Rare Neurodegenerative Disease Research Articles

New human ATM variants are able to regain ATM functions in ataxia telangiectasia disease

Ataxia telangiectasia is a rare neurodegenerative disease caused by biallelic mutations in the ataxia telangiectasia mutated gene. No cure is currently available for these patients but positive effects on neurologic features in AT patients have been achieved by dexamethasone administration through autologous erythrocytes (EryDex) in phase II and phase III clinical trials, leading us to explore the molecular mechanisms behind the drug action. During these investigations, new ATM variants, which originated from alternative splicing of ATM messenger, were discovered, and detected in vivo in the blood of AT patients treated with EryDex. Some of the new ATM variants, alongside an in silico designed one, were characterized and examined in AT fibroblast cell lines. ATM variants were capable of rescuing ATM activity in AT cells, particularly in the nuclear role of DNA DSBs recognition and repair, and in the cytoplasmic role of modulating autophagy, antioxidant capacity and mitochondria functionality, all of the features that are compromised in AT but essential for neuron survival. These outcomes are triggered by the kinase and further functional domains of the tested ATM variants, that are useful for restoring cellular functionality. The in silico designed ATM variant eliciting most of the functionality recover may be exploited in gene therapy or gene delivery for the treatment of AT patients.

Atypic subacute sclerosing panensefalitis in a six-year-old male

Subacute sclerosing panencephalitis is a rare, slow, and insidious neurodegenerative disease caused by measles. This disease mostly has a classic course. However, sometimes it can be presented with atypical manifestations. In this paper, we aim to present a six years old male patient that was hospitalized due to seizures and ataxia. Cerebral magnetic resonance imaging was normal on the first day of admission, but within a few days, the patient started to be apathetic. On the seventh day, magnetic resonance imaging showed hyperintense lesions in the thalamic, brainstem, and periventricular areas. Periodic epileptiform discharges were detected in the repeated electroencephalogram. Investigations from the cerebrospinal fluid showed markedly elevated measles virus IgG at 230U/ml consistent with the diagnosis of SSPE which should always be ruled out when a patient comes in with uncontrollable seizures, ataxia and apathy.

PEBAT, an Intriguing Neurodegenerative Tubulinopathy Caused by a Novel Homozygous Variant in TBCD: A Case Series and Literature Review

Progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT) is a severe and rare progressive neurodegenerative disease (OMIM 617913). This condition has been described in individuals with pathogenic variants affecting tubulin-specific chaperone protein D (TBCD), which is responsible for proper folding and assembly of tubulin subunits. Here we describe two unrelated infants from Central America presenting with worsening neuromuscular weakness, respiratory failure, polyneuropathy, and neuroimaging findings of severe cerebral volume loss with thin corpus callosum. These individuals harbored the same homozygous variant of uncertain significance in the TBCD gene on whole exome sequencing (WES). Predicted protein modeling of this variant confirmed disruption of the protein helix at the surface of TBCD. The goal of this report is to emphasize the importance of rapid WES, careful interpretation of uncertain variants, prognostication, and family counseling especially when faced with a neurodegenerative clinical course.

CSPα in neurodegenerative diseases.

Adult-onset neuronal ceroid lipofuscinosis (ANCL) is a rare neurodegenerative disease characterized by epilepsy, cognitive degeneration, and motor disorders caused by mutations in the DNAJC5 gene. In addition to being associated with ANCL disease, the cysteine string proteins α (CSPα) encoded by the DNAJC5 gene have been implicated in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease. However, the pathogenic mechanism responsible for these neurodegenerative diseases has not yet been elucidated. Therefore, this study examines the functional properties of the CSPα protein and the related mechanisms of neurodegenerative diseases.

Tau seeds from patients induce progressive supranuclear palsy pathology and symptoms in primates.

