-
Acta Neuropathologica Aug 2023Hereditary spastic paraplegias (HSP) are rare, inherited neurodegenerative or neurodevelopmental disorders that mainly present with lower limb spasticity and muscle...
Hereditary spastic paraplegias (HSP) are rare, inherited neurodegenerative or neurodevelopmental disorders that mainly present with lower limb spasticity and muscle weakness due to motor neuron dysfunction. Whole genome sequencing identified bi-allelic truncating variants in AMFR, encoding a RING-H2 finger E3 ubiquitin ligase anchored at the membrane of the endoplasmic reticulum (ER), in two previously genetically unexplained HSP-affected siblings. Subsequently, international collaboration recognized additional HSP-affected individuals with similar bi-allelic truncating AMFR variants, resulting in a cohort of 20 individuals from 8 unrelated, consanguineous families. Variants segregated with a phenotype of mainly pure but also complex HSP consisting of global developmental delay, mild intellectual disability, motor dysfunction, and progressive spasticity. Patient-derived fibroblasts, neural stem cells (NSCs), and in vivo zebrafish modeling were used to investigate pathomechanisms, including initial preclinical therapy assessment. The absence of AMFR disturbs lipid homeostasis, causing lipid droplet accumulation in NSCs and patient-derived fibroblasts which is rescued upon AMFR re-expression. Electron microscopy indicates ER morphology alterations in the absence of AMFR. Similar findings are seen in amfra-/- zebrafish larvae, in addition to altered touch-evoked escape response and defects in motor neuron branching, phenocopying the HSP observed in patients. Interestingly, administration of FDA-approved statins improves touch-evoked escape response and motor neuron branching defects in amfra-/- zebrafish larvae, suggesting potential therapeutic implications. Our genetic and functional studies identify bi-allelic truncating variants in AMFR as a cause of a novel autosomal recessive HSP by altering lipid metabolism, which may potentially be therapeutically modulated using precision medicine with statins.
Topics: Animals; Humans; Spastic Paraplegia, Hereditary; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Zebrafish; Mutation; Motor Neurons; Receptors, Autocrine Motility Factor
PubMed: 37119330
DOI: 10.1007/s00401-023-02579-9 -
Journal of Lipids 2024Gangliosides, sialic acid-containing glycosphingolipids, are abundant in cell membranes and primarily involved in controlling cell signaling and cell communication. The... (Review)
Review
Gangliosides, sialic acid-containing glycosphingolipids, are abundant in cell membranes and primarily involved in controlling cell signaling and cell communication. The altered ganglioside pattern has been demonstrated in several neurodegenerative diseases, characterized during early-onset or infancy, emphasizing the significance of gangliosides in the brain. Enzymes required for the biosynthesis of gangliosides are linked to several devastating neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegia (HSP). In this review, we summarized not only the critical roles of biosynthetic enzymes and their inhibitors in ganglioside metabolism but also the efficacy of treatment strategies of ganglioside to address their significance in those diseases.
PubMed: 38623278
DOI: 10.1155/2024/4530255 -
Asian Journal of Surgery May 2024
PubMed: 38749834
DOI: 10.1016/j.asjsur.2024.05.034 -
Cureus Mar 2024Isolated spinal pachymeningitis is rarely encountered in clinical practice. Narrowing down the specific cause in individual patients is challenging as the possible...
Isolated spinal pachymeningitis is rarely encountered in clinical practice. Narrowing down the specific cause in individual patients is challenging as the possible etiologies are broad, there is substantial overlap in clinical presentation, and obtaining adequate data is complex, often affected by prior empiric treatments, including steroids. Here, we describe a rare patient with spinal pachymeningitis resulting in subacute to chronic progressive lower extremity weakness and eventually paraplegia. We discuss how we obtained the final diagnosis, provide our diagnostic framework, and offer practical advice in evaluating these patients.
PubMed: 38601395
DOI: 10.7759/cureus.55963 -
Journal of Neurology Oct 2023Tubulinopathies encompass neurodevelopmental disorders caused by mutations in genes encoding for different isotypes of α- and β-tubulins, the structural components of...
Tubulinopathies encompass neurodevelopmental disorders caused by mutations in genes encoding for different isotypes of α- and β-tubulins, the structural components of microtubules. Less frequently, mutations in tubulins may underlie neurodegenerative disorders. In the present study, we report two families, one with 11 affected individuals and the other with a single patient, carrying a novel, likely pathogenic, variant (p. Glu415Lys) in the TUBA4A gene (NM_006000). The phenotype, not previously described, is that of spastic ataxia. Our findings widen the phenotypic and genetic manifestations of TUBA4A variants and add a new type of spastic ataxia to be taken into consideration in the differential diagnosis.
