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INTRODUCTION: Myokymic discharges are classically associated with nerve injury from prior radiation but may occur in other neuromuscular disorders. Using quantitative analysis we aimed to identify the spectrum of conditions in which myokymic discharges are present and determine if there are electrophysiological features that distinguish postradiation from nonradiation causes of myokymia. METHODS: We reviewed the clinical history of all patients examined in our electromyography labs with myokymic discharges recorded from June 2017 to February 2020. Quantitative analysis of each myokymic discharge was performed using a custom MATLAB script, assessing features such as burst frequency, spikes per burst, and burst regularity. RESULTS: Eighty-eight distinct myokymic discharges (70 patients) were analyzed: 51 postradiation recordings from 35 patients and 37 recordings from 35 nonradiation patients. The diagnostic spectrum of nonradiation cases was diverse, with common causes being median neuropathy (n = 8), cervical (n = 7), and lumbar (n = 5) radiculopathy, and motor neuron disease (n = 5). On quantitative analysis, postradiation myokymia had an increased burst-to-silence ratio (median, 0.29; nonradiation, 0.08) and greater peak number (median, 15; nonradiation, 7). Except for one patient with hereditary peripheral nerve hyperexcitability, all patients who had two or more muscles demonstrating myokymic discharges belonged to postradiation group. CONCLUSIONS: Myokymic discharges can be seen in diverse neuromuscular conditions; most common in our cohort was chronic median neuropathy. Postradiation myokymia appears to have distinguishing morphological features when quantitatively analyzed compared with nonradiation cases.
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Miocimia/etiología , Enfermedades del Sistema Nervioso Periférico/complicaciones , Traumatismos por Radiación/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Electromiografía , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Miocimia/fisiopatología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Traumatismos por Radiación/fisiopatología , Adulto JovenRESUMEN
INTRODUCTION: Routine ulnar nerve conduction studies may be normal in very mild ulnar neuropathies at the elbow (UNE). Short segment ulnar sensory stimulation across the elbow may detect mild abnormalities in these cases. METHODS: Short segment ulnar sensory nerve stimulation was performed in 20 controls and 15 patients with clinically suspected mild UNE. Greatest peak latency shift and amplitude drop between 2 adjacent stimulation sites were calculated. RESULTS: The upper limit of normal for peak latency shift and amplitude reduction between sites was 0.7 ms and 15%, respectively. Abnormal latency shift was detected in 12 of 15 patients and focal sensory conduction block in 6 of 15 patients. In 5 of 7 patients in whom all other studies were normal, sensory inching was abnormal. DISCUSSION: Ulnar sensory short segment stimulation may provide diagnostic confirmation and localization of the site of nerve compression in mild UNE, and may improve UNE detection when all other studies are normal. Muscle Nerve 59:125-129, 2019.
