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Brain : a Journal of Neurology Dec 2023Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease, usually caused by biallelic AAGGG repeat...
Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease, usually caused by biallelic AAGGG repeat expansions in RFC1. In this study, we leveraged whole genome sequencing data from nearly 10 000 individuals recruited within the Genomics England sequencing project to investigate the normal and pathogenic variation of the RFC1 repeat. We identified three novel repeat motifs, AGGGC (n = 6 from five families), AAGGC (n = 2 from one family) and AGAGG (n = 1), associated with CANVAS in the homozygous or compound heterozygous state with the common pathogenic AAGGG expansion. While AAAAG, AAAGGG and AAGAG expansions appear to be benign, we revealed a pathogenic role for large AAAGG repeat configuration expansions (n = 5). Long-read sequencing was used to characterize the entire repeat sequence, and six patients exhibited a pure AGGGC expansion, while the other patients presented complex motifs with AAGGG or AAAGG interruptions. All pathogenic motifs appeared to have arisen from a common haplotype and were predicted to form highly stable G quadruplexes, which have previously been demonstrated to affect gene transcription in other conditions. The assessment of these novel configurations is warranted in CANVAS patients with negative or inconclusive genetic testing. Particular attention should be paid to carriers of compound AAGGG/AAAGG expansions when the AAAGG motif is very large (>500 repeats) or the AAGGG motif is interrupted. Accurate sizing and full sequencing of the satellite repeat with long-read sequencing is recommended in clinically selected cases to enable accurate molecular diagnosis and counsel patients and their families.
Topics: Humans; Bilateral Vestibulopathy; Cerebellar Ataxia; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Syndrome; Vestibular Diseases
PubMed: 37450567
DOI: 10.1093/brain/awad240 -
The Veterinary Clinics of North... Aug 2022Neuroaxonal degenerative disease in the horse is termed equine neuroaxonal dystrophy (eNAD), when pathologic lesions are localized to the brainstem and equine... (Review)
Review
Neuroaxonal degenerative disease in the horse is termed equine neuroaxonal dystrophy (eNAD), when pathologic lesions are localized to the brainstem and equine degenerative myeloencephalopathy (EDM) and degenerative changes extend throughout the spinal cord. Both pathologic conditions result in identical clinical disease, most commonly characterized by the insidious onset of ataxia during early development. However, later onset of clinical signs and additional clinical features, such as behavior changes, is also observed. A definitive diagnosis of eNAD/EDM requires histologic evaluation of the caudal medulla and cervicothoracic spinal cord. Strong evidence has suggested that eNAD/EDM is an inherited disorder and there seems to be a role for vitamin E acting as an environmental modifier to determine the overall severity of the phenotype of horses affected with eNAD/EDM.
Topics: Animals; Horse Diseases; Horses; Neuroaxonal Dystrophies
PubMed: 35811203
DOI: 10.1016/j.cveq.2022.04.003 -
Neurologic Clinics May 2022Multiple sclerosis (MS) is an autoimmune inflammatory disease that results in demyelination of the central nervous system (CNS). MS affects as many as 350,000... (Review)
Review
Multiple sclerosis (MS) is an autoimmune inflammatory disease that results in demyelination of the central nervous system (CNS). MS affects as many as 350,000 individuals in the United States and commonly presents before the age of 45 years. Patients with MS, as the general population, are likely to encounter degenerative changes of the spine as they age, and this can pose a unique challenge to both patients with MS and physicians, as both conditions can have a great deal of symptomatic overlap despite stark differences in management. Currently there is no definitive approach that allows physicians to distinguish between the 2 conditions; however, specific clinical and radiologic findings have been identified as being useful in evaluating these patients.
