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BackgroundPathogenic variants in the WDR45 gene are typically associated with a spectrum of neurodevelopmental and neurodegenerative disorders. Characteristic clinical features include intellectual disability, epilepsy and stereotypies, developmental regression, dystonia and behavioral changes. We report a rare clinical entity of a WDR45 mutation associated with abnormal brain iron accumulation on MRI known as beta-propeller protein-associated neurodegeneration (BPAN).MethodsCase Report.ResultsA 30-year-old female with a background of significant global developmental delay presented with a 6-month history of progressive functional and cognitive decline with stereotyped episodes of unresponsiveness. Her carers also noted worsening proximal weakness, new urinary incontinence and increased apathy.EEG demonstrated generalized slowing without epileptiform activity. MRI brain revealed basal ganglia changes with SWI signal abnormality and T2 hypointensity suggestive of neurodegeneration with brain iron accumulation.Genetic testing demonstrated heterozygosity for a pathogenic variant in the WDR45 gene which was consistent with the phenotype. The patient and her family were referred for genetic counselling. Baclofen was commenced with symptomatic benefit.ConclusionsSecondary progression in adulthood in a static childhood encephalopathy should prompt the clinician to consider testing for WDR45 and related diagnoses.

Introduction Sleep disruption is thought to increase tau hyperphosphorylation and tangle formation. This study aims to identify the impact of chronic early-life sleep disruption on late-life tau burden, neurodegeneration, and spatial memory. Methods Eight-week-old PS19 (MAPT P301S) mice and wildtype littermates were subjected to chronic daily sleep disruption (SD) or allowed to sleep ad libitum (AL) for eight weeks. SD was achieved using an automated physical stimulus every 10 seconds for 18 hours daily between ZT 0 and 18. Spatial memory testing occurred at 6, 8, and 10 months of age using the Barnes maze where latencies to find and enter the escape box were recorded on 4 consecutive days (n: WT AL=22, WT SD=21, PS19 AL=15, PS19 SD=28). Brains were subsequently collected between 10 and 14 months of age and analyzed in a subset. Tau pathology was analyzed with AT8 immunohistochemistry on paraffin sections and quantified by counting tau-positive hippocampal neurons using QuPath software. Neurodegeneration was quantified by measuring the combined area of both the lateral and third ventricles. Results Spatial memory was equivalent among all genotypes and sleep conditions at 6 months. We observed a main effect of PS19 genotype with worse spatial memory at 8 and 10 months. Notably, early life SD imparted a protective effect on spatial memory at 8 and 10 months vs ad lib sleep in PS19 mice with no effect on controls. PS19 mice experiencing early life SD showed no difference in late-life hippocampal tau burden (SD: mean 462 AT8+ neurons (SEM: 268), n=5, AL: 284 AT8+ neurons (SEM: 98), n=5, p=0.56) as well as no difference in total ventricle area (SD: mean 1.2 square mm (SEM: 0.5), n=5, AL: 2.0 square mm (SEM: 0.4), n=5, p=0.26). Conclusion Counter to our initial hypothesis, early-life SD resulted in preservation of late-life spatial memory, without changes to neurodegeneration as measured by ventricle area or changes to tau hyperphosphorylation in the hippocampus. Dissociation of tau burden and memory has been observed in models of immune modulation suggesting further investigation regarding effects of sleep disruption on immune function in the context of neurodegenerative models. Support (if any)

[This corrects the article DOI: 10.1371/journal.pone.0075189.].

