Rare Neurodegenerative Disease Research Articles

Amyotrophic lateral sclerosis: new era, new challenges

Amyotrophic lateral sclerosis is a rare but fatal neurodegenerative disease, that typically leads to muscle weakness, atrophy, and eventually respiratory failure within 2–4 years after symptom onset. A Series of two papers in The Lancet Neurology1,2 review the latest advances in amyotrophic lateral sclerosis research, providing an updated overview of its genetic architecture, pathophysiology, diagnosis, and prognosis.

Transcriptomic characterization of tissues from patients and subsequent pathway analyses reveal biological pathways that are implicated in spastic ataxia

BackgroundSpastic ataxias (SAs) encompass a group of rare and severe neurodegenerative diseases, characterized by an overlap between ataxia and spastic paraplegia clinical features. They have been associated with pathogenic variants in a number of genes, including GBA2. This gene codes for the non-lysososomal β-glucosylceramidase, which is involved in sphingolipid metabolism through its catalytic role in the degradation of glucosylceramide. However, the mechanism by which GBA2 variants lead to the development of SA is still unclear.MethodsIn this work, we perform next-generation RNA-sequencing (RNA-seq), in an attempt to discover differentially expressed genes (DEGs) in lymphoblastoid, fibroblast cell lines and induced pluripotent stem cell-derived neurons derived from patients with SA, homozygous for the GBA2 c.1780G > C missense variant. We further exploit DEGs in pathway analyses in order to elucidate candidate molecular mechanisms that are implicated in the development of the GBA2 gene-associated SA.ResultsOur data reveal a total of 5217 genes with significantly altered expression between patient and control tested tissues. Furthermore, the most significant extracted pathways are presented and discussed for their possible role in the pathogenesis of the disease. Among them are the oxidative stress, neuroinflammation, sphingolipid signaling and metabolism, PI3K-Akt and MAPK signaling pathways.ConclusionsOverall, our work examines for the first time the transcriptome profiles of GBA2-associated SA patients and suggests pathways and pathway synergies that could possibly have a role in SA pathogenesis. Lastly, it provides a list of DEGs and pathways that could be further validated towards the discovery of disease biomarkers.

A Clinical Decision Support System for the Prediction of Quality of Life in ALS.

Amyotrophic Lateral Sclerosis (ALS), also known as Motor Neuron Disease (MND), is a rare and fatal neurodegenerative disease. As ALS is currently incurable, the aim of the treatment is mainly to alleviate symptoms and improve quality of life (QoL). We designed a prototype Clinical Decision Support System (CDSS) to alert clinicians when a person with ALS is experiencing low QoL in order to inform and personalise the support they receive. Explainability is important for the success of a CDSS and its acceptance by healthcare professionals. The aim of this work isto announce our prototype (C-ALS), supported by a first short evaluation of its explainability. Given the lack of similar studies and systems, this work is a valid proof-of-concept that will lead to future work. We developed a CDSS that was evaluated by members of the team of healthcare professionals that provide care to people with ALS in the ALS/MND Multidisciplinary Clinic in Dublin, Ireland. We conducted a user study where participants were asked to review the CDSS and complete a short survey with a focus on explainability. Healthcare professionals demonstrated some uncertainty in understanding the system’s output. Based on their feedback, we altered the explanation provided in the updated version of our CDSS. C-ALS provides local explanations of its predictions in a post-hoc manner, using SHAP (SHapley Additive exPlanations). The CDSS predicts the risk of low QoL in the form of a probability, a bar plot shows the feature importance for the specific prediction, along with some verbal guidelines on how to interpret the results. Additionally, we provide the option of a global explanation of the system’s function in the form of a bar plot showing the average importance of each feature. C-ALS is available online for academic use.

Wolfram Syndrome 1: From Genetics to Therapy.

Wolfram syndrome 1 (WS1) is a rare neurodegenerative disease transmitted in an autosomal recessive mode. It is characterized by diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), and sensorineural hearing loss (D) (DIDMOAD). The clinical picture may be complicated by other symptoms, such as urinary tract, endocrinological, psychiatric, and neurological abnormalities. WS1 is caused by mutations in the WFS1 gene located on chromosome 4p16 that encodes a transmembrane protein named wolframin. Many studies have shown that wolframin regulates some mechanisms of ER calcium homeostasis and therefore plays a role in cellular apoptosis. More than 200 mutations are responsible for WS1. However, abnormal phenotypes of WS with or without DM, inherited in an autosomal dominant mode and associated with one or more WFS1 mutations, have been found. Furthermore, recessive Wolfram-like disease without DM has been described. The prognosis of WS1 is poor, and the death occurs prematurely. Although there are no therapies that can slow or stop WS1, a careful clinical monitoring can help patients during the rapid progression of the disease, thus improving their quality of life. In this review, we describe natural history and etiology of WS1 and suggest criteria for a most pertinent approach to the diagnosis and clinical follow up. We also describe the hallmarks of new therapies for WS1.

