RESUMEN
Extracellular vesicles (EVs), exhibiting their functional activity after internalization by recipient cells, are involved in the pathogenesis of drug-induced polyneuropathy (DIPN), a common complication of antitumor therapy. In this work, the internalization of EVs obtained from colorectal cancer patients undergoing polychemotherapy and its relationship with neurotoxicity were assessed using a model system of mononuclear leukocytes. Circulating EVs were isolated from 8 colorectal cancer patients who received antitumor therapy according to the FOLFOX or XELOX regimens before the start of chemotherapy (point 1) and after 3-4 courses (point 2). Mononuclear leukocytes of a healthy donor served as a cellular model system for EV internalization in vitro. EV internalization was assessed using fluorescence microscopy. It was shown that internalization of EVs obtained from colorectal cancer patients with high neurotoxicity was higher than in the group with low neurotoxicity. The ability of CD11b-positive (CD11bâº) and CD11b-negative (CD11bâ») mononuclear leukocytes of a healthy donor to internalize EVs obtained from patients before and after chemotherapy did not reveal significant differences. A direct relationship was found between the relative number of CD11bâ» cells with internalized EVs and the integral index of neurotoxicity according to the NRS scale at the peak of its manifestation (point 2) (r=0.675, p.
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Protocolos de Quimioterapia Combinada Antineoplásica , Vesículas Extracelulares , Leucocitos Mononucleares , Humanos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/efectos de los fármacos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Fluorouracilo/efectos adversos , Fluorouracilo/farmacología , Capecitabina/efectos adversos , Capecitabina/farmacología , Antígeno CD11b/metabolismo , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/farmacología , Leucovorina/farmacología , Oxaloacetatos , Adulto , Polineuropatías/inducido químicamente , Polineuropatías/metabolismo , Polineuropatías/patologíaAsunto(s)
Antibacterianos , Humanos , Antibacterianos/efectos adversos , Fluoroquinolonas/efectos adversos , Polineuropatías/inducido químicamente , Masculino , Enfermedades Desmielinizantes/inducido químicamente , Femenino , Persona de Mediana Edad , Anciano , Conducción Nerviosa/efectos de los fármacosRESUMEN
INTRODUCTION: The revised international standards for neurological classification of spinal cord injury (ISNCSCI) have facilitated the documentation of non-spinal cord injury-related impairments, such as chronic peripheral nerve injuries and muscle weakness due to immobility. This advancement addresses potential biases in muscle strength examinations. Utilizing electrically evoked contractions from paralyzed muscles, enhanced by electrodiagnosis, holds promise in identifying false-negative diagnoses of non-responsiveness to neuromuscular electrical stimulation. This concept prompts the exploration of polyneuromyopathy arising from nonuse in paralyzed muscles. CASE SERIES PRESENTATION: To substantiate our hypothesis, we recruited nine participants for a case series aimed at elucidating the potential benefits of incorporating the stimulus electrodiagnostic test (SET) to mitigate non-responsiveness during preparation for functional electrical stimulation (FES)-assisted cycling. In our convenience sample (n = 5), we conducted neurological mapping based on ISNCSCI and applied SET on the quadriceps. The SET guided optimal dosimetry for evoking contractions and revealed responses similar to those observed in peripheral neuropathies, with α coefficients equal to or lower than 2.00. This observation is likely attributable to nonuse of paralyzed muscles, indicative of an ongoing polyneuropathy in individuals with chronic spinal cord injury (SCI). DISCUSSION: Among the nine initially recruited subjects, seven exhibited responsiveness to neuromuscular electrical stimulation (78% responsiveness), with two participants excluded based on exclusion criteria. In the final five reported cases, all displayed α coefficient values indicating impaired neuromuscular accommodation, and one presented no α coefficient within the normal range. The inclusion of electrodiagnosis appears effective in averting non-responsiveness, suggesting the presence of ongoing polyneuropathies in paralyzed muscles.
