-
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 -
International Journal of Molecular... Jan 2017
Topics: Animals; DNA Damage; DNA Repair; Diet; Disease; Epigenesis, Genetic; Humans; Oxidative Stress
PubMed: 28275213
DOI: 10.3390/ijms18010166 -
Pediatric Clinics of North America Jun 2015Spinal muscular atrophies (SMAs) are hereditary degenerative disorders of lower motor neurons associated with progressive muscle weakness and atrophy. Proximal 5q SMA is... (Review)
Review
Spinal muscular atrophies (SMAs) are hereditary degenerative disorders of lower motor neurons associated with progressive muscle weakness and atrophy. Proximal 5q SMA is caused by decreased levels of the survival of motor neuron (SMN) protein and is the most common genetic cause of infant mortality. Its inheritance pattern is autosomal recessive, resulting from mutations involving the SMN1 gene on chromosome 5q13. Unlike other autosomal recessive diseases, the SMN gene has a unique structure (an inverted duplication) that presents potential therapeutic targets. Although there is currently no effective treatment of SMA, the field of translational research in this disorder is active and clinical trials are ongoing. Advances in the multidisciplinary supportive care of children with SMA also offer hope for improved life expectancy and quality of life.
Topics: Age of Onset; Child, Preschool; Gene Deletion; Gene Dosage; Genotype; Humans; Infant; Muscular Atrophy, Spinal; Mutation; Phenotype; Quality of Life
PubMed: 26022173
DOI: 10.1016/j.pcl.2015.03.010 -
Handbook of Clinical Neurology 2016Myelopathy is an inclusive term, referring to pathology leading to a neurologic deficit related to the spinal cord. The clinical diagnosis of myelopathy requires a... (Review)
Review
Myelopathy is an inclusive term, referring to pathology leading to a neurologic deficit related to the spinal cord. The clinical diagnosis of myelopathy requires a detailed history and physical examination to define the clinical syndrome. Neuroimaging is indicated in most instances of new-onset myelopathy. It is indicated also when the worsening of a myelopathy is unexplained. Advances in neuroimaging have proved to play a vital role in diagnosis. Appropriate diagnosis and treatment are dependent upon an adequate imaging evaluation to establish the presence of mechanical stability, extrinsic spinal cord compression, or an intramedullary lesion. The most frequent etiology of myelopathy is related to degenerative disease of the spine from osteophyte or extruded disc material causing compression of the spinal cord in the cervical or thoracic spine. The next common etiologies are spinal cord compression due to extradural masses caused by metastatic disease to bone or blunt trauma. In these cases, emergency imaging should be performed to assess the nature of the lesion causing the myelopathy and plan the most appropriate treatment. Also urgent imaging should be performed when an abscess in the spinal canal is suspected. Less urgent is imaging of primary neoplasms of the meninges, roots, or spinal cord, as well as noninfectious inflammatory processes, such as multiple sclerosis, and neurodegenerative, vascular, nutritional, or idiopathic disorders leading to myelopathy. Although a survey of the entire spinal cord can be performed with imaging, it is more appropriate to define from the clinical findings what levels of the spine and spinal cord should be imaged. This approach helps limit the likelihood of false-positive imaging findings that may encourage needless attempts to fix what is not broken. Similarly, the most appropriate imaging study and protocol should be selected in order to provide a timely and accurate diagnosis. To do so requires detailed knowledge regarding the strengths and limitations of the multiple imaging modalities available. This chapter outlines an approach to proper study selection based on the likely etiology of myelopathy from the clinical findings. Chapters 33-39 cover these disorders in detail.