Progressive supranuclear palsy is a primary tauopathy affecting both neurons and glia and is responsible for both motor and cognitive symptoms. Recently, it has been suggested that progressive supranuclear palsy tauopathy may spread in the brain from cell to cell in a 'prion-like' manner. However, direct experimental evidence of this phenomenon, and its consequences on brain functions, is still lacking in primates. In this study, we first derived sarkosyl-insoluble tau fractions from post-mortem brains of patients with progressive supranuclear palsy. We also isolated the same fraction from age-matched control brains. Compared to control extracts, the in vitro characterization of progressive supranuclear palsy-tau fractions demonstrated a high seeding activity in P301S-tau expressing cells, displaying after incubation abnormally phosphorylated (AT8- and AT100-positivity), misfolded, filamentous (pentameric formyl thiophene acetic acid positive) and sarkosyl-insoluble tau. We bilaterally injected two male rhesus macaques in the supranigral area with this fraction of progressive supranuclear palsy-tau proteopathic seeds, and two other macaques with the control fraction. The quantitative analysis of kinematic features revealed that progressive supranuclear palsy-tau injected macaques exhibited symptoms suggestive of parkinsonism as early as 6 months after injection, remaining present until euthanasia at 18 months. An object retrieval task showed the progressive appearance of a significant dysexecutive syndrome in progressive supranuclear palsy-tau injected macaques compared to controls. We found AT8-positive staining and 4R-tau inclusions only in progressive supranuclear palsy-tau injected macaques. Characteristic pathological hallmarks of progressive supranuclear palsy, including globose and neurofibrillary tangles, tufted astrocytes and coiled bodies, were found close to the injection sites but also in connected brain regions that are known to be affected in progressive supranuclear palsy (striatum, pallidum, thalamus). Interestingly, while glial AT8-positive lesions were the most frequent near the injection site, we found mainly neuronal inclusions in the remote brain area, consistent with a neuronal transsynaptic spreading of the disease. Our results demonstrate that progressive supranuclear palsy patient-derived tau aggregates can induce motor and behavioural impairments in non-human primates related to the prion-like seeding and spreading of typical pathological progressive supranuclear palsy lesions. This pilot study paves the way for supporting progressive supranuclear palsy-tau injected macaque as a relevant animal model to accelerate drug development targeting this rare and fatal neurodegenerative disease.

Multiple System Atrophy with Syndrome of Inappropriate Antidiuretic Hormone

Multiple System Atrophy (MSA) is a rare neurodegenerative disease which mainly affects extrapyramidal system, cerebellum and autonomic nervous system as well as hypothalamus. Hypothalamic disturbances can lead to the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) and resultant hyponatremia. MSA with SIADH is rarely reported. We reported a 71-year-old woman was admitted to our hospital because of fever for two months. She was diagnosed with probable multiple system atrophy based on poorly L-Dopa responsive parkinsonism, urinary incontinence and orthostatic hypotension. Hyponatremia, and the urine sodium and osmolality increased indicating that she had SIADH at the same time. Hyponatremia was corrected after water restriction and sodium supplementation. In this report, we describe the clinical characteristics and treatment in regard to MSA with SIADH.

Targeting Circuit Abnormalities in Neurodegenerative Disease.

Despite significant improvement in our ability to diagnose both common and rare neurodegenerative diseases and understand their underlying biologic mechanisms, there remains a disproportionate lack of effective treatments, reflecting the complexity of these disorders. Successfully advancing novel treatments for neurodegenerative disorders will require reconsideration of traditional approaches, which to date have focused largely on specific disease proteins or cells of origin. This article proposes reframing these diseases as conditions of dysfunctional circuitry as a complement to ongoing efforts. Specifically reviewed is how aberrant spiking is a common downstream mechanism in numerous neurodegenerative diseases, often driven by dysfunction in specific ion channels. Surgical modification of this electrical activity via deep brain stimulation is already an approved modality for many of these disorders. Therefore, restoring proper electrical activity by targeting these channels pharmacologically represents a viable strategy for intervention, not only for symptomatic management but also as a potential disease-modifying therapy. Such an approach is likely to be a promising route to treating these devastating disorders, either as monotherapy or in conjunction with current drugs. SIGNIFICANCE STATEMENT: Despite extensive research and improved understanding of the biology driving neurodegenerative disease, there has not been a concomitant increase in approved therapies. Accordingly, it is time to shift our perspective and recognize these diseases also as disorders of circuitry to further yield novel drug targets and new interventions. An approach focused on treating dysfunctional circuitry has the potential to reduce or reverse patient symptoms and potentially modify disease course.

