Rare Neurodegenerative Disease Research Articles

Clinical prognostic factors in progressive supranuclear palsy: Implications for clinical trials

Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease with diverse clinical phenotypes, prompting the development of new diagnostic criteria known as the MDS-PSP classification. However, little is known about the prognostic value of this classification in order to better stratify patients for the clinical trials. Objective To assess the impact of the different clinical phenotypes according to the MDS-PSP classification on prognosis using the clinical milestones of death, severe dysphagia, institutionalization, and need for walking aid. Methods A prospective cohort of 205 PSP patients from Lille University Hospital was analyzed retrospectively. Patients were classified into different MSD-PSP phenotypes according to their clinical presentation after 3 years of follow-up. The milestones of death, severe dysphagia, institutionalization, and need for walking aid were recorded, and a survival analysis was performed to describe the prognosis of each disease presentation. Results Median survival time was 6.4 (interquartile range (IQR): 4.8–8.6) years and mean diagnostic delay from symptom onset was 38.1 ± 22.5 months. PSP Richardson Syndrome (PSP-RS) had a poorer survival rate and a higher occurrence of severe dysphagia and need for walking aid compared to PSP variants such as PSP Parkinsonism (PSP-P), PSP postural instability without ocular motor dysfunction (PSP-PI), and other rare phenotypes. Conclusions PSP-RS has a less favorable prognosis compared to PSP variants stratified according to the MDS-PSP classification. This classification could assist in selecting patients for clinical trials and help design outcomes that account for the disease heterogeneity.

A Novel Human TBCK- Neuronal Cell Model Results in Severe Neurodegeneration and Partial Rescue with Mitochondrial Fission Inhibition.

TBCK syndrome is a rare fatal pediatric neurodegenerative disease caused by biallelic loss-of-function mutations in the TBCK gene. Previous studies by our lab and others have implicated mTOR, autophagy, lysosomes, and intracellular mRNA transport, however the exact primary pathologic mechanism is unknown. This gap has prevented the development of targeted therapies. We employed a human neural progenitor cell line (NPC), ReNcell VM, which can differentiate into neurons and astrocytes, to understand the role of TBCK in mTORC1 activity and neuronal autophagy and cellular mechanisms of pathology. We used shRNA technology to knockdown TBCK in ReNcells. These data showed that loss of TBCK did not inhibit mTORC1 activity in neither NPC nor neurons. Additionally, analysis of eight patient-derived cells and TBCK knock down HeLa cells showed that mTORC1 inhibition is inconsistent across different patients and cell types. We showed that TBCK knockdown in ReNcells affected NPC differentiation to neurons and astrocytes. Specifically, differentiation defects are coupled to cell cycle defects in NPC and increased cell death during differentiation. RNAseq analysis indicated the downregulation of several different neurodevelopmental and differentiation pathways. We observed a higher number of LC3-positive vesicles in the soma and neurites of TBCK knockdown cells. Further, TBCK knockdown altered mitochondrial dynamics and membrane potential in NPC, neurons and astrocytes. We found partial mitochondrial rescue with the mitochondrial fission inhibitor mdivi-1. This work outlines a new Human Cell Model for TBCK-related neurodegeneration and the essential role of mitochondrial health and partial rescue with mitochondrial fission inhibitor. This data, along with human neurons and astrocytes, illuminate mechanisms of neurodegeneration and provide a possible novel therapeutic avenue for affected patients.

Findings from the individualized management of a patient with Acyl-CoA Oxidase-1 (ACOX1) deficiency: A bedside-to-bench-to-bedside strategy