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Electrodiagnóstico , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Polineuropatías/diagnóstico , Estimulación Eléctrica , Traumatismos de la Médula Espinal/diagnóstico , Traumatismos de la Médula Espinal/rehabilitación , Traumatismos de la Médula Espinal/complicaciones , Electromiografía , Contracción Muscular/fisiología , Debilidad Muscular/diagnóstico , Anciano , Músculo EsqueléticoRESUMEN
BACKGROUND: A comprehensive understanding of the genetic basis of rare diseases and their regulatory mechanisms is essential for human molecular genetics. However, the genetic mutant spectrum of pathogenic genes within the Chinese population remains underrepresented. Here, we reported previously unreported functional ABHD12 variants in two Chinese families and explored the correlation between genetic polymorphisms and phenotypes linked to PHARC syndrome. METHODS: Participants with biallelic pathogenic ABHD12 variants were recruited from the Chinese Deafness Genetics Cohort. These participants underwent whole-genome sequencing. Subsequently, a comprehensive literature review was conducted. RESULTS: Two Han Chinese families were identified, one with a compound heterozygous variant and the other with a novel homozygous variant in ABHD12. Among 65 PHARC patients, including 62 from the literature and 3 from this study, approximately 90% (57 out of 63) exhibited hearing loss, 82% (50 out of 61) had cataracts, 82% (46 out of 56) presented with retinitis pigmentosa, 79% (42 out of 53) experienced polyneuropathy, and 63% (36 out of 57) displayed ataxia. Seventeen different patterns were observed in the five main phenotypes of PHARC syndrome. A total of 33 pathogenic variants were identified in the ABHD12. Compared with other genotypes, individuals with biallelic truncating variants showed a higher incidence of polyneuropathy (p = 0.006), but no statistically significant differences were observed in the incidence of hearing loss, ataxia, retinitis pigmentosa and cataracts. CONCLUSIONS: The diagnosis of PHARC syndrome is challenging because of its genetic heterogeneity. Therefore, exploring novel variants and establishing genotype-phenotype correlations can significantly enhance gene diagnosis and genetic counseling for this complex disease.
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Ataxia , Catarata , Estudios de Asociación Genética , Monoacilglicerol Lipasas , Linaje , Fenotipo , Polineuropatías , Retinitis Pigmentosa , Humanos , Masculino , Femenino , Ataxia/genética , Catarata/genética , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/patología , Polineuropatías/genética , Monoacilglicerol Lipasas/genética , Mutación , Adulto , Niño , Adolescente , GenotipoRESUMEN
OBJECTIVE: Multifocal motor neuropathy is a rare chronic immune-mediated neuropathy with impaired grip strength representing a common symptom. While intravenous immunoglobulin G is an effective treatment for the disease, significant variation in treatment response has been observed but not well understood. This analysis characterized dose-exposure-response relationships in multifocal motor neuropathy, using grip strength as a clinical efficacy measure. METHODS: Serum immunoglobulin G trough concentrations and grip strength data for the more affected hand from a Phase 3, randomized, double-blind, placebo-controlled, crossover trial of intravenous immunoglobulin 10% in 44 patients with multifocal motor neuropathy (NCT00666263) were used to develop a population pharmacokinetic-pharmacodynamic model. RESULTS: The model adequately described the observed pharmacokinetic and pharmacodynamic data and relationships between intravenous immunoglobulin 10% dose, serum immunoglobulin G trough levels, grip strength, and inter-patient variabilities in multifocal motor neuropathy. Model-based simulations for various dosing regimens (0.4-2.0 g/kg every 2-4 weeks) indicated that ≥1.6 g/kg/month would achieve clinically meaningful improvements in grip strength (≥4 kg) in ≥70% of patients. More frequent dosing at an equivalent monthly dose led to a more consistent response in grip strength. Furthermore, splitting the dose over multiple days for high doses (>1 g/kg) did not impact grip strength. INTERPRETATION: These findings suggest that the majority of patients with multifocal motor neuropathy would respond rapidly to intravenous immunoglobulin 10% with a range of dosing regimens. Shorter dosing intervals may avoid the diminishing response seen with longer dosing intervals. Dose-splitting provided similar outcomes while offering flexibility and convenience.