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Estimulación Eléctrica , Nervio Cubital/fisiología , Neuropatías Cubitales/diagnóstico , Neuropatías Cubitales/fisiopatología , Adulto , Codo/inervación , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Conducción Nerviosa/fisiología , Proyectos Piloto , Tiempo de Reacción , Muñeca/inervaciónRESUMEN
KEY POINTS: Although they are unable to utilize muscle glycogen, McArdle mice adapt favourably to an individualized moderate-intensity endurance exercise training regime. Yet, they fail to reach the performance capacity of healthy mice with normal glycogen availability. There is a remarkable difference in the protein networks involved in muscle tissue adaptations to endurance exercise training in mice with and without glycogen availability. Indeed, endurance exercise training promoted the expression of only three proteins common to both McArdle and wild-type mice: LIMCH1, PARP1 and TIGD4. In turn, trained McArdle mice presented strong expression of mitogen-activated protein kinase 12 (MAPK12). ABSTRACT: McArdle's disease is an inborn disorder of skeletal muscle glycogen metabolism that results in blockade of glycogen breakdown due to mutations in the myophosphorylase gene. We recently developed a mouse model carrying the homozygous p.R50X common human mutation (McArdle mouse), facilitating the study of how glycogen availability affects muscle molecular adaptations to endurance exercise training. Using quantitative differential analysis by liquid chromatography with tandem mass spectrometry, we analysed the quadriceps muscle proteome of 16-week-old McArdle (n = 5) and wild-type (WT) (n = 4) mice previously subjected to 8 weeks' moderate-intensity treadmill training or to an equivalent control (no training) period. Protein networks enriched within the differentially expressed proteins with training in WT and McArdle mice were assessed by hypergeometric enrichment analysis. Whereas endurance exercise training improved the estimated maximal aerobic capacity of both WT and McArdle mice as compared with controls, it was â¼50% lower than normal in McArdle mice before and after training. We found a remarkable difference in the protein networks involved in muscle tissue adaptations induced by endurance exercise training with and without glycogen availability, and training induced the expression of only three proteins common to McArdle and WT mice: LIM and calponin homology domains-containing protein 1 (LIMCH1), poly (ADP-ribose) polymerase 1 (PARP1 - although the training effect was more marked in McArdle mice), and tigger transposable element derived 4 (TIGD4). Trained McArdle mice presented strong expression of mitogen-activated protein kinase 12 (MAPK12). Through an in-depth proteomic analysis, we provide mechanistic insight into how glycogen availability affects muscle protein signalling adaptations to endurance exercise training.
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Modelos Animales de Enfermedad , Enfermedad del Almacenamiento de Glucógeno Tipo V/fisiopatología , Glucógeno/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/fisiología , Condicionamiento Físico Animal , Proteómica/métodos , Animales , Tolerancia al Ejercicio , Enfermedad del Almacenamiento de Glucógeno Tipo V/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mapas de Interacción de ProteínasRESUMEN
Limb-shaking transient ischemic attacks (LSTIAs) are a phenomenon that occurs due to transient hypoperfusion to a cerebral motor territory with a chronically outstripped autoregulatory vascular reserve. First described in 1962 by Miller Fisher, the pathogenesis and the global understanding of this presentation have undergone a significant advancement throughout the years. Typically, patients will present with this syndrome of transient hypoperfusion in the context of extracranial carotid intrinsic vessel stenosis or by intracranial vascular stenosis to select motor pathways. We present within this case report a novel mechanism by which LSTIAs may emerge. Through this knowledge, clinicians may need to consider expansion of their diagnostic breadth to include proximal vasculature luminal integrity.
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Arteriopatías Oclusivas/complicaciones , Tronco Braquiocefálico , Extremidades/inervación , Ataque Isquémico Transitorio/etiología , Corteza Motora/irrigación sanguínea , Temblor/etiología , Anciano , Angiografía , Arteriopatías Oclusivas/diagnóstico por imagen , Arteriopatías Oclusivas/fisiopatología , Arteriopatías Oclusivas/cirugía , Tronco Braquiocefálico/diagnóstico por imagen , Tronco Braquiocefálico/fisiopatología , Circulación Cerebrovascular , Constricción Patológica , Humanos , Ataque Isquémico Transitorio/diagnóstico , Ataque Isquémico Transitorio/fisiopatología , Ataque Isquémico Transitorio/cirugía , Masculino , Resultado del Tratamiento , Temblor/diagnóstico , Temblor/fisiopatología , Injerto Vascular , Grado de Desobstrucción VascularRESUMEN
This chapter focuses on neuropathies that present with focal involvement of nerve roots, plexus, and/or peripheral nerves associated with autoimmune and inflammatory mechanisms that present with focal involvement of nerve roots, plexus and/or peripheral nerves. The clinical presentation, diagnosis, and treatment of focal autoimmune demyelinating neuropathies, focal nonsystemic vasculitic disorders (diabetic and nondiabetic radiculoplexus neuropathies, postsurgical inflammatory neuropathy, and neuralgic amyotrophy), and focal neuropathies associated with sarcoidosis and bacterial and viral infections are reviewed.
