Browsing by Subject "NEUROPATHY"

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  • Rönkkö, Julius; Molchanova, Svetlana; Revah-Politi, Anya; Pereira, Elaine M.; Auranen, Mari; Toppila, Jussi; Kvist, Jouni; Ludwig, Anastasia; Neumann, Julika; Bultynck, Geert; Humblet-Baron, Stephanie; Liston, Adrian; Paetau, Anders; Rivera, Claudio; Harms, Matthew B.; Tyynismaa, Henna; Ylikallio, Emil (2020)
    Objective ITPR3, encoding inositol 1,4,5-trisphosphate receptor type 3, was previously reported as a potential candidate disease gene for Charcot-Marie-Tooth neuropathy. Here, we present genetic and functional evidence thatITPR3is a Charcot-Marie-Tooth disease gene. Methods Whole-exome sequencing of four affected individuals in an autosomal dominant family and one individual who was the only affected individual in his family was used to identify disease-causing variants. Skin fibroblasts from two individuals of the autosomal dominant family were analyzed functionally by western blotting, quantitative reverse transcription PCR, and Ca(2+)imaging. Results Affected individuals in the autosomal dominant family had onset of symmetrical neuropathy with demyelinating and secondary axonal features at around age 30, showing signs of gradual progression with severe distal leg weakness and hand involvement in the proband at age 64. Exome sequencing identified a heterozygousITPR3p.Val615Met variant segregating with the disease. The individual who was the only affected in his family had disease onset at age 4 with demyelinating neuropathy. His condition was progressive, leading to severe muscle atrophy below knees and atrophy of proximal leg and hand muscles by age 16. Trio exome sequencing identified ade novo ITPR3variant p.Arg2524Cys. Altered Ca2+-transients in p.Val615Met patient fibroblasts suggested that the variant has a dominant-negative effect on inositol 1,4,5-trisphosphate receptor type 3 function. Interpretation Together with two previously identified variants, our report adds further evidence thatITPR3is a disease-causing gene for CMT and indicates altered Ca(2+)homeostasis in disease pathogenesis.
  • Sainio, Markus T.; Aaltio, Juho; Hyttinen, Virva; Kortelainen, Mika; Ojanen, Simo; Paetau, Anders; Tienari, Pentti; Ylikallio, Emil; Auranen, Mari; Tyynismaa, Henna (2022)
    Objectives Clinical diagnostics in adults with hereditary neurological diseases is complicated by clinical and genetic heterogeneity, as well as lifestyle effects. Here, we evaluate the effectiveness of exome sequencing and clinical costs in our difficult-to-diagnose adult patient cohort. Additionally, we expand the phenotypic and genetic spectrum of hereditary neurological disorders in Finland. Methods We performed clinical exome sequencing (CES) to 100 adult patients from Finland with neurological symptoms of suspected genetic cause. The patients were classified as myopathy (n = 57), peripheral neuropathy (n = 16), ataxia (n = 15), spastic paraplegia (n = 4), Parkinsonism (n = 3), and mixed (n = 5). In addition, we gathered the costs of prior diagnostic work-up to retrospectively assess the cost-effectiveness of CES as a first-line diagnostic tool. Results The overall diagnostic yield of CES was 27%. Pathogenic variants were found for 14 patients (in genes ANO5, CHCHD10, CLCN1, DES, DOK7, FKBP14, POLG, PYROXD1, SCN4A, TUBB3, and TTN) and likely pathogenic previously undescribed variants for 13 patients (in genes ABCD1, AFG3L2, ATL1, CACNA1A, COL6A1, DYSF, IRF2BPL, KCNA1, MT-ATP6, SAMD9L, SGCB, and TPM2). Age of onset below 40 years increased the probability of finding a genetic cause. Our cost evaluation of prior diagnostic work-up suggested that early CES would be cost-effective in this patient group, in which diagnostic costs increase linearly with prolonged investigations. Conclusions Based on our results, CES is a cost-effective, powerful first-line diagnostic tool in establishing the molecular diagnosis in adult neurological patients with variable symptoms. Importantly, CES can markedly shorten the diagnostic odysseys of about one third of patients.