Topics: Humans; Neuroimaging; Spinal Cord Diseases
PubMed: 27430455
DOI: 10.1016/B978-0-444-53486-6.00052-1 -
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 -
Journal of Neural Transmission (Vienna,... Apr 2023Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by early postural instability and falls, oculomotor dysfunction (vertical supranuclear... (Review)
Review
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by early postural instability and falls, oculomotor dysfunction (vertical supranuclear gaze palsy), parkinsonism with poor response to levodopa, pseudobulbar palsy, and cognitive impairment. This four-repeat tauopathy is morphologically featured by accumulation of tau protein in neurons and glia causing neuronal loss and gliosis in the extrapyramidal system associated with cortical atrophy and white matter lesions. Cognitive impairment being frequent in PSP and more severe than in multiple system atrophy and Parkinson disease, is dominated by executive dysfunction, with milder difficulties in memory, and visuo-spatial and naming dysfunctions. Showing longitudinal decline, it has been related to a variety of pathogenic mechanisms associated with the underlying neurodegenerative process, such as involvement of cholinergic and muscarinergic dysfunctions, and striking tau pathology in frontal and temporal cortical regions associated with reduced synaptic density. Altered striatofrontal, fronto-cerebellar, parahippocampal, and multiple subcortical structures, as well as widespread white matter lesions causing extensive connectivity disruptions in cortico-subcortical and cortico-brainstem connections, support the concept that PSP is a brain network disruption disorder. The pathophysiology and pathogenesis of cognitive impairment in PSP, as in other degenerative movement disorders, are complex and deserve further elucidation as a basis for adequate treatment to improve the quality of life of patients with this fatal disease.
Topics: Humans; Supranuclear Palsy, Progressive; Quality of Life; Parkinsonian Disorders; Parkinson Disease; Neurodegenerative Diseases; Cognitive Dysfunction
PubMed: 36862189
DOI: 10.1007/s00702-023-02613-w -
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 -
Brain and Nerve = Shinkei Kenkyu No... Apr 2019Xeroderma pigmentosum is a DNA repair disorder characterized by the occurrence of pigmented freckles and skin cancers on sun-exposed areas. Additionally, more than 50%...
Xeroderma pigmentosum is a DNA repair disorder characterized by the occurrence of pigmented freckles and skin cancers on sun-exposed areas. Additionally, more than 50% of patients present with progressive degenerative neurological symptoms. Eight clinical subtypes of this condition are known, and neurological symptoms can be seen in XP-A, B, D, F, G complementation groups.
Topics: DNA Repair; Humans; Pigmentation Disorders; Skin Diseases; Skin Neoplasms; Xeroderma Pigmentosum
PubMed: 30988228
DOI: 10.11477/mf.1416201283 -
Movement Disorders : Official Journal... Aug 2019Currently, few disease-modifying therapies exist for degenerative movement disorders. Antisense oligonucleotides are small DNA oligonucleotides, usually encompassing... (Review)
Review
Currently, few disease-modifying therapies exist for degenerative movement disorders. Antisense oligonucleotides are small DNA oligonucleotides, usually encompassing ∼20 base pairs, that can potentially target any messenger RNA of interest. Antisense oligonucleotides often contain modifications to the phosphate backbone, the sugar moiety, and the nucleotide base. The development of antisense oligonucleotide therapies spinal muscular atrophy and Duchenne muscular dystrophy suggest potentially wide-ranging therapeutic applications for antisense oligonucleotides in neurology. Successes with these two diseases have heightened interest in academia and the pharmaceutical industry to develop antisense oligonucleotides for several movement disorders, including, spinocerebellar ataxias, Huntington's disease, and Parkinson's disease. Compared to small molecules, antisense oligonucleotide-based therapies have an advantage because the target disease gene sequence is the immediate path to identifying the therapeutically effective complementary antisense oligonucleotide. In this review we describe the different types of antisense oligonucleotide chemistries and their potential use for the treatment of human movement disorders. © 2019 International Parkinson and Movement Disorder Society.
Topics: Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; Humans; Huntington Disease; Machado-Joseph Disease; Morpholinos; Movement Disorders; Oligonucleotides, Antisense; Parkinson Disease; Spinocerebellar Ataxias; tau Proteins
PubMed: 31283857
DOI: 10.1002/mds.27782