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Estudios Cruzados , Fuerza de la Mano , Inmunoglobulinas Intravenosas , Humanos , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/farmacología , Método Doble Ciego , Persona de Mediana Edad , Masculino , Femenino , Adulto , Anciano , Polineuropatías/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/farmacología , Factores Inmunológicos/farmacocinéticaRESUMEN
BACKGROUND: Oxidative stress is a risk factor for distal sensorimotor polyneuropathy (DSPN). Selenoprotein P is a protein with antioxidant properties but has not been investigated in the context of DSPN. This study aimed to assess the associations between selenoprotein P and DSPN in people without and with type 2 diabetes (T2D). METHODS: Cross-sectional and prospective analyses were based on 1053 (including 217 with T2D) and 513 participants (including 79 with T2D), respectively, aged 61-82 years from the population-based KORA F4 survey. DSPN at baseline (KORA F4) and in the follow-up survey KORA FF4 was defined based on the Michigan Neuropathy Screening Instrument. Serum levels of full-length selenoprotein P were quantified by ELISA. Associations between selenoprotein P and prevalent or incident DSPN were estimated using logistic regression analysis adjusting for multiple confounders. RESULTS: Selenoprotein P levels were not associated with prevalent DSPN in the total sample. However, there was a significant interaction by diabetes status. Higher levels of selenoprotein P were associated with lower odds of prevalent DSPN in individuals without T2D (fully adjusted model: OR 0.825 [95 % CI 0.682, 0.998], p = 0.0476), but not in those with T2D (OR [95 % CI] 1.098 [0.829, 1.454], p = 0.5132; pinteraction = 0.0488). Selenoprotein P levels were not associated with incident DSPN over a follow-up of 6.5 years. CONCLUSION: In individuals without T2D from the older general population, lower selenoprotein P levels were associated with a higher prevalence of DSPN. Whether the antioxidant properties of selenoprotein P are responsible for the observed associations remains to be elucidated in future research.
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Diabetes Mellitus Tipo 2 , Selenoproteína P , Humanos , Selenoproteína P/sangre , Masculino , Anciano , Femenino , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/epidemiología , Estudios Transversales , Estudios Prospectivos , Anciano de 80 o más Años , Estrés Oxidativo , Factores de Riesgo , Polineuropatías/epidemiología , Polineuropatías/sangre , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/etiología , PrevalenciaRESUMEN
BACKGROUND: Increasing evidence indicates a higher prevalence of polyneuropathy (PNP) in Parkinson's disease (PD). However, the involvement of large fiber neuropathy in PD still remains poorly understood. Given the lack of longitudinal data, we investigated the course of PNP associated with PD. METHODS: In total, 41 PD patients underwent comprehensive clinical evaluation including motor and non-motor assessments as well as nerve conduction studies at baseline and at 2 years of follow-up. The definition of PNP was based on electrophysiological standard criteria. Common causes of PNP were excluded. RESULTS: At baseline, PNP was diagnosed in 65.85% of PD patients via electroneurography. Patients with PNP presented with higher age (p = 0.019) and PD motor symptom severity (UPDRS III; p < 0.001). Over the course of 2 years, PNP deteriorated in 21.95% of cases, and 26.83% remained without PNP. Deterioration of nerve amplitude was most prevalent in the median sensory nerve affecting 57.58% of all PD cases with an overall reduction of median sensory nerve amplitude of 45.0%. With regard to PD phenotype, PNP progression was observed in 33.33% of the tremor dominant and 23.81% of the postural instability/gait difficulties subtype. Decrease of sural nerve amplitude correlated with lower quality of life (PDQ-39, p = 0.037) and worse cognitive status at baseline (MoCA, p = 0.042). CONCLUSION: The study confirms the high PNP rate in PD, and demonstrates a significant electrophysiological progression also involving nerves of the upper extremities. Longitudinal studies with larger cohorts are urgently needed and should elucidate the link between PD and PNP with the underlying pathomechanisms.
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Progresión de la Enfermedad , Conducción Nerviosa , Enfermedad de Parkinson , Polineuropatías , Humanos , Masculino , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/fisiopatología , Femenino , Anciano , Polineuropatías/fisiopatología , Polineuropatías/diagnóstico , Polineuropatías/etiología , Polineuropatías/epidemiología , Persona de Mediana Edad , Estudios Longitudinales , Conducción Nerviosa/fisiología , Índice de Severidad de la EnfermedadRESUMEN
Contactin-associated protein 1 (Caspr1) is widespread in both the peripheral and central nervous systems (CNS). However, anti-Caspr1 antibody-positive nodopathy associated with CNS symptoms has not previously been reported. In this case, a 69-year-old man presented with polyneuropathy and memory loss. The patient had negative myoclonus, positive myoclonus, and pseudoathetosis in the upper limbs, and we detected anti-Caspr1 antibodies in the serum and cerebrospinal fluid. Therefore, anti-Caspr1 nodopathy was diagnosed. After rituximab treatment, all symptoms of polyneuropathy, involuntary movements, and memory impairment improved. In conclusion, anti-Caspr1 antibodies might also affect the CNS; therefore, CNS symptoms of anti-Caspr1 nodopathy require attention.