Acyl-CoA Oxidase-1 (ACOX1) deficiency (MIM 264470) is an autosomal recessive disease characterized by impairments in the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs, which is the first step in the catalysis of the β-oxidative breakdown of very long chain fatty acids (VLCFA) occuring in peroxisomes. The deleterious accumulation of VLCFA in several organs, including the brain, is a key biochemical feature of this disease which has devastating neurological consequences. ACOX1 deficiency is ultra-rare; as such, few studies have been conducted to determine the leading causes of symptoms or uncover new therapeutics. When confronted with one such case, we decided to bring drug discovery tools to the patient's bedside in an attempt to identify a cure. A skin biopsy was performed on a young patient with ACOX1 deficiency, following which screening technologies and mass spectrometry analysis techniques were applied to design a cellular assay that enabled the direct measurement of the effect of small molecules on the patient's primary fibroblasts. This approach is particularly well adapted to inherited metabolic disorders such as ACOX1 deficiency. Through the evaluation of a proprietary library of repurposable drugs, we found that the anthelmintic drug niclosamide led to a significant reduction in VLCFA in vitro. This drug was subsequently administered to the patient for more than six years. This study outlines the screening and drug selection processes. Additionally, we present our comprehensive clinical and biochemical findings that aided in understanding the patient's natural history and analysis of the progression of the patient's symptoms throughout the treatment period. Although the patient's overall lifespan was extended compared to the average age at death in severe early onset cases of ACOX1 deficiency, we did not observe any definitive evidence of clinical or biochemical improvement during niclosamide treatment. Nonetheless, our study shows a good safety profile of long-term niclosamide administration in a child with a rare neurodegenerative disease, and illustrates the potential of individualized therapeutic strategies in the management of inherited metabolic disorders, which could benefit both patients and the broader scientific and medical communities.

A scoping review of the role of managed entry agreements in upcoming drugs for amyotrophic lateral sclerosis: learning from the case of spinal muscular atrophy

Introduction: The therapeutic options for spinal muscular atrophy (SMA) are encouraging. However, there is currently no cure for amyotrophic lateral sclerosis (ALS). The clinical and economic uncertainty surrounding innovative treatments for rare neurodegenerative diseases makes it necessary to understand managed entry agreements (MEAs). The aim of this study was to review whether models of MEAs in SMA could be extrapolated to ALS. Methods: We performed a scoping review with information on MEAs on SMA in Web of Science (WOS), PubMed, Lyfegen Library, the National Institute for Health and Care Excellence (NICE), and the Canadian Agency for Drugs and Technologies in Health (CADTH). Results: We found 45 results in WOS and PubMed. After an initial survey, 10 were reviewed to assess eligibility, and three were selected. We obtained 44 results from Lyfegen Library, and three results each from NICE and CADTH. Conclusion: The main objective of MEAs is to reduce uncertainty in the financing of drugs with a high budgetary impact and clinical concerns, as is the case with drugs for SMA and ALS. While the information available on MEAs in SMA is scarce, some conceptual models are publicly available. MEAs for long-term treatments for SMA could be used for the design of MEAs in ALS because of their similarities in economic and clinical uncertainty.

Dentatorubral-pallidoluysian atrophy: a case report and review of literature

BackgroundDentatorubral-pallidoluysian atrophy is a rare autosomal dominant neurodegenerative disease. It is a rare disease in the world. Therefore, sharing clinical encounters of this case can deepen global awareness and understanding of the disease.Case presentationThe patient was a 34-year-old male of Han nationality who was unmarried. The patient was admitted owing to weakness of the left lower limb with walking instability for 2 months and aggravation for 1 month. There was no dizziness, headache, numbness of limbs, convulsions, nausea, vomiting, abdominal pain, ataxia, nausea, vomiting, or abdominal pain. No nausea, vomiting, diarrhea, abdominal distension, tinnitus, hearing loss, fever, cough, expectoration. Personal history: worked in Cambodia 5 years ago, worked in Dubai 3 years ago, engaged in computer work, smoking or drinking habits. The patient was unmarried. Family history: the mother had symptoms similar to walking unsteadily (undiagnosed). Positive signs include a wide-base gait with a rotatory nystagmus that jumps upward in both eyes. Bilateral finger-nose instability test was quasi-positive, rapid alternating test was negative, and eye closure tolerance test was positive. Tendon reflexes were active in both upper limbs and hyperreflexia in both lower limbs. Stability of the heel, knee, and tibia. Genetic testing showed that the number of repeats in the dentatorubral-pallidoluysian atrophy ATN1 gene was 18 and 62, and the (CAG)n repeat sequence in the ATN1 gene was abnormal, with a repeat number of 62, and the patient was a pathogenic variant. The patient was diagnosed with dentatorubral-pallidoluysian atrophy. Dentatorubral-pallidoluysian atrophy remains a progressive neurodegenerative disease with no effective treatment. At present, the proband is taking 5 mg of buspirone three times a day, which has been reported to improve the symptoms. The patient was followed up for 6 months after taking buspirone, and there was no significant improvement in the temporary symptoms. At present, there are few cases of dentatorubral-pallidoluysian atrophy, and the characteristics of nystagmus in this disease have not been proposed in the past. This case reported the unusual presentation of nystagmus.ConclusionDentatorubral-pallidoluygur atrophy is a rare neurodegenerative disease with autosomal dominant inheritance. To the best of our knowledge, our present case report is the first case report of dentatorubral-pallidoluygur atrophy with specific nystagmus. We describe the special eye shake and its positive signs to increase dentatorubral-pallidoluysian atrophy clinical positive signs.