Upstream lipid and metabolic systems are potential causes of Alzheimer's disease, Parkinson's disease and dementias.

Brain health requires circuits, cells and molecular pathways to adapt when challenged and to promptly reset once the challenge has resolved. Neurodegeneration occurs when adaptability becomes confined, causing challenges to overwhelm neural circuitry. Studies of rare and common neurodegenerative diseases suggest that the accumulation of lipids can compromise circuit adaptability. Using microglia as an example, we review data that suggest increased lipid concentrations cause dysfunctional inflammatory responses to immune challenges, leading to Alzheimer's disease, Parkinson's disease and dementia. We highlight current approaches to treat lipid metabolic and clearance pathways and identify knowledge gaps towards restoring adaptive homeostasis in individuals who are at-risk of losing cognition.

Living with primary brain calcification with PDGFB variants: A qualitative study.

IntroductionPrimary brain calcification (PBC) is a rare and intractable neurodegenerative disease. SLC20A2 and PDGFB are two major causative genes. As there is no effective treatment to avoid further progression or to prevent the onset of the disease, the patients may experience psychological distress. There is a qualitative study on the experiences of patients with primary brain calcification with SLC20A2 variants. However, the experiences of patients with PDGFB variants of the disease have not been explored. The purpose of this study is to identify the experiences of patients with PDGFB variants after diagnosis.Materials and methodsSemi-structured interviews were conducted once or twice a year for three years with five patients over the age of 21. The data were analyzed using inductive qualitative methods.ResultsSeven categories, 15 subcategories, and 129 codes were extracted. The seven categories are as follows: [Shock at hearing the term ‘brain calcification’ for the first time], [Anxiety regarding the risk of heredity], [Anxiety, along with severe headaches, and various other symptoms], [Gratitude for the family members who care], [Accepting the disease as a non-life-threatening illness], [Feeling alienated due to the rare intractable disease], and [Modifying lifestyle due to the illness].DiscussionThe most stressful aspect of the disease was the headache that persisted even with the use of analgesics, which was different from patients with the SLC20A2 variants. In addition, we found unique concepts such as anxiety regarding the risk of heredity and a feeling of alienation due to the rare and intractable disease.

NCS1 overexpression restored mitochondrial activity and behavioral alterations in a zebrafish model of Wolfram syndrome

Wolfram syndrome (WS) is a rare neurodegenerative disease resulting in deafness, optic atrophy, diabetes, and neurological disorders. Currently, no treatment is available for patients. The mutated gene, WFS1, encodes an endoplasmic reticulum (ER) protein, Wolframin. We previously reported that Wolframin regulated the ER-mitochondria Ca2+ transfer and mitochondrial activity by protecting NCS1 from degradation in patients' fibroblasts. We relied on a zebrafish model of WS, the wfs1ab KO line, to analyze the functional and behavioral impact of NCS1 overexpression as a novel therapeutic strategy. The wfs1ab KO line showed an increased locomotion in the visual motor and touch-escape responses. The absence of wfs1 did not impair the cellular unfolded protein response, in basal or tunicamycin-induced ER stress conditions. In contrast, metabolic analysis showed an increase in mitochondrial respiration in wfs1ab KO larvae. Interestingly, overexpression of NCS1 using mRNA injection restored the alteration of mitochondrial respiration and hyperlocomotion. Taken together, these data validated the wfs1ab KO zebrafish line as a pertinent experimental model of WS and confirmed the therapeutic potential of NCS1. The wfs1ab KO line therefore appeared as an efficient model to identify novel therapeutic strategies, such as gene or pharmacological therapies targeting NCS1 that will correct or block WS symptoms.