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare genetic disorder characterised by progressive generalised dystonia and brain iron accumulation. We assessed whether the iron chelator deferiprone can reduce brain iron and slow disease progression. We did an 18-month, randomised, double-blind, placebo-controlled trial (TIRCON2012V1), followed by a pre-planned 18-month, open-label extension study, in patients with PKAN in four hospitals in Germany, Italy, England, and the USA. Patients aged 4 years or older with a genetically confirmed diagnosis of PKAN, a total score of at least 3 points on the Barry-Albright Dystonia (BAD) scale, and no evidence of iron deficiency, neutropenia, or abnormal hepatic or renal function, were randomly allocated (2:1) to receive an oral solution of either deferiprone (30 mg/kg per day divided into two equal doses) or placebo for 18 months. Randomisation was done with a centralised computer random number generator and with stratification based on age group at onset of symptoms. Patients were allocated to groups by a randomisation team not masked for study intervention that was independent of the study. Patients, caregivers, and investigators were masked to treatment allocation. Co-primary endpoints were the change from baseline to month 18 in the total score on the BAD scale (which measures severity of dystonia in eight body regions) and the score at month 18 on the Patient Global Impression of Improvement (PGI-I) scale, which is a patient-reported interpretation of symptom improvement. Efficacy analyses were done on all patients who received at least one dose of the study drug and who provided a baseline and at least one post-baseline efficacy assessment. Safety analyses were done for all patients who received at least one dose of the study drug. Patients who completed the randomised trial were eligible to enrol in a single-arm, open-label extension study of another 18 months, in which all participants received deferiprone with the same regimen as the main study. The trial was registered on ClinicalTrials.gov, number NCT01741532, and EudraCT, number 2012-000845-11. Following a screening of 100 prospective patients, 88 were randomly assigned to the deferiprone group (n=58) or placebo group (n=30) between Dec 13, 2012, and April 21, 2015. Of these, 76 patients completed the study (49 in the deferiprone group and 27 in the placebo group). After 18 months, the BAD score worsened by a mean of 2·48 points (SE 0·63) in patients in the deferiprone group versus 3·99 points (0·82) for patients in the control group (difference −1·51 points, 95% CI −3·19 to 0·16, p=0·076). No subjective change was detected as assessed by the PGI-I scale: mean scores at month 18 were 4·6 points (SE 0·3) for patients in the deferiprone group versus 4·7 points (0·4) for those in the placebo group (p=0·728). In the extension study, patients continuing deferiprone retained a similar rate of disease progression as assessed by the BAD scale (1·9 points [0·5] in the first 18 months vs 1·4 points [0·4] in the second 18 months, p=0·268), whereas progression in patients switching from placebo to deferiprone seemed to slow (4·4 points [1·1] vs 1·4 points [0·9], p=0·021). Patients did not detect a change in their condition after the additional 18 months of treatment as assessed by the PGI-I scale, with mean scores of 4·1 points [0·2] in the deferiprone–deferiprone group and of 4·7 points [0·3] in the placebo–deferiprone group. Deferiprone was well tolerated and adverse events were similar between the treatment groups, except for anaemia, which was seen in 12 (21%) of 58 patients in the deferiprone group, but was not seen in any patients in the placebo group. No patient discontinued therapy because of anaemia, and three discontinued because of moderate neutropenia. There was one death in each group of the extension study and both were secondary to aspiration. Neither of these events was considered related to deferiprone use. Deferiprone was well tolerated, achieved target engagement (lowering of iron in the basal ganglia), and seemed to somewhat slow disease progression at 18 months, although not significantly, as assessed by the BAD scale. These findings were corroborated by the results of an additional 18 months of treatment in the extension study. The subjective PGI-I scale was largely unchanged during both study periods, indicating that might not be an adequate tool for assessment of disease progression in patients with PKAN. Our trial provides the first indication of a decrease in disease progression in patients with neurodegeneration with brain iron accumulation. The extensive information collected and long follow-up of patients in the trial will improve the definition of appropriate endpoints, increase the understanding of the natural history, and thus help to shape the design of future trials in this ultra-orphan disease. European Commission, US Food and Drug Administration, and ApoPharma Inc.