Two novel DnaJ chaperone proteins CG5001 and P58IPK regulate the pathogenicity of Huntington’s disease related aggregates

Huntington’s disease (HD) is a rare neurodegenerative disease caused due to aggregation of Huntingtin (HTT) protein. This study involves the cloning of 40 DnaJ chaperones from Drosophila, and overexpressing them in yeasts and fly models of HD. Accordingly, DnaJ chaperones were catalogued as enhancers or suppressors based on their growth phenotypes and aggregation properties. 2 of the chaperones that came up as targets were CG5001 and P58IPK. Protein aggregation and slow growth phenotype was rescued in yeasts, S2 cells, and Drosophila transgenic lines of HTT103Q with these overexpressed chaperones. Since DnaJ chaperones have protein sequence similarity across species, they can be used as possible tools to combat the effects of neurodegenerative diseases.

Progressive gray matter atrophy in parkinsonian variant of multiple system atrophy assessed by using causal structural covariance network.

Multiple system atrophy (MSA), a rare neurodegenerative disease, is usually accompanied by brain morphological alterations. However, the causal relationships between progressive gray matter atrophy in MSA parkinsonian (MSA-P) subtype remain unknown. In total, thirty-five MSA-P patients and thirty-five healthy controls (HC) underwent three-dimensional high-resolution T1-weighted structural imaging and voxel-based morphometry analysis. The causal structural covariance network (CaSCN) of gray matter was assessed to explore the causal relationships in MSA-P. With greater illness duration, the reduction of gray matter was originated from right cerebellum and progressed to bilateral cerebellum, fusiform gyrus, insula, putamen, caudate nucleus, frontal lobe, right angular gyrus, right precuneus, left middle occipital lobe and left inferior temporal lobe, then expanded to midbrain, bilateral para-hippocampus, thalamus, temporal lobe, inferior parietal lobule (IPL), precentral gyrus, postcentral gyrus and middle cingulate cortex. The right cerebellum was revealed to be the core node of the directional network and projected positive causal effects to bilateral cerebellum, caudate nucleus and left IPL. MSA-P patients showed progression of gray matter atrophy over time, with the right cerebellum probably as a primary hub. Furthermore, the early structural vulnerability of cerebellum in MSA-P may play a pivotal role in the modulation of motor and non-motor circuits at the structural level.

Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy

BackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs).MethodIn this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed.ResultsOur analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP.ConclusionsThrough WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Multimodal, Longitudinal Profiling of SCA1 Identifies Predictors of Disease Severity and Progression.

Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant neurodegenerative disease. Objective surrogate markers sensitive to detect changes in disease severity are needed to reduce sample sizes in interventional trials and identification of predictors of faster disease progression would facilitate patient selection, enrichment, or stratification in such trials. We performed a prospective 1-year longitudinal, multimodal study in 34 ataxic SCA1 individuals and 21 healthy controls. We collected clinical, patient-reported outcomes, biochemical and magnetic resonance (MR) biomarkers at baseline and after 1 year. We determined 1-year progression and evaluated the potential predictive value of several baseline markers on 1-year disease progression. At baseline, multiple structural and spectroscopic MR markers in pons and cerebellum differentiated SCA1 from healthy controls and correlated with disease severity. Plasma and cerebrospinal fluid (CSF) neurofilament light (NfL) chain and CSF glial fibrillary acidic protein (GFAP) were elevated in SCA1. In longitudinal analysis, total brainstem and pontine volume change, inventory of non-ataxia signs (INAS) count, and SCA functional index (SCAFI) showed larger responsiveness compared to the Scale for Assessment and Rating of Ataxia (SARA). Longer disease duration, longer non-expanded CAG repeat length, and higher disease burden were associated with faster SARA increase after 1-year in the SCA1 group. Similarly, lower baseline brainstem, pontine, and cerebellar volumes, as well as lower levels of N-acetylaspartate and glutamate in the cerebellar white matter, were also associated with faster SARA increase. Our results guide the selection of the most sensitive measures of disease progression in SCA1 and have identified features associated with accelerated progression that could inform the design of clinical trials. ANN NEUROL 2024;96:774-787.