Topics: Central Nervous System; Humans; Middle Aged; Multiple Sclerosis
PubMed: 35465872
DOI: 10.1016/j.ncl.2021.11.004 -
Otolaryngologic Clinics of North America Oct 2021Initial diagnosis of peripheral vestibulopathy requires a detailed history, physical examination, and, in some cases, audiovestibular testing, radiographic imaging, or... (Review)
Review
Initial diagnosis of peripheral vestibulopathy requires a detailed history, physical examination, and, in some cases, audiovestibular testing, radiographic imaging, or serology. Differentiation of a peripheral vestibulopathy as progressive or degenerative is often nuanced and influenced by a characterization of a patient's symptoms or natural history over time. A diverse group of vestibular pathology may fit into this category, including Ménière's disease, autoimmune conditions, congenital pathologies, ototoxic medications, radiation therapy, and perilymphatic fistula. Differentiation among these entities may be guided by initial or subsequent symptomatology, with various combinations of audiovestibular testing, serology, and imaging. Treatment options are disparate and disease-specific, ranging from observation to medical management or surgical intervention, underscoring the need for astute investigation and diagnosis.
Topics: Autoimmune Diseases; Humans; Meniere Disease; Radiography
PubMed: 34301401
DOI: 10.1016/j.otc.2021.05.015 -
British Journal of Hospital Medicine... Jan 2023Achalasia, characterised by the absence of peristalsis and failure of relaxation of the lower oesophageal sphincter, is an uncommon degenerative condition that results... (Review)
Review
Achalasia, characterised by the absence of peristalsis and failure of relaxation of the lower oesophageal sphincter, is an uncommon degenerative condition that results in dysphagia. If left untreated it can lead to aspiration, oesophageal perforation, oesophagitis and malnutrition. It has a range of immune, allergic, viral and genetic aetiological causes. Successful diagnosis relies on the use of oesophagogastroduodenoscopy, barium swallow and oesophageal manometry to characterise the severity of the disease and to rule out underlying malignancy. Although no treatment can reverse the degenerative process, therapeutic strategies including lifestyle modification, medication, endoscopic and operative intervention can help to reduce symptoms. This article reviews the latest methods used to investigate and manage achalasia.
Topics: Humans; Esophageal Achalasia; Esophageal Sphincter, Lower; Deglutition Disorders; Manometry; Esophagoscopy
PubMed: 36708337
DOI: 10.12968/hmed.2022.0437 -
Cells Mar 2023Alzheimer's disease (AD) is the most common degenerative disorder in the elderly in developed countries. Currently, growing evidence is pointing at endothelial... (Review)
Review
Alzheimer's disease (AD) is the most common degenerative disorder in the elderly in developed countries. Currently, growing evidence is pointing at endothelial dysfunction as a key player in the cognitive decline course of AD. As a main component of the blood-brain barrier (BBB), the dysfunction of endothelial cells driven by vascular risk factors associated with AD allows the passage of toxic substances to the cerebral parenchyma, producing chronic hypoperfusion that eventually causes an inflammatory and neurotoxic response. In this process, the levels of several biomarkers are disrupted, such as an increase in adhesion molecules that allow the passage of leukocytes to the cerebral parenchyma, increasing the permeability of the BBB; moreover, other vascular players, including endothelin-1, also mediate artery inflammation. As a consequence of the disruption of the BBB, a progressive neuroinflammatory response is produced that, added to the astrogliosis, eventually triggers neuronal degeneration (possibly responsible for cognitive deterioration). Recently, new molecules have been proposed as early biomarkers for endothelial dysfunction that can constitute new therapeutic targets as well as early diagnostic and prognostic markers for AD.
Topics: Humans; Aged; Alzheimer Disease; Endothelial Cells; Blood-Brain Barrier; Cognition Disorders; Vascular Diseases; Biomarkers
PubMed: 36980302
DOI: 10.3390/cells12060962 -
Connective Tissue Research May 2023The formyl peptide receptor (FPR) participates in the immune response, with roles in infection and inflammation. In this review article, we summarize the current... (Review)
Review
PURPOSE/AIM OF THE STUDY
The formyl peptide receptor (FPR) participates in the immune response, with roles in infection and inflammation. In this review article, we summarize the current literature on these roles before discussing the function of FPRs in the pathogenesis of musculoskeletal disorders including osteoarthritis (OA), degenerative disc disease (DDD), and rheumatoid arthritis (RA). Additionally, we discuss the potential diagnostic and therapeutic roles of FPRs in these domains.
METHODS
PubMed and Ovid MEDLINE searches were performed from 1965 through March 2022. Keywords included "FPR, tissue expression, inflammation, infection, musculoskeletal disorder, bone, rheumatoid arthritis, osteoarthritis, degenerative disc disease, mitochondria."