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Autoanticuerpos , Humanos , Masculino , Anciano , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Autoanticuerpos/inmunología , Moléculas de Adhesión Celular Neuronal/inmunología , Polineuropatías/inmunología , Polineuropatías/sangre , Polineuropatías/tratamiento farmacológicoRESUMEN
The study aimed to show the potential clinical application of supplements used among sportsmen for patients suffering from Intensive Care Unit-acquired Weakness (ICUAW) treatment. ICUAW is a common complication affecting approximately 40% of critically ill patients, often leading to long-term functional disability. ICUAW comprises critical illness polyneuropathy, critical illness myopathy, or a combination of both, such as critical illness polyneuromyopathy. Muscle degeneration begins shortly after the initiation of mechanical ventilation and persists post-ICU discharge until proteolysis and autophagy processes normalize. Several factors, including prolonged bedrest and muscle electrical silencing, contribute to muscle weakness, resulting from an imbalance between protein degradation and synthesis. ICUAW is associated with tissue hypoxia, oxidative stress, insulin resistance, reduced glucose uptake, lower adenosine triphosphate (ATP) formation, mitochondrial dysfunction, and increased free-radical production. Several well-studied dietary supplements and pharmaceuticals commonly used by athletes are proven to prevent the aforementioned mechanisms or aid in muscle building, regeneration, and maintenance. While there is no standardized treatment to prevent the occurrence of ICUAW, nutritional interventions have demonstrated the potential for its mitigation. The use of ergogenic substances, popular among muscle-building sociates, may offer potential benefits in preventing muscle loss and aiding recovery based on their work mechanisms.
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Enfermedad Crítica , Suplementos Dietéticos , Unidades de Cuidados Intensivos , Debilidad Muscular , Humanos , Enfermedad Crítica/terapia , Anabolizantes/uso terapéutico , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Polineuropatías/tratamiento farmacológicoRESUMEN
Immune checkpoint inhibitors (ICIs) have significantly improved the clinical outcome in multiple types of advanced or metastatic malignancies and are prescribed increasingly. However, immune-related adverse events (irAEs) occur frequently. Here, we present a patient with multifocal motor neuropathy and melanoma, with worsening of muscle weakness upon ICI therapy and concomitant use of steroids for the treatment of hepatitis, which was considered an irAE. Upon treatment with highly dosed immunoglobulins and steroid tapering, the patients' muscular symptoms improved while hepatitis resolved. This case highlights the importance of careful evaluation of patients with multifocal motor neuropathy treated with ICIs, highlights the risks of treatment with steroids in multifocal motor neuropathy patients and suggests an alternative treatment of irAEs with intravenous immunoglobulins.
[Box: see text].
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Inhibidores de Puntos de Control Inmunológico , Melanoma , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/inmunología , Masculino , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunoglobulinas Intravenosas/efectos adversos , Persona de Mediana Edad , Polineuropatías/inducido químicamente , FemeninoRESUMEN
BACKGROUND AND PURPOSE: Hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTRv-PN [v for variant]) is a rare, progressive disease associated with multisystemic impairments. This study assessed the real-world outcomes of patients with ATTRv-PN who switched from tafamidis to patisiran, as well as the reasons for the treatment switch. METHODS: This was a retrospective chart review study at a large expert referral center. Data were extracted from medical charts of patients with ATTRv-PN who switched from tafamidis to patisiran on or before 30 August 2019. Data elements included demographic and clinical characteristics, rationale for switch, and disease measures evaluated from tafamidis initiation through the 12-month patisiran treatment period. RESULTS: Among the 24 patients with ATTRv-PN included in the study, 50.0% had a V30M variant, and the mean (SD) age was 67.3 (8.0) years. During tafamidis treatment (mean [SD] = 30.1 [17.5] months) before switching to patisiran, patients worsened across multiple polyneuropathy measures, including walking ability, Neuropathy Impairment Score, and autonomic function. Neuropathic disease progression on tafamidis was the principal reason for switching to patisiran. After 12 months on patisiran (mean [SD] = 11.7 [1.4] months), patients experienced attenuated disease progression or improvement in the aforementioned measures of polyneuropathy. CONCLUSIONS: Switching from tafamidis to patisiran attenuated the rate of functional decline, and most patients experienced stabilization or improvement of at least one polyneuropathy measure within 12 months of patisiran treatment. Timely switch from tafamidis to patisiran can be beneficial to avoid rapid disease progression in patients with ATTRv-PN.