Clinical and genetic spectrum of Ataxia Telangiectasia Tunisian patients: Bioinformatic analysis unveil mechanisms of ATM variants pathogenicity

Ataxia Telangiectasia (AT) is a rare multisystemic neurodegenerative disease caused by biallelic mutations in the ATM gene. Few clinical studies on AT disease have been conducted in Tunisia, however, the mutational landscape is still undefined. Our aim is to determine the clinical and genetic spectrum of AT Tunisian patients and to explore the potential underlying mechanism of variant pathogenicity.Sanger sequencing was performed for nine AT patients. A comprehensive computational analysis was conducted to evaluate the possible pathogenic effect of ATM identified variants. Genetic screening of ATM gene has identified nine different variants from which six have not been previously reported. In silico analysis has predicted a pathogenic effect of identified mutations. This was corroborated by a structural bioinformatics study based on molecular modeling and docking for novel missense mutations. Our findings suggest a profound impact of identified mutations not only on the ATM protein stability, but also on the ATM-ligand interactions.Our study characterizes the mutational landscape of AT Tunisian patients which will allow to set up genetic counseling and prenatal diagnosis for families at risk and expand the spectrum of ATM variants worldwide. Furthermore, understanding the mechanism that underpin variant pathogenicity could provide further insights into disease pathogenesis.

A family with neuronal intranuclear inclusion disease with focal segmental glomerulosclerosis.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease caused by the expansion of GGC repeats in the 5'-untranslated region (5'-UTR) of NOTCH2NLC. Although increasing evidence suggests that NIID affects various organs, its association with renal involvement remains unclear. We studied the genetic background of a family with NIID, in which four of five members presented with proteinuria as the initial manifestation. The renal pathology of three patients was diagnosed as focal segmental glomerulosclerosis (FSGS) at a previous hospital. These patients also presented with tremors, retinal degeneration, and episodic neurological events. Finally, one patient exhibited reversible bilateral thalamic high-intensity signal changes on diffusion-weighted imaging during episodic neurological events. Exome sequencing (ES) and nanopore long-read whole-genome sequencing (LR-WGS) were performed on the index case, followed by nanopore target sequencing using Cas9-mediated PCR-free enrichment and methylation analysis. ES revealed no candidate variants; however, nanopore LR-WGS in the index case revealed expansion of short tandem repeats (STR) in NOTCH2NLC. Subsequent nanopore target sequencing using Cas9-mediated PCR-free enrichment showed STR expansion of NOTCH2NLC in an affected sibling and asymptomatic father. Methylation analysis using nanopore data revealed hypermethylation of the expanded allele in the asymptomatic father and partial hypermethylation in a mildly symptomatic sibling, whereas the expanded allele was hypomethylated in the index case. This investigation expands the clinical spectrum of NIID, suggesting that STR expansion of NOTCH2NLC is a cause of renal diseases, including FSGS.

Communicating the diagnosis of spinal muscular atrophy in endogamous vs. non-endogamous regions