  • Laursen, J.C.; Hansen, C.S.; Bordino, M.; Vistisen, D.; Zobel, E.H.; Winther, S.A.; Groop, P-H.; Frimodt-Møller, M.; Bernardi, L.; Rossing, P. (2020)
    Abstract Aim Acute oxygen inhalation and slow deep breathing improve measures of autonomic function transiently in individuals with short-duration type 1 diabetes. Our aims were to examine these interventions and changes in autonomic function in individuals with long-duration type 1 diabetes and to explore interactions with the presence of macroalbuminuria or existing cardiovascular autonomic neuropathy. Methods Individuals with type 1 diabetes (n = 54) were exposed to acute oxygen inhalation, slow deep breathing and a combination of both (hereafter ?the combination?). Primary outcomes were change in baroreflex sensitivity and heart rate variability. Associations between changes in outcomes were evaluated using mixed effects models. Results Mean age ± sd was 60 ± 10 years and diabetes duration was 38 ± 14 years. Changes are presented as per cent difference from baseline with 95% confidence intervals. Acute oxygen inhalation, slow deep breathing and the combination increased baroreflex sensitivity by 21 (10, 34)%, 32 (13, 53)% and 30 (10, 54)%, respectively. Acute oxygen inhalation trended towards increasing heart rate variability 8 (?1, 17)% (P = 0.056), and slow deep breathing and the combination increased heart rate variability by 33 (18, 49)% and 44 (27, 64)% respectively. Macroalbuminuria or cardiovascular autonomic neuropathy did not modify results. Conclusion Autonomic function is improved transiently in individuals with long-duration type 1 diabetes and normoalbuminuria or macroalbuminuria by acute oxygen inhalation and slow deep breathing. There is a risk of survival bias. Autonomic dysfunction might be a reversible condition, and hypoxia might represent a target of intervention.
  • Laursen, Jens Christian; Clemmensen, Kim Katrine Bjerring; Hansen, Christian Stevns; Diaz, Lars Jorge; Bordino, Marco; Groop, Per-Henrik; Frimodt-Moller, Marie; Bernardi, Luciano; Rossing, Peter (2021)
    Introduction Blood oxygen saturation is low compared with healthy controls (CONS) in the supine body position in individuals with type 1 diabetes (T1D) and has been associated with complications. Since most of daily life occurs in the upright position, it is of interest if this also applies in the standing body position. In addition, tissue oxygenation in other anatomical sites could show different patterns in T1D. Therefore, we investigated blood, arm and forehead oxygen levels in the supine and standing body positions in individuals with T1D (n=129) and CONs (n=55). Research design and methods Blood oxygen saturation was measured with pulse oximetry. Arm and forehead mixed tissue oxygen levels were measured with near-infrared spectroscopy sensors applied on the skin. Results Data are presented as least squares means +/- SEM and differences (95% Cls). Overall blood oxygen saturation was lower in T1D (CON: 97.6%+/- 0.2%; T1D: 97.0%+/--0.1 degrees/0; difference: -0.5% (95% CI -0.9% to -0.0%); p=0.034). In all participants, blood oxygen saturation increased after standing up (supine: 97.1%-+/- 0.1%; standing: 97.6%+/- 0.2%; difference: +0.6% (95% Cl 0.4% to 0.8%); p Conclusion Compared with CON, individuals with T1D exhibit possible detrimental patterns of tissue oxygen adaptation to standing, with preserved adaptation of forehead oxygenation. Further studies are needed to explore the consequences of these differences.