Multiple Sclerosis and Vitamin D: Is there a Link in the Multifactorial Model?

MS is a rare neurodegenerative disease with an immunopathological background. Although, it has a rather low global prevalence, it can be considered among one of the most common youth disabling disorders that are not related to trauma. It is also classified as a complex disease with many susceptibility genes incriminated in its etiology and prognosis. In addition, several well identified and extensively studied environmental factors are implicated as vitamin D metabolism & ultraviolet B (UVB) exposure, Epstein Barr virus (EBV) infection, smoking and morbid obesity. The infamous relationship between Vitamin D and MS has been an area of extensive research in many aspects; pathophysiology, disease course, prognosis and even response to treatment.

Overcoming therapeutic nihilism. Breaking bad news of amyotrophic lateral sclerosis—a patient-centred perspective in rare diseases

Amyotrophic lateral sclerosis (ALS) is a rare, incurable, and fatal neurodegenerative disease with median survival time from onset to death ranging from 20 to 48 months. Breaking bad news about ALS diagnosis is a challenging task for physicians and a life-changing experience for patients. Several protocols for delivering difficult information are available, including SPIKES and EMPATHY. Our goal was to assess to what extent these guidelines are followed in Polish ALS patients’ experience as well as to identify any other patients’ preferences not addressed by the guidelines. Participants of our study were recruited via a neurology clinic. Twenty-four patients with confirmed ALS diagnosis were interviewed using in-depth interview and a self-constructed questionnaire: 9 females, 15 males in age ranging from 30–39 to 60–69. The analysis showed a pattern of shortcomings and fundamental violations of available protocols reported by ALS patients. Patients also had to deal with therapeutic nihilism, as they were perceived as “hopeless cases”; unlike in oncological setting, their end-of-life needs were not accommodated by some standard schemes. As a conclusion, we recommend using extended breaking bad news protocols with special emphasis on preparing a treatment plan, giving the patient hope and sense of purpose, offering psychological support and counselling directed to patients and caregivers, and providing the patient with meaningful information about the disease, social support, treatment options, and referral to appropriate health care centres.

Two case reports of chorea-acanthocytosis and review of literature

BackgroundChorea-acanthocytosis (ChAc), as the most common subtype of neuroacanthocytosis syndrome, is characterized by the presence of acanthocytes and neurological symptoms. It is thought to be caused by the VPS13A (vacuolar protein sorting-associated protein 13A) mutations. This article reports two confirmed cases of ChAc and summarizes some suggestive features, which provide direction for the diagnosis and treatment of acanthocytosis in the future.Case presentationHere, we present two cases of ChAc diagnosed based on typical clinical symptoms, neuroimaging features, genetic findings of VPS13A, and response to the symptomatic treatment.ConclusionsChorea-acanthocytosis is a rare neurodegenerative disease with various early clinical manifestations. The final diagnosis of the ChAc can be established by either genetic analysis or protein expression by Western blotting. Supportive treatments and nursing are helpful to improve the quality of the patient’s life. Nevertheless, it is imperative to investigate the impact of neuroimaging and neuropathological diagnosis in a larger group of ChAc in future studies.

Vitamin E prevents lipid peroxidation and iron accumulation in PLA2G6-Associated Neurodegeneration