IntroductionThe high prevalence of endogamy, or inbreeding, in northeastern Brazil, is due to historical and cultural factors, with large families living in cities far from the coast and subject to low socioeconomic and infrastructure levels. This breeding practice results in low genetic variability with an increased prevalence of rare autosomal recessive and neurodegenerative diseases, such as spinal muscular atrophy (SMA).ObjectiveUnderstanding the impact of communicating the diagnosis of SMA on the mental health of patients and their families and the differences between the Northeast (endogamous region) and the other regions of Brazil (non-endogamous ones).MethodsCross-sectional study obtained through a structured questionnaire about the moment of receiving the SMA diagnosis, containing the Impact of Event Scale-Revised.Results and discussionThe sample consisted of 100 volunteers from all regions of Brazil, 47 patients diagnosed with SMA and 53 family members present at the time of the diagnosis. There was a predominance of females (83%) and homogeneity between the groups for the variables gender, age, color, education, religion, and SMA subtype (1, 2, 3, and 4). The Northeast region, representing 43% of the sample, despite being less economically favored, showed greater satisfaction with medical care and inclusion in health services, with less self-reported psychological trauma and fewer signs of post-traumatic stress disorder (PTSD) related to the moment of receiving the diagnosis. The non-endogamous regions, in turn, reported the presence of strong waves of emotion, sleep problems, feelings of irritability, anger, and the presence of bad thoughts related to this situation.ConclusionThe feeling of inclusion in health services and satisfaction with medical care in the endogamous region had a positive impact on the mental health of those involved, reducing psychological trauma and signs of PTSD arising from the communication of the SMA diagnosis.

Early Symptoms and Treatment Outcomes in Neuronal Ceroid Lipofuscinosis Type 2: Croatian Experience.

Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare neurodegenerative disease that generally appears in children between 2 and 4 years old, leading to seizures and a progressive loss of language and motor functions. As the disease progresses, affected individuals typically experience blindness and ultimately pass away in late childhood. Treatment with intracerebroventricular cerliponase alfa has been shown to slow the deterioration of motor and language functions compared to the natural progression of the disease. We aim to highlight the early symptoms of CLN2 which help with early diagnosis and timely treatment initiation in children with specific medical indications, as well as identify medical contraindications for enzyme replacement therapy. We describe five Croatian patients and one Bosnia and Herzegovinian patient with CLN2 disease, analyzing the clinical characteristics, neuroimaging findings, electroencephalogram results, genetic analysis, treatment indications and contraindications, and disease progression. All six patients presented with seizures: focal seizures (n = 1), myoclonic-atonic seizures (n = 1), febrile seizures (n = 2), and tonic-clonic seizures (n = 2), along with language delay (n = 6). Despite this, one patient refused treatment, two were initially included in the clinical trial and then continued treatment, one did not indicate starting treatment, and three continued treatment. One patient, after 4.5 years of treatment, no longer had medical indications for the therapy, which was discontinued. The other two patients who received treatment had a significant slowing of disease progression. The early onset of seizures between ages 2 and 4, alongside delayed language development, is a defining characteristic of CLN2 disease. Enzyme replacement therapy using cerliponase alfa represents the initial treatment for neuronal ceroid lipofuscinosis type 2, targeting the underlying cause of the disease. It effectively delays the progression of language and motor decline in patients diagnosed with this condition.

Modeling riboflavin transporter deficiency type 2: from iPSC-derived motoneurons to iPSC-derived astrocytes.

Riboflavin transporter deficiency type 2 (RTD2) is a rare neurodegenerative autosomal recessive disease caused by mutations in the SLC52A2 gene encoding the riboflavin transporters, RFVT2. Riboflavin (Rf) is the precursor of FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide), which are involved in different redox reactions, including the energetic metabolism processes occurring in mitochondria. To date, human induced pluripotent stem cells (iPSCs) have given the opportunity to characterize RTD2 motoneurons, which reflect the most affected cell type. Previous works have demonstrated mitochondrial and peroxisomal altered energy metabolism as well as cytoskeletal derangement in RTD2 iPSCs and iPSC-derived motoneurons. So far, no attention has been dedicated to astrocytes. Here, we demonstrate that in vitro differentiation of astrocytes, which guarantee trophic and metabolic support to neurons, from RTD2 iPSCs is not compromised. These cells do not exhibit evident morphological differences nor significant changes in the survival rate when compared to astrocytes derived from iPSCs of healthy individuals. These findings indicate that differently from what had previously been documented for neurons, RTD2 does not compromise the morpho-functional features of astrocytes.