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Enfermedades del Sistema Nervioso Periférico , Humanos , Enfermedades del Sistema Nervioso Periférico/diagnósticoRESUMEN
Introduction: Recessive mutations in the gene encoding the histidine triad nucleotide-binding protein 1 (HINT1) are associated with axonal motor-predominant Charcot-Marie-Tooth (CMT) disease with neuromyotonia. A total of 24 HINT1 gene mutations have been reported so far. Some of these cases had mild to moderate elevations of creatinine kinase with no earlier reports of muscle biopsy findings in these cases. In this study, we describe a patient with axonal motor-predominant neuropathy and myopathy with rimmed vacuoles, likely due to a novel HINT1 gene mutation. Case report: A 35-year-old African American man presented with insidious onset and progressive symmetric distal leg weakness followed by hand muscle atrophy and weakness since the age of 25. He had no muscle cramps or sensory complaints. His 38-year-old brother developed similar symptoms beginning in his early 30 s. On neurologic examination, the patient had distal weakness and atrophy in all limbs, claw hands, pes cavus, absent Achilles reflexes, and normal sensory examination. Electrodiagnostic studies revealed absent/reduced compound motor action potential amplitudes distally with normal sensory responses with no neuromyotonia. His sural nerve biopsy showed a chronic non-specific axonal neuropathy, and a biopsy of the tibialis anterior muscle demonstrated myopathic features and several muscle fibers harboring rimmed vacuoles without inflammation in addition to chronic denervation changes. A homozygous variant, p.I63N (c.188T > A), in the HINT1 gene was found in both brothers. Conclusion: We describe a novel, likely pathogenic, HINT1 pI63N (c.188T > A) homozygous variant associated with hereditary axonal motor-predominant neuropathy without neuromyotonia in two African American brothers. The presence of rimmed vacuoles on muscle biopsy raises the possibility that mutations in the HINT1 gene may also cause myopathy.
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This article focuses on principles of nerve conduction studies and needle electromyography applied to the electrodiagnosis of polyneuropathy. The components of the electrodiagnostic evaluation of polyneuropathy and the electrophysiological characteristics of axonal and demyelinating neuropathies and nodo-paranodopathies are reviewed.
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Conducción Nerviosa , Polineuropatías , Axones , Electrodiagnóstico , Electromiografía , Humanos , Polineuropatías/diagnósticoRESUMEN
Ranolazine is an anti-ischemic drug often used along with statins in patients with ischemic heart disease. Ranolazine-induced proximal myopathy or rhabdomyolysis have been rarely reported, but toxic effects of statins could not be completely ruled out in those cases. We report a 68-year-old man with ranolazine-induced myopathy who presented with respiratory insufficiency and head drop. Creatine kinase level was normal. The Patient continued to worsen despite statin cessation but markedly improved after stopping ranolazine. Muscle biopsy showed excessive lipid accumulation predominantly in type 1 myofibers. The precise mechanism of toxicity is not clear. Treating physicians should be aware of this rare but potentially debilitating adverse effect of ranolazine. Prognosis is good upon discontinuation of the offending drug.