BackgroundPLA2G6-Associated Neurodegeneration (PLAN) is a rare neurodegenerative disease with autosomal recessive inheritance, which belongs to the NBIA (Neurodegeneration with Brain Iron Accumulation) group. Although the pathogenesis of the disease remains largely unclear, lipid peroxidation seems to play a central role in the pathogenesis. Currently, there is no cure for the disease. ObjectiveIn this work, we examined the presence of lipid peroxidation, iron accumulation and mitochondrial dysfunction in two cellular models of PLAN, patients-derived fibroblasts and induced neurons, and assessed the effects of α-tocopherol (vitamin E) in correcting the pathophysiological alterations in PLAN cell cultures. MethodsPathophysiological alterations were examined in fibroblasts and induced neurons generated by direct reprograming. Iron and lipofuscin accumulation were assessed using light and electron microscopy, as well as biochemical analysis techniques. Reactive Oxygen species production, lipid peroxidation and mitochondrial dysfunction were measured using specific fluorescent probes analysed by fluorescence microscopy and flow cytometry. ResultsPLAN fibroblasts and induced neurons clearly showed increased lipid peroxidation, iron accumulation and altered mitochondrial membrane potential. All these pathological features were reverted with vitamin E treatment. ConclusionsPLAN fibroblasts and induced neurons reproduce the main pathological alterations of the disease and provide useful tools for disease modelling. The main pathological alterations were corrected by Vitamin E supplementation in both models, suggesting that blocking lipid peroxidation progression is a critical therapeutic target.

Genetics in hereditary spastic paraplegias: Essential but not enough.

Hereditary spastic paraplegias consist of a group of rare neurodegenerative diseases characterized by lower limb spasticity. These inherited Mendelian disorders show high genetic variability associated with wide clinical diversity. Pathophysiological investigations have suggested that mutations in genes affecting the same cellular pathway generally lead to similar clinical symptoms, highlighting the importance of genetic mutation in these diseases. However, phenotype-genotype correlations have failed to explain the observed large inter-individual variability linked to mutations in a single gene, suggesting that genetics alone is not sufficient to explain symptom diversity. The identification of biomarkers, such as neurofilament light chain, could fill the gap and predict disease evolution.

Ambulatory blood pressure and drug treatment for orthostatic hypotension as predictors of mortality in patients with multiple system atrophy.

Multiple system atrophy (MSA) is a rare fatal neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. This study was aimed at investigating possible associations between mortality, 24-h blood pressure (BP) level and variability, and drug treatments for orthostatic hypotension (OH) in MSA patients. A total of 129 patients followed at the French Reference Center for MSA who underwent routine 24-h ambulatory BP monitoring were included. Unified MSA Rating Scale (UMSARS) scores, drug treatments and the occurrence and cause of death were recorded. Seventy patients died during follow-up (2.9±1.8years), mainly from terminal illness, pulmonary or sudden death. Multivariate Cox regression analysis, after adjustment for gender, disease duration and severity (UMSARS I+II score), showed that increased daytime systolic BP variability, OH severity and OH drug treatment were independently correlated with mortality. OH treatment was associated with the risk of cardiac causes and/or sudden death (p=0.01). In a fully adjusted model, male gender [(female vs. male) hazard ratio (HR) 0.56, 95% CI 0.34-0.94, p=0.03], UMSARS I+II score (HR 1.04, 95% CI 1.02-1.06, p<0.01), systolic BP daytime variability (HR 3.66, 95% CI 1.46-9.17, p<0.01) and OH treatment (HR: 2.13, 95% CI 1.15-3.94, p=0.02) predicted mortality. Increased daytime BP variability and OH treatment were predictive of mortality in patients with MSA, independently from disease severity. Further studies are required to assess if these associations are explained by more severe autonomic dysfunction or if OH treatment exposes per se to a specific risk in this population.

A Case Report on Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP) is a quite rare neurodegenerative disease that affects mainly the brain stem, basal ganglia, and cerebellum in the central nervous system. PSP is classified in the rubric of parkinsonism plus syndromes, which causes progressive degeneration in the midbrain areas those controls eye movements. PSP often goes under diagnosed, hence making it essential for physicians to be well-known of this disorder. We present a case of PSP of a 65- year-old female, which came primarily with reiterative falls due to postural instability and speech disturbances. Radiodiagnosis with magnetic resonance imaging (MRI) of brain diagnosed a classical sign of PSP.

Chinese patients with hereditary spastic paraplegias (HSPs): a protocol for a hospital-based cohort study

IntroductionHereditary spastic paraplegias (HSPs) are uncommon but not rare neurodegenerative diseases. More than 100 pathogenic genes and loci related to spastic paraplegia symptoms have been reported. HSPs have the same...