Safety and efficacy of deoxycytidine/deoxythymidine combination therapy in POLG-related disorders: 6-month interim results of an open-label, single arm, phase 2 trial

DNA polymerase gamma (POLG)-related disorders are a group of rare neurodegenerative mitochondrial diseases caused by pathogenic variants in POLG, the gene encoding POLG. Patients may experience a range of signs and symptoms, including seizures, vision loss, myopathy, neuropathy, developmental impairment or regression, and liver failure. The diseases follow a progressive, degenerative course, with most affected individuals dying within 3 months-12 years of diagnosis. At present, there are no effective treatments for POLG-related disorders. In this study we report the interim 6-month data from a long term open-label, single arm phase 2 trial, in which we assessed the safety and efficacy of combination therapy with deoxycytidine and deoxythymidine (dC/dT) in children with POLG-related disorders. dC/dT was given enterally in powder form, dissolved in water. The primary outcome measures included Newcastle Mitochondrial Disease Scale (NMDS) score, serum growth differentiation factor 15 (GDF-15; a biomarker of mitochondrial dysfunction), electroencephalography (EEG), seizure diary, and blood and urine tests to assess end organ and mitochondrial function. Secondary outcome measures included recording of all adverse events to evaluate the safety of the intervention. The trial is registered with ClinicalTrials.gov, NCT04802707 (https://clinicaltrials.gov/ct2/show/NCT04802707). Data were collected from 14 October, 2021 to 13 December,2023. We present 6-month interim data from the first ten people with POLG-related disorders enrolled in the trial, six with Alpers-Huttenlocher syndrome, two with ataxia-neuropathy spectrum, and two who do not fit into a classical POLG-related phenotype. During the 6 months of treatment, NMDS score improved from a mean of 27.3at baseline to 20.7at 6 months (estimated difference 6.0; 95% CI 2.5-∞). GDF-15 values remained stable or decreased in all patients; the mean decreased from 1031pg/ml to 729pg/ml (estimated difference 200; 95% CI 12-∞). 8/10 patients had abnormal baseline EEG; improvement in EEG was seen in 5 of these 8. There were no significant changes in other blood and urine testing. Regarding adverse events, two patients experienced diarrhea that spontaneously resolved. dC/dT is a promising treatment option for people with POLG-related disorders. Further research is needed to assess the long-term safety and efficacy in POLG-related disorders, as well as safety and efficacy in other mitochondrial DNA depletion disorders. This study was primarily funded by the Liam Foundation, with additional funding from the Savoy Foundation, Grand Défi Pierre Lavoie Foundation, and Fonds de Recherche du Québec - Santé.

DNA methylation patterns in the frontal lobe white matter of multiple system atrophy, Parkinson’s disease, and progressive supranuclear palsy: a cross-comparative investigation

Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by neuronal loss and gliosis, with oligodendroglial cytoplasmic inclusions (GCIs) containing α-synuclein being the primary pathological hallmark. Clinical presentations of MSA overlap with other parkinsonian disorders, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and progressive supranuclear palsy (PSP), posing challenges in early diagnosis. Numerous studies have reported alterations in DNA methylation in neurodegenerative diseases, with candidate loci being identified in various parkinsonian disorders including MSA, PD, and PSP. Although MSA and PSP present with substantial white matter pathology, alterations in white matter have also been reported in PD. However, studies comparing the DNA methylation architectures of white matter in these diseases are lacking. We therefore aimed to investigate genome-wide DNA methylation patterns in the frontal lobe white matter of individuals with MSA (n = 17), PD (n = 17), and PSP (n = 16) along with controls (n = 15) using the Illumina EPIC array, to identify shared and disease-specific DNA methylation alterations. Genome-wide DNA methylation profiling of frontal lobe white matter in the three parkinsonian disorders revealed substantial commonalities in DNA methylation alterations in MSA, PD, and PSP. We further used weighted gene correlation network analysis to identify disease-associated co-methylation signatures and identified dysregulation in processes relating to Wnt signaling, signal transduction, endoplasmic reticulum stress, mitochondrial processes, RNA interference, and endosomal transport to be shared between these parkinsonian disorders. Our overall analysis points toward more similarities in DNA methylation patterns between MSA and PD, both synucleinopathies, compared to that between MSA and PD with PSP, which is a tauopathy. Our results also highlight several shared DNA methylation changes and pathways indicative of converging molecular mechanisms in the white matter contributing toward neurodegeneration in all three parkinsonian disorders.

