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    Assessing diabetic polyneuropathy in Spanish‐speaking patients: Translation and validation of the Toronto Clinical Neuropathy Score
    (2023)
    IDIAQUEZ RIOS, JUAN FRANCISCO  
    ;
    Ignacio Acosta
    ;
    Alberto Prat
    ;
    Francesca Gattini
    ;
    Francisca Pino
    <jats:title>Abstract</jats:title><jats:sec><jats:title>Background and Aims</jats:title><jats:p>Diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes. The Toronto Clinical Neuropathy Score (TCNS) is a useful tool for detecting DSP. However, it is not available in Spanish. The study aimed to translate and culturally adapt the TCNS and modified (mTCNS) scales into Spanish and evaluate their measurement properties.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A multistep forward‐backward method was used for translation and cultural adaptation. A panel of physicians subjected the final Spanish versions of TCNS and mTCNS (TCÑS, mTCÑS) to cognitive debriefing. Consecutive patients with diabetes mellitus and DSP were recruited from an outpatient clinic, and the TCÑS and mTCÑS were tested for construct validity, along with other measures.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>The internal consistency of both TCÑS and mTCÑS was excellent, as evidenced by Cronbach's Alpha coefficients of 0.83 and 0.85, respectively. Furthermore, there was a robust positive correlation between TCÑS and mTCÑS. In addition, TCÑS was found to exhibit a strong negative correlation with sural sensory nerve action potential amplitude (<jats:italic>r</jats:italic> = −0.9206) and peroneal compound motor action potential amplitude (<jats:italic>r</jats:italic> = −0.729), while demonstrating a positive and strong correlation with the Michigan Neuropathy Screening Instrument (<jats:italic>r</jats:italic> = 0.713).</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>The TCÑS and mTCÑS are reliable and valid translations of the original TCNS. The TCÑS and mTCÑS can be used to diagnose and measure the severity of neuropathy in Spanish‐speaking patients with diabetes.</jats:p></jats:sec>
      9Scopus© Citations 2
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    Scopus© Citations 7  1
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    Analysing an allelic series of rare missense variants of <i>CACNA1I</i> in a Swedish schizophrenia cohort
    (2021)
    David Baez-Nieto
    ;
    Andrew Allen
    ;
    Seth Akers-Campbell
    ;
    Lingling Yang
    ;
    Nikita Budnik
    <jats:title>Abstract</jats:title> <jats:p>CACNA1I is implicated in the susceptibility to schizophrenia by large-scale genetic association studies of single nucleotide polymorphisms. However, the channelopathy of CACNA1I in schizophrenia is unknown. CACNA1I encodes CaV3.3, a neuronal voltage-gated calcium channel that underlies a subtype of T-type current that is important for neuronal excitability in the thalamic reticular nucleus and other regions of the brain. Here, we present an extensive functional characterization of 57 naturally occurring rare and common missense variants of CACNA1I derived from a Swedish schizophrenia cohort of more than 10 000 individuals. Our analysis of this allelic series of coding CACNA1I variants revealed that reduced CaV3.3 channel current density was the dominant phenotype associated with rare CACNA1I coding alleles derived from control subjects, whereas rare CACNA1I alleles from schizophrenia patients encoded CaV3.3 channels with altered responses to voltages. CACNA1I variants associated with altered current density primarily impact the ionic channel pore and those associated with altered responses to voltage impact the voltage-sensing domain. CaV3.3 variants associated with altered voltage dependence of the CaV3.3 channel and those associated with peak current density deficits were significantly segregated across affected and unaffected groups (Fisher’s exact test, P = 0.034). Our results, together with recent data from the SCHEMA (Schizophrenia Exome Sequencing Meta-Analysis) cohort, suggest that reduced CaV3.3 function may protect against schizophrenia risk in rare cases. We subsequently modelled the effect of the biophysical properties of CaV3.3 channel variants on thalamic reticular nucleus excitability and found that compared with common variants, ultrarare CaV3.3-coding variants derived from control subjects significantly decreased thalamic reticular nucleus excitability (P = 0.011). When all rare variants were analysed, there was a non-significant trend between variants that reduced thalamic reticular nucleus excitability and variants that either had no effect or increased thalamic reticular nucleus excitability across disease status. Taken together, the results of our functional analysis of an allelic series of &amp;gt;50 CACNA1I variants in a schizophrenia cohort reveal that loss of function of CaV3.3 is a molecular phenotype associated with reduced disease risk burden, and our approach may serve as a template strategy for channelopathies in polygenic disorders.</jats:p>
    Scopus© Citations 22  1
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      7Scopus© Citations 8