Progressive Supranuclear Palsy Following as Major Depressive Disorder: A Case Report

Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disease that is classified among Parkinson plus syndromes, manifesting itself with behavioral, cognitive and emotional symptoms as well as parkinsonian symptoms such as postural instability, ophthalmoplegia, bradykinesia, rigidity affecting the brain stem, basal ganglia and cerebellum. Although there is sufficient information about the pathological process and clinical presentation of PSP, there is no valid biomarker for diagnosis, clinical findings and neuroimaging are very important in diagnosis, patients often get misdiagnosis at their first application. It has been reported that psychiatric symptoms are common in these individuals due to the involvement of the frontal-subcortical circuits, and therefore patients can get psychiatric diagnoses in the early period. We aimed to present a 72-year-old female patient who was followed up with the diagnosis of major depressive disorder in various centers for about 4 years, who did not benefit from psychiatric treatment, and diagnosed with PSP eventually. We also aimed to emphasize that importance of considering neurodegenerative diseases in differential diagnosis in patients whose depressive symptoms begin at an advanced age, are resistant to treatment and have atypical symptoms such as the presence of accompanying neurological findings, and psychiatric symptoms may be the first symptom of neurodegenerative diseases.

Incidence and morphology of secondary TDP-43 proteinopathies: Part 1.

Transactive response DNA binding protein of 43 kDa (TDP-43) is considered to play an essential role in the pathogenesis of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Growing body of evidence indicate that pathological TDP-43 inclusions frequently occur in the context of other distinctive hallmark pathologies, referred to as secondary TDP-43 proteinopathies. Comorbid TDP-43 pathology is well-documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, multiple system atrophy, or progressive supranuclear palsy. It may also appear as a consequence of less obvious disease etiologies, i.e. post-traumatic (chronic traumatic encephalopathy), neoplastic (pilocytic astrocytoma), or post-infectious (post-encephalitic parkinsonism). The aim of the present review was to evaluate the incidence, morphology, and role of TDP-43 pathology in the secondary TDP-43 proteinopathies. This article (Part 1) discussed TDP-43 pathology in more common neurodegenerative diseases, including Alzheimer's disease, Lewy body disease, Huntington's disease, multiple system atrophy, corticobasal degeneration, and progressive supranuclear palsy. A follow-up article (Part 2) will describe abnormal TDP-43 changes in rare neurodegenerative diseases or neurological diseases with nondegenerative etiology.

Creutzfeldt Jacob’s Disease: A Senegalese Observation

Creuzfelt-Jakob Disease is a rare and progressive neurodegenerative disease that results in fatal, transmissible, subacute, spongiform encephalopathy characterized by rapidly progressive dementia and movement disorder. We present a 62-year-old male with no medical history who was admitted to our hospital because of gait and balance disturbance, language impairment and progressive motor deficit of the four limbs. A neurological examination found frontal lobe syndrome signs, myoclonic movements, pyramidal and extra-pyramidal signs. Brain Magnetic Resonance Imaging detected high intensity areas in the basal ganglia. EEG showed generalized triphasic sharp-wave complexes. A Cerebro Spinal Fluid examination found protein 14-3-3. Death occurred six months after onset. This is the first known case of Creuzfelt-Jakob Disease documented in Senegal.

A resting-state fMRI pattern of spinocerebellar ataxia type 3 and comparison with 18F-FDG PET

Spinocerebellar ataxia type 3 (SCA3) is a rare genetic neurodegenerative disease. The neurobiological basis of SCA3 is still poorly understood, and up until now resting-state fMRI (rs-fMRI) has not been used to study this disease. In the current study we investigated (multi-echo) rs-fMRI data from patients with genetically confirmed SCA3 (n = 17) and matched healthy subjects (n = 16). Using independent component analysis (ICA) and subsequent regression with bootstrap resampling, we identified a pattern of differences between patients and healthy subjects, which we coined the fMRI SCA3 related pattern (fSCA3-RP) comprising cerebellum, anterior striatum and various cortical regions. Individual fSCA3-RP scores were highly correlated with a previously published 18F-FDG PET pattern found in the same sample (rho = 0.78, P = 0.0003). Also, a high correlation was found with the Scale for Assessment and Rating of Ataxia scores (r = 0.63, P = 0.007). No correlations were found with neuropsychological test scores, nor with levels of grey matter atrophy. Compared with the 18F-FDG PET pattern, the fSCA3-RP included a more extensive contribution of the mediofrontal cortex, putatively representing changes in default network activity. This rs-fMRI identification of additional regions is proposed to reflect a consequence of the nature of the BOLD technique, enabling measurement of dynamic network activity, compared to the more static 18F-FDG PET methodology. Altogether, our findings shed new light on the neural substrate of SCA3, and encourage further validation of the fSCA3-RP to assess its potential contribution as imaging biomarker for future research and clinical use.