Topics: Humans; Spinocerebellar Ataxias; Optic Atrophy; Muscle Spasticity; Intellectual Disability; Mutation; Phenotype; Spastic Paraplegia, Hereditary
PubMed: 37418012
DOI: 10.1007/s00415-023-11816-w -
Brain : a Journal of Neurology Oct 2023Hereditary spastic paraplegia is a neurological condition characterized by predominant axonal degeneration in long spinal tracts, leading to weakness and spasticity in...
Hereditary spastic paraplegia is a neurological condition characterized by predominant axonal degeneration in long spinal tracts, leading to weakness and spasticity in the lower limbs. The nicotinamide adenine dinucleotide (NAD+)-consuming enzyme SARM1 has emerged as a key executioner of axonal degeneration upon nerve transection and in some neuropathies. An increase in the nicotinamide mononucleotide/NAD+ ratio activates SARM1, causing catastrophic NAD+ depletion and axonal degeneration. However, the role of SARM1 in the pathogenesis of hereditary spastic paraplegia has not been investigated. Here, we report an enhanced mouse model for hereditary spastic paraplegia caused by mutations in SPG7. The eSpg7 knockout mouse carries a deletion in both Spg7 and Afg3l1, a redundant homologue expressed in mice but not in humans. The eSpg7 knockout mice recapitulate the phenotypic features of human patients, showing progressive symptoms of spastic-ataxia and degeneration of axons in the spinal cord as well as the cerebellum. We show that the lack of SPG7 rewires the mitochondrial proteome in both tissues, leading to an early onset decrease in mito-ribosomal subunits and a remodelling of mitochondrial solute carriers and transporters. To interrogate mechanisms leading to axonal degeneration in this mouse model, we explored the involvement of SARM1. Deletion of SARM1 delays the appearance of ataxic signs, rescues mitochondrial swelling and axonal degeneration of cerebellar granule cells and dampens neuroinflammation in the cerebellum. The loss of SARM1 also prevents endoplasmic reticulum abnormalities in long spinal cord axons, but does not halt the degeneration of these axons. Our data thus reveal a neuron-specific interplay between SARM1 and mitochondrial dysfunction caused by lack of SPG7 in hereditary spastic paraplegia.
Topics: Animals; Humans; Mice; Armadillo Domain Proteins; ATPases Associated with Diverse Cellular Activities; Axons; Cerebellum; Cytoskeletal Proteins; Metalloendopeptidases; NAD; Spastic Paraplegia, Hereditary
PubMed: 37086482
DOI: 10.1093/brain/awad136 -
World Neurosurgery Apr 2024Traumatic spinal cord injury (TSCI) is a debilitating neurological condition with significant long-term consequences on the mental health and well-being of affected... (Review)
Review
BACKGROUND
Traumatic spinal cord injury (TSCI) is a debilitating neurological condition with significant long-term consequences on the mental health and well-being of affected individuals. We aimed to investigate anxiety and depression in individuals with pediatric-onset TSCI.
METHODS
PubMed, Scopus, and Web of Science databases were searched from inception to December 20th, 2022 following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, and studies were included according to the eligibility criteria.
RESULTS
A total of 1013 articles were screened, and 18 studies with 4234 individuals were included in the final review. Of these, 1613 individuals (38.1%) had paraplegia, whereas 1658 (39.2%) had tetraplegia. A total of 1831 participants (43.2%) had complete TSCI, whereas 1024 (24.2%) had incomplete TSCI. The most common etiology of TSCI with 1545 people (36.5%) was motor vehicle accidents. The youngest mean age at the time of injury was 5.92 ± 4.92 years, whereas the oldest was 14.6 ± 2.8 years. Patient Health Questionnaire-9 was the most common psychological assessment used in 9 studies (50.0%). Various risk factors, including pain in 4 studies (22.2%), reduced sleep quality, reduced functional independence, illicit drug use, incomplete injury, hospitalization, reduced quality of life, and duration of injury in 2 (11.1%) studies, each, were associated with elevated anxiety and depression.
CONCLUSIONS
Different biopsychosocial risk factors contribute to elevated rates of anxiety and depression among individuals with pediatric-onset TSCI. Individuals at risk of developing anxiety and depression should be identified, and targeted support should be provided. Future large-scale studies with long-term follow-up are required to validate and extend these findings.
