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Introduction: Causes of small-fiber peripheral neuropathies (SFN) are often undefined. In this study we investigated associations of serum autoantibodies, immunoglobulin G (IgG) vs fibroblast growth factor receptor-3 (FGFR-3), and immunoglobulin M (IgM) vs trisulfated heparan disaccharide (TS-HDS) in cryptogenic SFN.Methods: One hundred fifty-five patients with biopsy-proven SFN and no identified cause for their neuropathy were blindly tested for serum IgM vs TS-HDS and IgG vs FGFR-3.Results: Forty-eight percent of SFN patients had serum antibodies, 37% with IgM vs TS-HDS and 15% with IgG vs FGFR-3. TS-HDS antibodies were more frequent in SFN patients than in controls (P = .0012). Both antibodies were more common in females, and with non-length-dependent nerve pathology. Nintey-two percent of patients with acute-onset SFN had serum IgM vs TS-HDS.Discussion: Autoantibodies directed against TS-HDS and FGFR-3 suggest an immune disorder in otherwise idiopathic SFN. Serum IgM vs TS-HDS may be a marker for SFN with an acute onset. [ABSTRACT FROM AUTHOR]

Background: Dominant-intermediate Charcot-Marie-Tooth neuropathy subtype C (DI-CMTC) is associated with mutations in the YARS gene. The aim of this study is to investigate the long-term natural history of the disease.Methods: In a 5-generation DI-CMTC family, we compared data from 2016 to that of 2000 in 13 of 21 original participants.Results: Five women and 8 men were examined. While most symptoms and signs progressed, only gait progression was statistically significant (P = .016). The median CMT Neuropathy Score was 6.08 in 2000 and 11 in 2016 (P = .001). Quality of life (QOL) deteriorated in mobility (P = .008), pain/discomfort (P = .011), and anxiety/depression (P = .014). Median and ulnar compound muscle action potential amplitudes decreased from 9.35 ± 2.90 mV to 6.0 ± 2.9 mV (P = .002), and from 9.24 ± 2.10 mV to 6.06 ± 1.81 mV (P = .004), respectively, whereas motor nerve conduction velocities remained unchanged.Conclusions: DI-CMTC in this family is a slowly progressive disease with axonal degeneration, deteriorating mobility and QOL. [ABSTRACT FROM AUTHOR]

Background: Creutzfeldt--Jakob disease (CJD) is a rare, rapidly progressive neurodegenerative disease that almost always results in death in under a year from onset of symptoms. Here, we report four cases of CJD with different clinical presentations diagnosed at our institution over a 2-year period. Cases: The first patient is an 82-year-old woman who presented with depression, cognitive decline, and word-finding difficulty over 4 weeks. The patient deteriorated neurologically to akinetic mutism and death within 6 weeks of presentation. The second patient is a 54-year-old woman with liver cirrhosis who presented with confusion, ataxia, and multiple falls over 4 weeks. She was treated initially for hepatic encephalopathy but continued to progress to mutism, startle myoclonus, and obtundation. Death occurred within 4 weeks of presentation. The third patient is a 58-year-old woman who presented with an 8-week history of confusion, urinary incontinence, Parkinsonism, ataxia, and myoclonus. Death occurred within 2 months from presentation. The fourth patient is a 67-year-old man who presented with a 6-week history of headache, blurred vision, ataxia, and personality change and progressed to confusion, myoclonus, akinetic mutism, and obtundation. Death occurred within 3 weeks from presentation. Conclusion: These four cases highlight the varied possible clinical presentations of CJD and demonstrate the importance of considering CJD in patients with atypical presentations of rapidly progressive cognitive decline. To diagnose CJD, brain biopsy remains the gold standard. However, the presence of CSF protein 14-3-3, typical MRI findings and suggestive EEG abnormalities, all support the diagnosis. [ABSTRACT FROM AUTHOR]