Postural control in Parkinsonisms during a short static sway

Neurological diseases, such as Parkinsonisms, are often associated with static postural instability. Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease classified among atypical Parkinsonisms. In the earliest stages, PSP is similar to Parkinson’s disease (PD) [1]. Static postural stability is an important contributor to the balance control framework and balance impairment can be quantified with a postural sway measure [2]. The main goal of our study was to compare postural sway changes in both PSP and PD subjects, using a standing single task of 5-6 seconds, in order to prove that a shorter sway time may be useful to distinguish Parkinsonisms. We assessed fifteen individuals with early PSP and fifteen individuals with recent diagnosis of PD (De Novo PD). Stabilometric analysis was performed for the evaluation of balance through a BTS Bioengineering system. The patient was instructed to stand on the force plate with the eyes open and measures of 5-6 seconds were taken. To find differences between the groups, univariate statistical analysis on sway data was conducted, and an alpha significance level was set to p-value < 0.05. The statistical analysis showed significant differences between De Novo PD and PSP groups for Medio- Lateral (M-L) sway (p-value=0.01), M-L range (p-value=0.023) and radius (p-value=0.026); minimum oscillation from the center of gravity and area showed a statistical trend with a p-value slightly above the 0.05 (p-value=0.056 and p-value=0.061, respectively). Several studies have demonstrated that balance dysfunction in PD is directionally dependent [2,3]. In agreement with our data, patients with atypical Parkinsonism show balance impairment on M-L direction as attested by augmented M-L sway, M-L range and radius. These results indicate that a short static sway of 5-6 seconds, could provide the clinician with a reliable and non-invasive tool to distinguish PSP from PD since the earliest stages.

An in-silico approach to studying a very rare neurodegenerative disease using a disease with higher prevalence with shared pathways and genes: Cerebral adrenoleukodystrophy and Alzheimer's disease.

Cerebral adrenoleukodystrophy (cALD) is a rare neurodegenerative disease characterized by inflammatory demyelination in the central nervous system. Another neurodegenerative disease with a high prevalence, Alzheimer’s disease (AD), shares many common features with cALD such as cognitive impairment and the alleviation of symptoms by erucic acid. We investigated cALD and AD in parallel to study the shared pathological pathways between a rare disease and a more common disease. The approach may expand the biological understandings and reveal novel therapeutic targets. Gene set enrichment analysis (GSEA) and weighted gene correlation network analysis (WGCNA) were conducted to identify both the resemblance in gene expression patterns and genes that are pathologically relevant in the two diseases. Within differentially expressed genes (DEGs), GSEA identified 266 common genes with similar up- or down-regulation patterns in cALD and AD. Among the interconnected genes in AD data, two gene sets containing 1,486 genes preserved in cALD data were selected by WGCNA that may significantly affect the development and progression of cALD. WGCNA results filtered by functional correlation via protein–protein interaction analysis overlapping with GSEA revealed four genes (annexin A5, beta-2-microglobulin, CD44 molecule, and fibroblast growth factor 2) that showed robust associations with the pathogeneses of cALD and AD, where they were highly involved in inflammation, apoptosis, and the mitogen-activated protein kinase pathway. This study provided an integrated strategy to provide new insights into a rare disease with scant publicly available data (cALD) using a more prevalent disorder with some pathological association (AD), which suggests novel druggable targets and drug candidates.

