers were compared between the patients with NOTCH3 and those without known genetic mutations. Results:After excluding patients with other causes of ICH (structural lesions, systemic/ medication related or amyloid angiopathy) and those without neuroimaging, 45 NOTCH3 mutation patients and 109 nongenetic ICH patients were included. The NOTCH3 mutation patients were more likely to have thalamic haemorrhage, a family history of stroke and more severe CSVD neuroimaging markers. A five-point NOTCH3-ICH score was constructed and consisted of a history of stroke in siblings, thalamic haemorrhage, any deep nuclei lacunae, any hippocampal cerebral microbleed (CMB) and a thalamic CMB >5 (one point for each). A score ≥2 had a sensitivity of 88.9% and a specificity of 64.2% in identifying the NOTCH3 mutation. The NOTCH3 mutation patients had a higher risk of recurrent stroke (9.1 vs. 4.5 per 100 person-years, log-rank p = 0.03) during follow-up. Conclusion:The patients with NOTCH3-mutation-related ICH had a higher burden of CMBs in the hippocampus/thalamus and a higher recurrent stroke risk. The NOTCH3-ICH score may assist in identifying genetic causes of ICH.

BackgroundCerebral amyloid angiopathy-related inflammation (CAA-ri) is a clinical syndrome characterized by MRI findings of amyloid-related imaging abnormalities-edema (ARIA-E) suggestive of autoimmune and inflammatory reaction and hemorrhagic evidence of cerebral amyloid angiopathy. The longitudinal variation of amyloid PET and its imaging association with CAA-ri are undetermined. Moreover, tau PET in CAA-ri has been rarely investigated.MethodWe retrospectively described two cases of CAA-ri. We provided the temporal change of amyloid and tau PET in the first case, and the cross-sectional finding of amyloid and tau PET in the second case. We also performed a literature review of the imaging features of amyloid PET in reported cases of CAA-ri.ResultsIn the first case, an 88-year-old male presented with progressive consciousness and gait disturbances over 2 months. MRI showed disseminated cortical superficial siderosis. Amyloid PET prior to and after the CAA-ri revealed focally decreased amyloid load in the region of ARIA-E. In the second case, a 72-year-old male was initially suspected to have central nervous system cryptococcosis but later diagnosed with CAA-ri because of the characteristic MRI features and good response to corticosteroid treatment; a subsequent amyloid scan revealed positive amyloid deposition of the brain. Neither case suggested an association between the region of ARIA-E and higher amyloid uptake on PET before or after onset of CAA-ri. Our literature review revealed variable findings related to amyloid burden in post-inflammatory regions in previously reported CAA-ri cases with available amyloid PET. Our case is the first report of longitudinal changes on amyloid PET and show focal decreases in amyloid load after the inflammatory process.ConclusionThis case series highlights the need to better explore the potential of longitudinal amyloid PET in the understanding of the mechanisms of CAA-ri.

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