  • Ivanova, Larisa; Tammiku-Taul, Jaana; Sidorova, Yulia; Saarma, Mart; Karelson, Mati (2018)
    To find out potential GDNF family receptor alpha 1 (GFR alpha 1) agonists, small molecules were built up by molecular fragments according to the structure-based drug design approach. Molecular docking was used to identify their binding modes to the biological target GFRa1 in GDNF-binding pocket. Thereafter, commercially available compounds based on the best predicted structures were searched from ZINC and MolPort databases (similarity >= 80%). Five compounds from the ZINC library were tested in phosphorylation and luciferase assays to study their ability to activate GFR alpha 1-RET. A bidental compound with two carboxyl groups showed the highest activity in molecular modeling and biological studies. However, the relative position of these groups was important. The meta-substituted structure otherwise identical to the most active compound 2-[4-(5-carboxy-1H-1,3-benzodiazol-2-yl) phenyl]-1H-1,3-benzodiazole-5-carboxylic acid was inactive. A weaker activity was detected for a compound with a single carboxyl group, that is, 4-(1,3-benzoxazol-2-yl) benzoic acid. The substitution of the carboxyl group by the amino or acetamido group also led to the loss of the activity.
  • Jmaeff, Sean; Sidorova, Yulia; Lippiatt, Hayley; Barcelona, Pablo F.; Nedev, Hinyu; Saragovi, Lucia M.; Hancock, Mark A.; Saarma, Mart; Saragovi, H. Uri (2020)
    Glial cell line-derived neurotrophic factor (GDNF) binds the GFR alpha 1 receptor, and the GDNF-GFR alpha 1 complex binds to and activates the transmembrane RET tyrosine kinase to signal through intracellular Akt/Erk pathways. To dissect the GDNF-GFR alpha 1-RET signaling complex, agents that bind and activate RET directly and independently of GFR alpha 1 expression are valuable tools. In a focused naphthalenesulfonic acid library from the National Cancer Institute database, we identified small molecules that are genuine ligands binding to the RET extracellular domain. These ligands activate RET tyrosine kinase and afford trophic signals irrespective of GFR alpha 1 coexpression. However, RET activation by these ligands is constrained by GFR alpha 1, likely via an allosteric mechanism that can be overcome by increasing RET ligand concentration. In a mouse model of retinitis pigmentosa, monotherapy with a small-molecule RET agonist activates survival signals and reduces neuronal death significantly better than GDNF, suggesting therapeutic potential. SIGNIFICANCE STATEMENT A genuine ligand of RET receptor ectodomain was identified, which acts as an agonist. Binding and agonism are independent of a coreceptor glial cell line-derived neurotrophic factor family receptor a, which is required by the natural growth factor glial cell line-derived neurotrophic factor, and are selective for cells expressing RET. The lead agent protects neurons from death in vivo. This work validates RET receptor as a druggable therapeutic target and provides for potential leads to evaluate in neurodegenerative states. We also report problems that arise when screening chemical libraries.
  • Hulkkonen, Sina; Auvinen, Juha; Miettunen, Jouko; Karppinen, Jaro; Ryhänen, Jorma (2019)
    Ulnar nerve entrapment is the second most common compression neuropathy of the upper extremity. It has been associated with smoking in cross-sectional studies. Our aim was to study whether smoking is associated with ulnar nerve entrapment. The study population consisted of the Northern Finland Birth Cohort 1966 participants, who attended the 31-year follow-up in 1997 (N = 8,716). Information on smoking, body mass index (BMI), long-term illnesses, and socio-economic status were recorded at baseline in 1997. Data on hospitalizations due to ulnar nerve entrapment neuropathies was obtained from the Care Register for Health Care, 1997-2016. Hazard ratios (HR) with 95% confidence intervals (CI) and population attributable risk (PAR) were calculated adjusted for gender, BMI and socio-economic status. 66 patients were diagnosed with ulnar nerve entrapment in the follow-up 1997-2016. Before the age of 31 years, smoking 10 pack years with more than five-folded (HR = 5.61, 95% CI = 2.80-11.23) risk for ulnar nerve entrapment compared to non-smokers in the adjusted analyses. Adjusted PAR for smoking (reference of no smoking) was 53.6%. In our study, smoking associated with increased risk for ulnar nerve entrapment, accounting for considerable proportion of increased risk.