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Neuropatías Amiloides Familiares , Benzoxazoles , Polineuropatías , Humanos , Neuropatías Amiloides Familiares/tratamiento farmacológico , Neuropatías Amiloides Familiares/complicaciones , Masculino , Femenino , Anciano , Persona de Mediana Edad , Estudios Retrospectivos , Benzoxazoles/uso terapéutico , Polineuropatías/tratamiento farmacológico , Sustitución de Medicamentos , Resultado del Tratamiento , ARN Interferente PequeñoAsunto(s)
Edema , Trombocitosis , Humanos , Masculino , Edema/etiología , Trombocitosis/etiología , Trombocitosis/complicaciones , Cianosis/etiología , Paraproteinemias/complicaciones , Paraproteinemias/diagnóstico , Polineuropatías/diagnóstico , Polineuropatías/etiología , Persona de Mediana Edad , AncianoRESUMEN
AIMS: The aim of this study was to assess associations between neurological biomarkers and distal sensorimotor polyneuropathy (DSPN). MATERIALS AND METHODS: Cross-sectional analyses were based on 1032 participants aged 61-82 years from the population-based KORA F4 survey, 177 of whom had DSPN at baseline. The prevalence of type 2 diabetes was 20%. Prospective analyses used data from 505 participants without DSPN at baseline, of whom 125 had developed DSPN until the KORA FF4 survey. DSPN was defined based on the examination part of the Michigan Neuropathy Screening Instrument. Serum levels of neurological biomarkers were measured using proximity extension assay technology. Associations between 88 biomarkers and prevalent or incident DSPN were estimated using Poisson regression with robust error variance and are expressed as risk ratios (RR) and 95% CI per 1-SD increase. Results were adjusted for multiple confounders and multiple testing using the Benjamini-Hochberg procedure. RESULTS: Higher serum levels of CTSC (cathepsin C; RR [95% CI] 1.23 (1.08; 1.39), pB-H = 0.044) and PDGFRα (platelet-derived growth factor receptor A; RR [95% CI] 1.21 (1.08; 1.35), pB-H = 0.044) were associated with prevalent DSPN in the total study sample. CDH3, JAM-B, LAYN, RGMA and SCARA5 were positively associated with DSPN in the diabetes subgroup, whereas GCP5 was positively associated with DSPN in people without diabetes (all pB-H for interaction <0.05). None of the biomarkers showed an association with incident DSPN (all pB-H>0.05). CONCLUSIONS: This study identified multiple novel associations between neurological biomarkers and prevalent DSPN, which may be attributable to functions of these proteins in neuroinflammation, neural development and myelination.
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Biomarcadores , Humanos , Biomarcadores/sangre , Masculino , Femenino , Anciano , Estudios Transversales , Persona de Mediana Edad , Estudios Prospectivos , Anciano de 80 o más Años , Polineuropatías/sangre , Polineuropatías/epidemiología , Polineuropatías/diagnóstico , Polineuropatías/etiología , Estudios de Seguimiento , Neuropatías Diabéticas/epidemiología , Neuropatías Diabéticas/sangre , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/etiología , Pronóstico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/sangre , PrevalenciaRESUMEN
Creatine kinase (CK) has been associated with neuropathy, but the mechanisms are uncertain. We hypothesized that peripheral nerve function is impaired in subjects with persistent CK elevation (hyperCKemia) compared to age- and sex matched controls in a general population. The participants were recruited from the population based Tromsø study in Norway. Neuropathy impairment score (NIS), nerve conduction studies (NCS) and electromyography (EMG) in subjects with persistent hyperCKemia (n = 113; 51 men, 62 women) and controls (n = 128; 61 men, 67 women) were performed. The hyperCKemia group had higher NIS score than the controls (p = 0.050). NCS of the tibial nerve showed decreased compound motor action potential amplitude (p < 0.001), decreased motor conduction velocity (p < 0.001) and increased F-wave latency (p = 0.044). Also, reduced sensory amplitudes of the median, ulnar, and sural nerves were found. EMG showed significantly increased average motor unit potential amplitude in all examined muscles. CK correlated positively with glycated hemoglobin and non-fasting glucose in the hyperCKemia group, although not when controlled for covariates. The length dependent polyneuropathy demonstrated in the hyperCKemia group is unexplained, but CK leakage and involvement of glucose metabolism are speculated on.