Background Caesalpinia crista, commonly known as ’Katukarno,’ is a medicinal plant known for its neuroprotective effects attributed to its rich profile of bioactive compounds. Recent studies emphasize its potential in preventing and managing neurodegenerative diseases -Alzheimer’s, Parkinson’s, and other neuroinflammatory disorders. The neuroprotective effects of C.crista are largely associated with its bioactive compounds- flavonoids, terpenoids, alkaloids, and saponins, which exhibit antioxidant, & anti-inflammatory properties. These compounds help mitigate oxidative stress and inflammatory responses, two primary mechanisms contributing to neurodegeneration.ObjectiveIdentification and Extraction of bioactive compounds – Alkaloids, Terpenoids, Flavonoids and Saponins in Caesalpinia crista and their quantification and validation.MethodsSamples- seeds, leaves and bark of C. crista were collected and stored. Soxhlet extraction, Cold maceration, ultrasonication techniques were used to extract bioactive compounds. Fractionation was performed by Liquid-Liquid Partition, Column and TLC on these samples. Mass spectrometry was used for identifying and characterizing the bioactive compounds. HPLC and GC were employed to quantify and validate the concentration of these individual bioactive compounds in the extract.ResultsUsing HPLC and GC the below results were obtained for bioactive compounds of C. crista (table 1):Abstract 28 Table 1S.NO Name of the bioactive compound Yield obtained in mg/g1.Alkaloids2.52.Terpenoids43.Flavonoids34.Saponins6Conclusion C. crista shows considerable promise as a natural source of neuroprotective agents, making it a potential candidate for therapeutic intervention in neurodegenerative diseases. Further research, including clinical trials, is essential to validate these findings and understand the pharmacokinetics and optimal therapeutic doses of its bioactive compounds for neuroprotection

Aims To investigate the natural history and genotype‐phenotype correlation of pantothenate kinase‐associated neurodegeneration. Methods We collected data of patients with PKAN by searching from available publications in English and Chinese. Patients diagnosed in our center (Peking University First Hospital) were also included. The difference in natural history and genotype between early‐onset (<10 year of age at onset) and late‐onset patients (≥10 year of age at onset) with PKAN was compared. Results A total of 248 patients were included. The median age at onset was 3.0 years in the early‐onset group and 18.0 years in the late‐onset group. Dystonia in lower limbs was the most common initial symptom in both groups. In the early‐onset group, the median interval between the disease onset and occurrence of oromandibular dystonia, generalized dystonia, loss of independent ambulance was 6.0 years, 5.0 years, and 5.0 years. The corresponding values in late‐onset group were 1.0 year, 4.0 years, and 6.0 years. About 20.0% died at median age of 12.5 years and 9.5 years after the onset in early‐onset group. About 2.0% of the late‐onset patients died during the follow‐up. A total of 176 mutations were identified. Patients carrying two null alleles in PANK2 showed significantly earlier age of disease onset and progressed more rapidly to loss of independent ambulance. Conclusions This study provided a comprehensive review on the natural history and genotype of 248 patients with PKAN. The results will serve as a historical control data for future clinical trial on PKAN.

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive movement and vision disorder in the neurodegeneration with brain iron accumulation family of diseases. PKAN is caused by mutations in PANK2 , encoding pantothenate kinase 2, causing an inborn error of coenzyme A metabolism and leading to iron accumulation in the basal ganglia. Peripheral pigmentary retinopathy is common in people with PKAN. The knockout murine model of the orthologous Pank2 gene is known to manifest retinal degeneration through electroretinography, pupillary response and histology analyses. Our longitudinal characterization of the retinopathy in this model reveals reduced visual performance and reduced photoreceptor thickness compared to wild-type mice. Additionally, retinal perturbations in coenzyme A metabolism and dopamine metabolism pathways mimic those previously observed in the brain. These data extend the murine ocular phenotype associated with loss of function of Pank2. With a measurable behavioral, structural and mechanistic retinal phenotype, this mouse model is an ideal pre-clinical model that can be used to evaluate therapeutics for PKAN.