  • Esposito, Pasquale; Mereu, Roberto; De Barbieri, Giacomo; Rampino, Teresa; Di Toro, Alessandro; Groop, Per-Henrik; Dal Canton, Antonio; Bernardi, Luciano (2016)
    Cardiovascular autonomic dysfunction, evaluated as baroreflex sensitivity (BRS), could be acutely corrected by slow breathing or oxygen administration in patients with type 1 diabetes, thus suggesting a functional component of the disorder. We tested this hypothesis in patients with the type 2 diabetes with or without renal impairment. Twenty-six patients with type 2 diabetes (aged 61.0 +/- A 0.8 years, mean +/- A SEM; duration of diabetes 10.5 +/- A 2 years, BMI 29.9 +/- A 0.7 kg/m(2), GFR 68.1 +/- A 5.6 ml/min) and 24 healthy controls (aged 58.5 +/- A 1.0 years) were studied. BRS was obtained from recordings of RR interval and systolic blood pressure fluctuations during spontaneous and during slow, deep (6 breaths/min) controlled breathing in conditions of normoxia or hyperoxia (5 l/min oxygen). During spontaneous breathing, diabetic patients had lower RR interval and lower BRS compared with the control subjects (7.1 +/- A 1.2 vs. 12.6 +/- A 2.0 ms/mmHg, p <0.025). Deep breathing and oxygen administration significantly increased arterial saturation, reduced RR interval and increased BRS in both groups (to 9.6 +/- A 1.8 and 15.4 +/- A 2.4 ms/mmHg, respectively, p <0.05, hyperoxia vs. normoxia). Twelve diabetic patients affected by chronic diabetic kidney disease (DKD) presented a significant improvement in the BRS during slow breathing and hyperoxia (p <0.025 vs. spontaneous breathing during normoxia). Autonomic dysfunction present in patients with type 2 diabetes can be partially reversed by slow breathing, suggesting a functional role of hypoxia, also in patients with DKD. Interventions known to relieve tissue hypoxia and improve autonomic function, like physical activity, may be useful in the prevention and management of complications in patients with diabetes.
  • Miettinen, Laura; Ryhänen, Jorma; Shiri, Rahman; Karppinen, Jaro; Miettunen, Jouko; Auvinen, Juha; Hulkkonen, Sina (2021)
    Ulnar nerve entrapment (UNE) is the second most common entrapment neuropathy in the upper extremity. The aetiology of UNE is multifactorial and is still not fully understood. The aim of the study was to identify occupational risk factors for UNE and to determine whether smoking modifies the effects of work-related factors on UNE. The study population consisted of the Northern Finland Birth Cohort of 1966 (NFBC1966). In total, 6325 individuals active in working life participated at baseline in 1997. Occupational risk factors were evaluated by a questionnaire at baseline. The data on hospitalizations due to UNE were obtained from the Care Register for Health Care between 1997 and 2018. The incidence rate of hospitalization due to UNE was 47.6 cases per 100,000 person-years. After adjusting for confounders, entrepreneurs (Hazard ratio (HR)=3.68, 95% CI 1.20-11.27), smokers (HR=2.51, 95% CI 1.43-4.41), workers exposed to temperature changes (HR=1.72, 95% CI 1.00-2.93), workers with physically demanding jobs (HR=3.02, 95% CI 1.39-6.58), and workers exposed to hand vibration (HR=1.94, 95% CI 1.00-3.77) were at an increased risk of hospitalization for UNE. Exposure to work requiring arm elevation increased the risk of hospitalization due to UNE among smokers (HR=2.62, 95% CI 1.13-6.07), but not among non-smokers. Work-related exposure to vibration and temperature changes, and physically demanding work increase the risk of hospitalization for UNE. Smoking may potentiate the adverse effects of work-related factors on UNE.