The first family case of spinocerebellar ataxia type 14 in Russia

Spinocerebellar ataxia type 14 (SCA14) is a rare neurodegenerative disease with a predominant cerebellar affection and autosomal dominant inheritance. A characteristic clinical presentation is slowly progressive cerebellar ataxia, hyperreflexia, cognitive impairment and movement disorders (dystonia and myoclonus). Clinical and genetic characteristics of the first familial case of SCA14 in Russia (a 77‑year‑old female patient) caused by heterozygous pathogenic mutation c.155G&gt;C (p.Cys52Ser) in exon 1 in PRKCG gene (NM_002739.1) are presented. The total duration of the disease was 47 years, and the follow‑up period was 32 years. The disease phenotype corresponded to isolated ataxia with a slow rate of progression; brain MRI revealed atrophy of the cerebellar vermis and hemispheres, symmetrical hyperintensity of the dentate nucleus on T2‑weighted images. The features of the SCA14 clinical presentation and the effect of mutations in the regulatory and kinase domains of protein kinase C gamma on the formation of pure and complex phenotypes are discussed.

Clinical and mechanism advances of neuronal intranuclear inclusion disease.

Due to the high clinical heterogeneity of neuronal intranuclear inclusion disease (NIID), it is easy to misdiagnose this condition and is considered to be a rare progressive neurodegenerative disease. More evidence demonstrates that NIID involves not only the central nervous system but also multiple systems of the body and shows a variety of symptoms, which makes a clinical diagnosis of NIID more difficult. This review summarizes the clinical symptoms in different systems and demonstrates that NIID is a multiple-system intranuclear inclusion disease. In addition, the core triad symptoms in the central nervous system, such as dementia, parkinsonism, and psychiatric symptoms, are proposed as an important clue for the clinical diagnosis of NIID. Recent studies have demonstrated that expanded GGC repeats in the 5′-untranslated region of the NOTCH2NLC gene are the cause of NIID. The genetic advances and possible underlying mechanisms of NIID (expanded GGC repeat-induced DNA damage, RNA toxicity, and polyglycine-NOTCH2NLC protein toxicity) are briefly summarized in this review. Interestingly, inflammatory cell infiltration and inflammation were observed in the affected tissues of patients with NIID. As a downstream pathological process of NIID, inflammation could be a therapeutic target for NIID.

Clinical, radiological, and genetic variation in pontocerebellar hypoplasia disorder and our clinical experience

Pontocerebellar hypoplasia (PCH) constitutes a heterogeneous neurodegenerative/neurodevelopmental disorder of the pons and cerebellum with onset in the prenatal period. Our study aimed to present different clinical and radiological manifestations of our genetically diagnosed PCH patients.Method: Six patients were enrolled in this study from September 2018 to March 2021. All the clinical radiological and genetic investigations were done at Cukurova University Medical School.Results: Five children were diagnosed genetically and categorized under one of the types of PCH (type 10,7,11). Homozygous mutations in CLP1 In PCH type 10, TOE1 in PCH type 7, and TBC1D23 in PCH type 11 were respectively detected. Pateint with PCH type 11 and female patient with PCH type 7 could walk and speak few words. Male patient with PCH type 7 had disorder of sex development.Conclusion: According to our study, PCH is a rare neurodegenerative disease, although some types are static as PCH11 male gender and PCH7 female gender. Some clinical features are specific to a definite type. PCH7 express disorders of sex development most apparent in 46 XY. Some ethnic groups could express distinct subtypes. PCH10 is seen in the Turkish population. Radiological imaging is beneficial in pre-diagnosis; all the patients had different pons and cerebellar hypoplasia degrees. Genetic testing like whole exome sequencing -next-generation sequencing is essential in setting the definite diagnosis and determining the type/subtype of PCH.

A neglected neurodegenerative disease: Adult-onset globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD), or Krabbe disease (KD) is a rare neurodegenerative disease, and adult-onset GLD is more even neglected by clinicians. This review provides detailed discussions of the serum enzymes, genes, clinical manifestations, neuroimaging features, and therapies of GLD, with particular emphasis on the characteristics of adult-onset GLD, in an attempt to provide clinicians with in-depth insights into this disease.