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Creatina Quinasa , Electromiografía , Conducción Nerviosa , Polineuropatías , Humanos , Masculino , Femenino , Creatina Quinasa/sangre , Polineuropatías/sangre , Estudios de Casos y Controles , Anciano , Persona de Mediana Edad , NoruegaRESUMEN
Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy (FAP)) is an endemic amyloidosis involving the harmful aggregation of proteins, most commonly transthyretin (TTR) but sometimes also apolipoprotein A-1 or gelsolin. hATTR appears to be transmitted as an autosomal dominant trait. Over 100 point mutations have been identified, with the Val30Met substitution being the most common. Yet, the mechanism of pathogenesis and the overall origin of hATTR remain unclear. Here, we argue that hATTR could be related to harmful metal exposure. hATTR incidence is unevenly distributed globally, and the three largest defined clusters exist in Japan, Portugal, and Sweden. All three disease regions are also ancient mining districts with associated metal contamination of the local environment. There are two main mechanisms for how harmful metals, after uptake into tissues and body fluids, could induce hATTR. First, the metals could directly influence the expression, function, and/or aggregation of the proteins involved in hATTR pathology. Such metal-protein interactions might constitute molecular targets for anti-hATTR drug design. Second, metal exposure could induce hATTR -associated genetic mutations, which may have happened several generations ago. These two mechanisms can occur in parallel. In conclusion, the possibility that hATTR could be related to metal exposure in geochemically defined regions deserves further attention.
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Neuropatías Amiloides Familiares , Prealbúmina , Humanos , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/epidemiología , Prealbúmina/genética , Prealbúmina/metabolismo , Minería , Polineuropatías/genética , Polineuropatías/epidemiología , Polineuropatías/etiología , Portugal/epidemiologíaRESUMEN
Retinitis pigmentosa (RP) is an inherited retinal dystrophy caused by the loss of photoreceptors and retinal pigment epithelial atrophy, leading to severe visual impairment or blindness. RP can be classified as nonsyndromic or syndromic with complex clinical phenotypes. Three unrelated Polish probands affected with retinitis pigmentosa coexisting with cerebellar ataxia were recruited for this study. Clinical heterogeneity and delayed appearance of typical disease symptoms significantly prolonged the patients' diagnostic process. Therefore, many clinical and genetic tests have been performed in the past. Here, we provide detailed clinical and genetic analysis results of the patients. Whole-exome sequencing (WES) and targeted NGS analysis allow the identification of four novel and two previously reported variants in the following genes: ABHD12, FLVCR1, and PNPLA6. The use of next-generation sequencing (NGS) methods finally allowed for confirmation of the clinical diagnosis. Ultra-rare diseases such as PHARC, PCARP, and Oliver-McFarlane syndromes were diagnosed in patients, respectively. Our findings confirmed the importance of the application of next-generation sequencing methods, especially in ultra-rare genetic disorders with overlapping features.
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Secuenciación del Exoma , Retinitis Pigmentosa , Humanos , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/diagnóstico , Masculino , Femenino , Linaje , Secuenciación de Nucleótidos de Alto Rendimiento , Adulto , Ataxia Cerebelosa/genética , Ataxia Cerebelosa/diagnóstico , Proteínas de Transporte de Membrana/genética , Monoacilglicerol Lipasas/genética , Mutación , Ataxia/genética , Ataxia/diagnóstico , Fenotipo , Aciltransferasas , Catarata , Fosfolipasas , PolineuropatíasRESUMEN
Immune-mediated demyelinating polyneuropathies (IMDPs) are rare disorders in which dysregulated adaptive immune responses cause peripheral nerve demyelinating inflammation and axonal injury in susceptible individuals. Despite significant advances in understanding IMDP pathogenesis guided by patient data and representative mammalian models, specific therapies are lacking. Significant knowledge gaps in IMDP pathogenesis still exist, e.g. precise antigen(s) and mechanisms that initially trigger immune system activation and identification of large population disease susceptibility factors. The initial directional cues for antigen-specific effector or autoreactive leukocyte trafficking into peripheral nerves are also unknown. An overview of current animal models, with emphasis on the experimental autoimmune neuritis and spontaneous autoimmune peripheral polyneuropathy models, is provided. Insights on the initial directional cues for peripheral nerve tissue specific autoimmunity using a novel Major Histocompatibility Complex class II conditional knockout mouse strain are also discussed, suggesting an essential research tool to study cell- and time-dependent adaptive immunity in autoimmune diseases.