RESULTS
Sixty-nine studies were included in this review article. FPRs appear to be ubiquitous in the pathogenesis, diagnosis, and treatment of common musculoskeletal disorders. They can potentially be utilized for the earlier diagnosis of OA and DDD. They may be employed with mesenchymal stem cells (MSCs) to reverse OA and DDD pathologies. With anti-inflammatory, anti-osteolytic, and pro-angiogenic functions, they may broaden treatment options in RA.
CONCLUSIONS
FPRs appear to be heavily involved in the pathogenesis of common musculoskeletal conditions, including arthritis, degenerative disc disease, and rheumatoid arthritis. Furthermore, they demonstrate much promise in the diagnosis and treatment of these conditions. Their roles should continue to be explored.
Topics: Humans; Intervertebral Disc Degeneration; Receptors, Formyl Peptide; Inflammation; Arthritis, Rheumatoid; Osteoarthritis; Musculoskeletal Diseases
PubMed: 36440821
DOI: 10.1080/03008207.2022.2149397 -
Neuropathology : Official Journal of... Oct 2022The neuropathological background of parkinsonism includes various neurodegenerative disorders, including Lewy body disease (LBD), multiple system atrophy (MSA),... (Review)
Review
The neuropathological background of parkinsonism includes various neurodegenerative disorders, including Lewy body disease (LBD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). The pathological diagnostic procedure begins by assessing the macroscopic findings to evaluate the degenerative lesions in brains with the naked eye. Usually, degenerative lesions show variable atrophy and brownish discoloration in accordance with disease-specific profiles. These macroscopic appearances support neuropathologists in identifying the relevant regions for microscopic examination. The neuropathological diagnosis of parkinsonism is based on regional distribution and fundamental proteinopathies in neurons and glia cells. LBD and MSA are synucleinopathies, and PSP and CBD are tauopathies. Among them, glial-predominant proteinopathy (MSA, PSP, and CBD) may play a significant role in volume reduction. Therefore, macroscopic inspection provides the appropriate direction for assessment. The disease duration, the severity of lesions, and mixed pathologies make the validation of macroscopic observations more complicated. In this review, we outline the macroscopic diagnostic clues in LBD, MSA, PSP, and CBD that could help with pathological refinement.
Topics: Humans; Lewy Body Disease; Multiple System Atrophy; Parkinsonian Disorders; Supranuclear Palsy, Progressive; Tauopathies
PubMed: 35996308
DOI: 10.1111/neup.12853 -
Endokrynologia Polska 2021Wolfram syndrome (WFS) is a neurological and endocrinological degenerative disorder, also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus,...
INTRODUCTION
Wolfram syndrome (WFS) is a neurological and endocrinological degenerative disorder, also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy, and Deafness) syndrome. It is an autosomal recessive disorder, mostly involving the Wolfram syndrome 1 gene (WFS1). The phenotypic pleiomorphism, rarity, and molecular complexity complicate the follow-up of these patients.
MATERIAL AND METHODS
We aimed to describe the clinical characteristics and the follow-up of 11 patients with this disorder. We retrospectively analysed all WFS patients diagnosed between 1990 and 2020 in the Centro Hospitalar São João, a tertiary hospital in Northern Portugal.
RESULTS
Eleven patients were included. Four patients had all 4 components of DIDMOAD. The presentation was diabetes mellitus (DM) in 9 patients, optic atrophy (OA) in another patient, and diabetes insipidus (DI) in another one. The median age of DM and OA diagnosis was 6 and 14 years, respectively. Nine patients had diabetes mellitus, and the other 2 patients had impaired glucose tolerance. All patients had OA. Four patients presented DI, all of them diagnosed in adolescence. Four patients had hearing impairment, 5 had urological abnormalities, 5 had neurological disorders, and 8 had psychiatry disorders. Eight patients had a broad spectrum of recessive mutations in WFS1.
CONCLUSION
The information obtained in this study can facilitate further research in an attempt to improve prevention strategies for this devastating disease.
Topics: Adolescent; Child; Diabetes Insipidus; Humans; Membrane Proteins; Optic Atrophy; Portugal; Retrospective Studies; Wolfram Syndrome
PubMed: 34010437
DOI: 10.5603/EP.a2021.0038