Abstract: HIV-1 genomic RNA (gRNA) dimerization is important for viral infectivity and is regulated by proteolytic processing of the Gag precursor protein (Pr55gag) under the direction of the viral protease. The processing occurs in successive steps and, to date, the step associated with formation of a wild-type (WT) level of gRNA dimers has not been identified. The primary cleavage divides Pr55gag into two proteins. The C-terminal polypeptide is termed NCp15 (NCp7–p1–p6) because it contains the nucleocapsid protein (NC), a key determinant of gRNA dimerization and packaging. To examine the importance of precursor polypeptides NCp15 and NCp9 (NCp7–p1), we introduced mutations that prevented the proteolytic cleavages responsible for the appearance of NCp9 or NCp7. Using native Northern blot analysis, we show that gRNA dimerization was impaired when both the secondary (p1–p6) and tertiary (p7–p1) cleavage sites of NCp15 were abolished, but unaffected when only one or the other site was abolished. Though processing to NCp9 therefore suffices for a WT level of gRNA dimerization, we also show that preventing cleavage at the p7–p1 site abolished HIV-1 replication. To identify the minimum level of protease activity compatible with a WT level of gRNA dimers, we introduced mutations Thr26Ser and Ala28Ser in the viral protease to partially inactivate it, and we prepared composite HIV-1 resulting from the cotransfection of various ratios of WT and protease-inactive proviral DNAs. The results reveal that a 30% processing of Pr55gag into mature capsid proteins (CA/CA-p2) yielded a WT level of gRNA dimers, while a 10% Pr55gag processing hardly increased gRNA dimerization above the level seen in protease-inactive virions. We found that full gRNA dimerization required less than 50% WT NC in complementation asssays. Finally, we show that if we destroy alpha helix 1 of the capsid protein (CA), gRNA dimerization is impaired to the same extent as when the viral protease is inactivated. Cotransfection studies show that this CA mutation, in contrast to the NC-disabling mutations, has a dominant negative effect on HIV-1 RNA dimerization, viral core formation, and viral replication. This represents the first evidence that a capsid mutation can affect HIV-1 RNA dimerization. [Copyright &y& Elsevier]

Abstract: Retroviral genomic RNA (gRNA) dimerization appears essential for viral infectivity, and the nucleocapsid protein (NC) of human immunodeficiency virus type 1 (HIV-1) facilitates HIV-1 gRNA dimerization. To identify the relevant and dispensable positions of NC, 34 of its 55 residues were mutated, individually or in small groups, in a panel of 40 HIV-1 mutants prepared by site-directed mutagenesis. It was found that the amino-terminus, the proximal zinc finger, the linker, and the distal zinc finger of NC each contributed roughly equally to efficient HIV-1 gRNA dimerization. The N-terminal and linker segments appeared to play predominantly electrostatic and steric roles, respectively. Mutating the hydrophobic patch of either zinc finger, or substituting alanines for their glycine doublet, was as disabling as deleting the corresponding finger. Replacing the CysX2 CysX4 HisX4 Cys motif of either finger by CysX2 CysX4 CysX4 Cys or CysX2 CysX4 HisX4 His, interchanging the zinc fingers or, replacing one zinc finger by a copy of the other one, had generally intermediate effects; among these mutations, the His23→Cys substitution in the N-terminal zinc finger had the mildest effect. The charge of NC could be increased or decreased by up to 18%, that of the linker could be reduced by 75% or increased by 50%, and one or two electric charges could be added or subtracted from either zinc finger, without affecting gRNA dimerization. Shortening, lengthening, or making hydrophobic the linker was as disabling as deleting the N-terminal or the C-terminal zinc finger, but a neutral and polar linker was innocuous. The present work multiplies by 4 and by 33 the number of retroviral and lentiviral NC mutations known to inhibit gRNA dimerization, respectively. It shows the first evidence that gRNA dimerization can be inhibited by: 1) mutations in the N-terminus or the linker of retroviral NC; 2) mutations in the proximal zinc finger of lentiviral NC; 3) mutations in the hydrophobic patch or the conserved glycines of the proximal or the distal retroviral zinc finger. Some NC mutations impaired gRNA dimerization more than mutations inactivating the viral protease, indicating that gRNA dimerization may be stimulated by the NC component of the Gag polyprotein. Most, but not all, mutations inhibited gRNA packaging; some had a strong effect on virus assembly or stability. [Copyright &y& Elsevier]

The HIV-1 genome consists of two identical RNAs that are linked together through noncovalent interactions involving nucleotides from the 5′ untranslated region (5′ UTR) of each RNA strand. The 5′ UTR is the most conserved part of the HIV-1 RNA genome, and its 335 nucleotide residues form regulatory motifs that mediate multiple essential steps in the viral replication cycle. Here, studying the effect of selected mutations both singly and together with mutations disabling SL1 (SL1 is a 5′ UTR stem-loop containing a palindrome called the dimerization initiation site), we have done a rather systematic survey of the 5′ UTR requirements for full genomic RNA dimerization in grown-up (i.e., predominantly ≥10 h old) HIV-1 viruses produced by transfected human and simian cells. We have identified a role for the 5′ transactivation response element (5′ TAR) and a contribution of a long-distance base pairing between a sequence located at the beginning of the US region and nucleotides surrounding the AUG Gag initiation codon. The resulting intra- or intermolecular duplex is called the U5-AUG duplex. The other regions of the 5′ UTR have been shown to play no systematic role in genomic RNA dimerization, except for a sequence located around the 3′ end of a large stem-loop enclosing the primer binding site, and the well-documented SL1. Our data are consistent with a direct role for the 5′ TAR in genomic RNA dimerization (possibly via a palindrome encompassing the apical loop of the 5′ TAR). [ABSTRACT FROM AUTHOR]