Topics: Child; Humans; Infant; Child, Preschool; Depression; Quality of Life; Spinal Cord Injuries; Paraplegia; Anxiety
PubMed: 38143027
DOI: 10.1016/j.wneu.2023.12.092 -
Revista Espanola de Anestesiologia Y... 2024Iatrogenic extradural pneumorrhachis is a rare clinical entity, but anesthesiologists should be aware of this possibility when using the air technique for the... (Review)
Review
Iatrogenic extradural pneumorrhachis is a rare clinical entity, but anesthesiologists should be aware of this possibility when using the air technique for the identification of epidural space. Although in most published cases extradural pneumorrhachis is asymptomatic, relevant neurological consequences have been described, such as meningeal irritation, radicular pain, unilateral lower extremity weakness, cauda equina syndrome, paraplegia, and tetraplegia.We describe a very extensive extradural pneumorrachis (T9-S1), related to obstetric analgesia, in a patient with severe and atypical perineal pain after forceps-assisted delivery. Our aim is to synthesize and organize the available scientific evidence, analyzing preventive measures and summarizing the most appropriate diagnostic, follow-up and therapeutic techniques for symptomatic conditions, among which high concentrations of inspired oxygen, hyperbaric oxygen therapy and percutaneous or surgical decompression have been described.
Topics: Humans; Female; Pregnancy; Pneumorrhachis; Analgesia, Obstetrical; Adult; Obstetrical Forceps; Thoracic Vertebrae; Magnetic Resonance Imaging; Epidural Space
PubMed: 37683975
DOI: 10.1016/j.redare.2023.09.009 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Dec 2023An 11-day-old female neonate was admitted for cough with mouth foaming and feeding difficulties. The laboratory results indicated hyperlactatemia, elevated markers of...
An 11-day-old female neonate was admitted for cough with mouth foaming and feeding difficulties. The laboratory results indicated hyperlactatemia, elevated markers of myocardial injury and inflammation, and high levels of acylcarnitine octanoylcarnitine and decanoylcarnitine in tandem mass spectrometry. Ultrasonography and MRI suggested cardiac insufficiency and hypertrophic cardiomyopathy. Whole exome sequencing showed that both the proband and her elderly sister had a compound heterozygous variant of c.1492dup (p.T498Nfs*13) and c.1376T>C (p.F459S) in the gene, inherited from their father and mother, respectively. The diagnosis of Harel-Yoon syndrome was confirmed. The proband and her sister were born with clinical manifestations of metabolic acidosis, hyperlactatemia, feeding difficulties, elevated markers of myocardial injury as well as cardiac insufficiency, and both died in early infancy.
Topics: Humans; Infant, Newborn; Female; Aged; Mutation; Hyperlactatemia; ATPases Associated with Diverse Cellular Activities; Membrane Proteins; Mitochondrial Proteins
PubMed: 38105692
DOI: 10.3724/zdxbyxb-2023-0421 -
Journal of Neurology Dec 2023Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders characterized by progressive pyramidal tract involvement. SPG76 is a recently identified form of...
BACKGROUND AND OBJECTIVES
Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders characterized by progressive pyramidal tract involvement. SPG76 is a recently identified form of HSP, caused by biallelic calpain-1 (CAPN1) variants. The most frequently described MRI abnormality in SPG76 is mild cerebellar atrophy and non-specific white matter abnormalities were reported in only one case. Following the identification of prominent white matter abnormalities in a subject with CAPN1 variants, which delayed the diagnosis, we aimed to verify the presence of MRI patterns of white matter involvement specific to this HSP.
METHODS
We performed a retrospective radiological qualitative analysis of 15 subjects with SPG76 (4 previously unreported) initially screened for white matter involvement. Moreover, we performed quantitative analyses in our proband with available longitudinal studies.
RESULTS
We observed bilateral, periventricular white matter involvement in 12 subjects (80%), associated with multifocal subcortical abnormalities in 5 of them (33.3%). Three subjects (20%) presented only multifocal subcortical involvement. Longitudinal quantitative analyses of our proband revealed increase in multifocal white matter lesion count and increased area of periventricular white matter involvement over time.
DISCUSSION
SPG76 should be added to the list of HSPs with associated white matter abnormalities. We identified periventricular white matter involvement in subjects with SPG76, variably associated with multifocal subcortical white matter abnormalities. These findings, in the presence of progressive spastic paraparesis, can mislead the diagnostic process towards an acquired white matter disorder.
Topics: Humans; White Matter; Retrospective Studies; Spastic Paraplegia, Hereditary; Magnetic Resonance Imaging; Paraparesis, Spastic
PubMed: 37578488
DOI: 10.1007/s00415-023-11918-5