Alterations in electrochemical skin conductance as a marker of autonomic dysfunction in multiple system atrophy

BackgroundMultiple System Atrophy (MSA) is a rare neurodegenerative disease with pronounced autonomic failure (AF). Severe cardiovascular AF is associated with poor prognosis. Since sweating dysfunction is less well known, we investigated the interest of a quick and non-invasive assessment of sweating using electrochemical skin conductance (ESC) as a marker for AF in MSA. Methods138 MSA patients of the French Reference center for MSA with an annual follow-up including the Unified MSA Rating Scale (UMSARS), COMPASS (autonomic symptoms) and measurements of foot and hand ESC (Sudoscan®) participated to this study (age 65 ± 8 years, 66% probable MSA, 72% AMS-P). Statistical analysis included: (i) correlations between ESC and MSA type, age, disease duration, severity, blood pressure (BP), COMPASS, (ii) comparisons between groups with normal or abnormal ESC, and (iii) multivariate analysis by logistic regression. Relationships between severity progression during follow-up with ESC and other variables were modeled by Generalized Estimating Equation. ResultsHands and feet ESCs were abnormal in 81/138 (59%) and 93/138 (67%) cases, respectively. Abnormal ESCs were significantly correlated to disease severity and several features of AF. ESCs worsening over time was more pronounced than other autonomic features such as orthostatic hypotension. Abnormal ESCs at baseline were significantly associated with a higher progression of UMSARS's score during follow-up. ConclusionSweating dysfunction assessed by ESC is frequent in MSA and is significantly related to disease severity and AF. The gradual decrease in ESC with disease duration could be useful as a quantitative marker of autonomic dysfunction.

Rosiglitazone Ameliorates Cardiac and Skeletal Muscle Dysfunction by Correction of Energetics in Huntington's Disease.

Huntington’s disease (HD) is a rare neurodegenerative disease that is accompanied by skeletal muscle atrophy and cardiomyopathy. Tissues affected by HD (central nervous system [CNS], skeletal muscle, and heart) are known to suffer from deteriorated cellular energy metabolism that manifests already at presymptomatic stages. This work aimed to test the effects of peroxisome proliferator-activated receptor (PPAR)-γ agonist—rosiglitazone on grip strength and heart function in an experimental HD model—on R6/1 mice and to address the mechanisms. We noted that rosiglitazone treatment lead to improvement of R6/1 mice grip strength and cardiac mechanical function. It was accompanied by an enhancement of the total adenine nucleotides pool, increased glucose oxidation, changes in mitochondrial number (indicated as increased citric synthase activity), and reduction in mitochondrial complex I activity. These metabolic changes were supported by increased total antioxidant status in HD mice injected with rosiglitazone. Correction of energy deficits with rosiglitazone was further indicated by decreased accumulation of nucleotide catabolites in HD mice serum. Thus, rosiglitazone treatment may not only delay neurodegeneration but also may ameliorate cardio- and myopathy linked to HD by improvement of cellular energetics.

Amyotrophic Lateral Sclerosis (ALS) Impact on Minors’ Life: A Qualitative Study with Children of ALS Patients in Italy

Amyotrophic Lateral Sclerosis (ALS) is a rare progressive neurodegenerative disease that is currently not curable and complex to manage. This qualitative study aimed to describe how ALS impacted life of minors with a parent affected by this pathology. Twenty-seven participants (16 females and 22 males; aged 7–18 years – M = 11.61; SD = 2.97) responded to a semi-structured interview. From the analysis of their answers three thematic areas were found: difficulties in understanding the changes caused by ALS, difficulties in family life, loneliness, and friendship as source of resilience. Indications are reported on possible interventions to be implemented to support these young people.

Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy.

Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. We studied common genetic variations in Multiple System Atrophy cases (N=731) and controls (N=2898). The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.