Abstract: We have characterized the viral RNA conformation in wild-type, protease-inactive (PR–) and SL1-defective (ΔDIS) human immunodeficiency virus type 1 (HIV-1), as a function of the age of the viruses, from newly released to grown-up (≥24 h old). We report evidence for packaging HIV-1 genomic RNA (gRNA) in the form of monomers in PR– virions, viral RNA rearrangement (not maturation) within PR– HIV-1, protease-dependent formation of thermolabile dimeric viral RNAs, a new form of immature gRNA dimer at about 5 h post virion release, and slow-acting dimerization signals in SL1-defective viruses. The rates of gRNA dimer formation were ≥3-fold and ≥10-fold slower in ΔDIS and PR– viruses than in wild-type, respectively. Thus, the DIS, i.e. the palindrome in the apical loop of SL1, is a dimerization initiation signal, but its role can be masked by one or several slow-acting dimerization site(s) when grown-up SL1-inactive virions are investigated. Grown-up PR– virions are not flawless models for immature virions because gRNA dimerization increases with the age of PR– virions, indicating that the PR– mutation does not “freeze” gRNA conformation in a nascent primordial state. Our study is the first on gRNA conformation in newly released mutant or primate retroviruses. It shows for the first time that the packaged retroviral gRNA matures in more than one step, and that formation of immature dimeric viral RNA requires viral protein maturation. The monomeric viral RNAs isolated from budding HIV-1, as modeled by newly released PR– virions, may be seen as dimers that are much more fragile than thermolabile dimers. [Copyright &y& Elsevier]

Transverse myelitis (TM) is a frequently encountered inpatient neurological condition, usually with a broad differential of etiologies narrowed down by detailed history, temporal profile of symptom evolution, and pertinent diagnostic studies. We report a rare case of a 39-year-old man who presented with subacute onset of headaches and confusion, and three days later developed quadriplegia and areflexia. He was diagnosed with acute longitudinally extensive transverse myelitis (LETM) related to Epstein-Barr virus (EBV) superimposed on an initial presentation of streptococcal meningitis. As both etiologies are under-reported, we compare our case to the few similar cases in the literature to guide discussion of the clinical and radiologic findings of parainfectious TM related to EBV and streptococcal meningitis. Readers will have the challenge of attributing our patient's myelitis to one of these parainfectious sources and are encouraged to evaluate for rare infectious etiologies in acute settings., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Singh et al.)

Neuropsychiatric systemic lupus erythematosus (SLE) is a rare condition that has a multitude of mechanisms resulting in the emergence of variable clinical presentations. We describe a peculiar case of a 33-year-old female with a history of SLE presented with two weeks of fever, headache, and vomiting. On admission, she became obtunded and was emergently intubated. Initial lumbar puncture revealed pleocytosis (46% neutrophils, 320 corrected nucleated cells/μL), elevated protein (244 mg/dL; normal, 15-40 mg/dL), normal glucose (63 mg/dL), and negative cultures. Empiric acyclovir, ampicillin, ceftriaxone, and vancomycin were initiated without clinical improvement. Neurological examination was notable for limited ability to follow commands, vertical nystagmus, horizontal gaze palsy, diffuse hyperreflexia, and quadriparesis. Electroencephalogram (EEG) was consistent with diffuse encephalopathy. Brain magnetic resonance imaging demonstrated restricted diffusion and contrast enhancement in the posterior and central pons with edema. A cerebral angiogram showed no signs of vasculitis. Treatment with intravenous (IV) methylprednisolone 1 g and IV immunoglobulin 2 g/kg was initiated for five days. Despite these interventions, no discernible clinical improvement was observed, prompting the commencement of 500 mg/m 2  cyclophosphamide and daily maintenance of IV methylprednisolone at 2 mg/kg. A repeat MRI three weeks later revealed a marked reduction in the size of the lesion involving the pons. The patient also improved clinically over the month with successful extubation, complete return in mental capabilities, and the ability to ambulate short distances with assistance., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Polhemus et al.)