Chapter 6 - Clinical and neuroimaging characteristics of primary progressive aphasia

The chapter covers the clinical syndrome of a primary progressive aphasia (PPA), the demographics of this rare neurodegenerative disease, defining clinical and neuroanatomic characteristics of each PPA variant, disease progression, and behavioral features. The chapter begins with a brief introduction that includes references to seminal papers that defined this clinical syndrome and its three variants. The classic PPA subtypes discussed in the chapter are semantic variant PPA (svPPA), nonfluent/agrammatic PPA (nfaPPA), and logopenic variant PPA (lvPPA). The key language and cognitive characteristics, and language tasks that can elicit these language impairments, are detailed. Overlap in the clinical profiles of the PPA variants, which make differential diagnosis challenging, are explained. Disease progression is described, revealing that the PPA variants become more similar over time. Although PPA is language-predominant dementia, there are behavioral manifestations, particularly in svPPA. Changes in behavior in this variant are addressed as well as behavioral changes in nfaPPA and lvPPA that are less well recognized. The patterns of atrophy in the left temporal, parietal, and/or frontal cortices unique to each PPA variant are described. The underlying neuropathologies of the PPA variants are discussed, specifically tauopathies and non-tauopathies associated with svPPA and nfaPPA and Alzheimer's disease pathology in lvPPA.

FAHR’S SYNROME- A RARITY

Fahr’s disease/syndrome is a rare neurodegenerative disease characterized by symmetrical and bilateral calcication of the basal ganglia. Calcications are also seen in other areas such as thalamus, dentate nucleus and cerebral cortex. Both familial and non-familial cases of Fahr’s disease have been reported, predominently with autosomal-dominant pattern. It has a wide range of clinical manifestations. Diagnosis criteria and checklist have been helpful in diagnosis and differentiation of Fahr’s syndrome and Fahr’s disease. No specic treatment is available and the management of the patient is mainly symptomatic. Here we present a case report of a 12 year female child presented with Pancytopenia for evaluation with already diagnosed Fahrs disease.

Secondary Fahr’s disease: A differential to be considered in a COVID-19 pneumonia patient with neuropsychiatric presentations

Background, aim. Fahr’s disease is a rare neurodegenerative disease caused by intracranial classifications. This case report aims to accentuate the importance of considering rare disease like Fahr’s disease as the differential diagnosis of neuropsychiatric deficits, especially in patients with a history of thyroidectomy. Case presentation. A 50-year-old female who underwent thyroidectomy 5 years previously presented with incoherent speech, behavioral problems, and hand stiffness. On evaluation, several neurobehavioral deficits and carpopedal spasms were observed, along with low Mini-Mental State Examination (MMSE), Hachinski, Activities of Daily Living (ADL), and Instrumental Activities of Daily Living Scale (IADL) score of 22, 4, 13, and 12, respectively. Clinically significant laboratory abnormalities include low serum calcium of 4.7 mg/dl, low thyroid stimulating hormone (TSH) level of 0.113 mIU/l, and low parathyroid hormone (PTH) level of 1.2 pg/ml. In addition, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reverse transcription-polymerase chain reaction (RT-PCR) test showed a positive result. Meanwhile, brain computerized tomography (CT)-scan results showed multiple bilateral calcifications in the basal ganglia, bilateral cortical-subcortical calcifications in the frontal lobe, and subcortical calcification in the left frontal lobe. Results. The patient was diagnosed with Fahr’s disease secondary to post-thyroidectomy hypoparathyroidism and coronavirus disease 2019 (COVID-19). The patient was treated with calcium lactate, levothyroxine, donepezil, favipiravir for COVID’s infection, vitamin B1, B6, and B12. Conclusions. Fahr’s disease should be considered in patients with neuropsychiatric deficits and spasm disorders, especially in patients with a history of thyroidectomy. Routine follow-up CT-scans after thyroidectomy are recommended.

Marchiafava- Bignami disease (MBD): A rare case report

Marchiafava-Bignami disease (MBD) is a rare neuro degenerative disease characterized by demyelination of corpus callosum. Clinical diagnosis of MBD is challenging due to its nonspecific neurological manifestations. It’s promptly diagnosed by brain Magnetic Resonance Imaging (MRI). Prompt treatment with high dose thiamine could be lifesaving. Here we report a 68 year old male with chronic alcoholism who was diagnosed to have MBD and successfully treated with high doses of intravenous thiamine administration.