Reduction of sacsin levels in peripheral blood mononuclear cells as a diagnostic tool for spastic ataxia of Charlevoix-Saguenay.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare neurodegenerative disease caused by biallelic variants in the SACS gene encoding for sacsin. More than 200 pathogenic variants have been identified to date, most of which are missense. It is likely that the prevalence of autosomal recessive spastic ataxia of Charlevoix-Saguenay is underestimated due to the lack of an efficient diagnostic tool able to validate variants of uncertain significance. We have previously shown that sacsin is almost absent in fibroblasts of patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay regardless of the type of SACS variant, because sacsin carrying missense variants is cotranslationally degraded. In this work, we aimed to establish the pathogenicity of SACS variants by quantifying sacsin protein in blood samples, with relevant implications for autosomal recessive spastic ataxia of Charlevoix-Saguenay diagnosis. We developed a protocol to assess sacsin protein levels by western blot using small amounts of peripheral blood mononuclear cells, which can be propagated in culture and cryopreserved. The study involves eight patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay (including a novel case) carrying variants of different types and positions along the SACS gene and two parents who are carriers of heterozygous missense variants. We show that patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay (carrying either missense or truncating variants) almost completely lacked sacsin in peripheral blood mononuclear cells. Moreover, both carriers of a SACS missense variant showed 50% reduction in sacsin protein levels compared to controls. We also describe a patient with uniparental isodisomy carrying a homozygous nonsense variant near the 3' end of the SACS gene. This resulted in a stable sacsin protein lacking the last 202 amino acids, probably due to escape of nonsense-mediated decay of mRNA. In conclusion, we have optimized a minimally invasive diagnostic tool for autosomal recessive spastic ataxia of Charlevoix-Saguenay in blood samples based on sacsin protein level assessment. Indeed, our results provide definite evidence that sacsin carrying missense pathogenic variants undergoes cotranslational degradation. The quantitative reduction in sacsin levels in the case of missense variants of uncertain significance allows defining them as pathogenic variants, something which cannot be predicted bioinformatically with high certainty.

Total intravenous anesthesia using remimazolam for primary lateral sclerosis

Primary lateral sclerosis (PLS) is an extremely rare neurodegenerative muscle disease of unknown cause. The choice of anesthesia for surgery in patients with neurodegenerative muscle disease is extremely important, as it may affect the patient’s prognosis. In this case report, we describe a 74-year-old man with PLS who underwent surgical closure of the larynx owing to repeated aspiration pneumonia. The surgery was performed without muscle relaxants and with total intravenous anesthesia using remimazolam, a relatively new, ultra-short-acting benzodiazepine sedative. The patient underwent surgery safely with no complications and had stable intraoperative hemodynamics. General anesthesia using remimazolam and remifentanil without muscle relaxants may be an appropriate anesthesia technique in patients with PLS who require surgery.

ITPR1 variant-induced autosomal dominant hereditary spastic paraplegia in a Chinese family.

Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disease prominently characterized by slowly progressive lower limb weakness and spasticity. The significant genotypic and phenotypic heterogeneity of this disease makes its accurate diagnosis challenging. In this study, we identified the NM_001168272: c.2714A > G (chr3.hg19: g.4716912A > G, N905S) variant in the ITPR1 gene in a three-generation Chinese family with multiple individuals affected by HSP, which we believed to be associated with HSP pathogenesis. To confirm, we performed whole exome sequencing, copy number variant assays, dynamic mutation analysis of the entire family, and protein structure prediction. The variant identified in this study was in the coupling domain, and this is the first corroborated report assigning ITPR1 variants to HSP. These findings expand the clinical and genetic spectrum of HSP and provide important data for its genetic analysis and diagnosis.

An Overview of Huntington’s Disease using Machine Learning

Huntington’s disease (HD) is one of the rare neurodegenerative diseases caused because of genetic mutation of the Huntington gene and also characterized by progressive motor dysfunction, cognitive impairment, and psychiatric symptoms. Since no cure is possible and only symptomatic therapy is available, early detection and individualized therapy are guaranteed for effective disease treatment. Artificial intelligence has emerged as a transformative tool in healthcare, revolutionizing many aspects of medical practice and research, enabling the detection, monitoring and treatment of Huntington's disease. Additionally, this paper serves as a valuable resource for researchers in the field of machine learning and neurodegenerative disease detection, as well as healthcare professionals.