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Fármacos Cardiovasculares/efectos adversos , Errores Innatos del Metabolismo Lipídico/inducido químicamente , Distrofias Musculares/inducido químicamente , Ranolazina/efectos adversos , Insuficiencia Respiratoria/etiología , Bloqueadores de los Canales de Sodio/efectos adversos , Anciano , Humanos , MasculinoRESUMEN
OBJECTIVE: To test the hypothesis that myeloneuropathy is a presenting phenotype of paraneoplastic neurologic syndromes we retrospectively reviewed clinical, radiologic, and serologic features of 32 patients with concomitant paraneoplastic spinal cord and peripheral nervous system involvement. METHODS: Observational study investigating patients with myeloneuropathy and underlying cancer or onconeural antibody seropositivity. RESULTS: Among 32 patients with paraneoplastic myeloneuropathy, 20 (63%) were women with median age 61 years (range 27-84 years). Twenty-six patients (81%) had classified onconeural antibodies (amphiphysin, n = 8; antineuronal nuclear antibody [ANNA] type 1 [anti-Hu], n = 5; collapsin response mediator protein 5 [CRMP5] [anti-CV2], n = 6; Purkinje cell cytoplasmic antibody type 1 [PCA1] [anti-Yo], n = 1; Purkinje cell cytoplasmic antibody type 2 [PCA2], n = 2; kelch-like protein 11 [KLHL11], n = 1; and combinations thereof: ANNA1/CRMP5, n = 1; ANNA1/amphiphysin, n = 1; ANNA3/CRMP5, n = 1). Cancer was confirmed in 25 cases (onconeural antibodies, n = 19; unclassified antibodies, n = 3; no antibodies, n = 3). Paraneoplastic myeloneuropathies had asymmetric paresthesias (84%), neuropathic pain (78%), subacute onset (72%), sensory ataxia (69%), bladder dysfunction (69%), and unintentional weight loss >15 pounds (63%). Neurologic examination demonstrated concomitant distal or asymmetric hyporeflexia and hyperreflexia (81%), impaired vibration and proprioception (69%), Babinski response (68%), and asymmetric weakness (66%). MRI showed longitudinally extensive (45%), tract-specific spinal cord T2 hyperintensities (39%) and lumbar nerve root enhancement (38%). Ten of 28 (36%) were unable to ambulate independently at last follow-up (median 24 months, range 5-133 months). Combined oncologic and immunologic therapy had more favorable modified Rankin Scale scores at post-treatment follow-up compared to those receiving either oncologic or immunologic therapy alone (2 [range 1-4] vs 4 [range 2-6], p < 0.001). CONCLUSIONS: Paraneoplastic etiologies should be considered in the evaluation of subacute myeloneuropathies. Recognition of key characteristics of paraneoplastic myeloneuropathy may facilitate early tumor diagnosis and initiation of immunosuppressive treatment.
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Autoanticuerpos/sangre , Síndromes Paraneoplásicos del Sistema Nervioso/sangre , Síndromes Paraneoplásicos del Sistema Nervioso/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Polineuropatía Paraneoplásica/sangre , Polineuropatía Paraneoplásica/diagnóstico , Polineuropatía Paraneoplásica/terapia , Síndromes Paraneoplásicos del Sistema Nervioso/terapia , Estudios RetrospectivosRESUMEN
OBJECTIVE: Sensory loss with normal nerve conduction studies (NCS) from focal sensory root inflammatory demyelination is characteristic of chronic immune sensory polyradiculopathy (CISP). However, nonpure cases involving motor and distal sensory nerves exist (CISP-plus). We hypothesize that CISP-plus and CISP are fundamentally part of the same syndrome through comparison of clinical, neurophysiologic, and pathologic features. METHODS: CISP-plus (primary dorsal root with lesser motor and sensory nerve involvement) and CISP cases were retrospectively analyzed (1986-2019). RESULTS: We identified 44 CISP-plus and 28 CISP cases (n = 72) with 86% (38/44) of patients with CISP-plus and 79% (22/28) of patients with CISP experiencing imbalance. On examination, large fiber sensory loss was present in 98% (43/44) of patients with CISP-plus and 96% (27/28) of patients with CISP. Gait ataxia was evident in 93% (41/44) of patients with CISP-plus and 79% (22/28) of patients with CISP. Mild distal weakness was common in CISP-plus (75%, 33/44). NCS showed mild abnormalities in all patients with CISP-plus and were normal (by definition) in all patients with CISP. Elevated CSF protein, slowing of somatosensory evoked potentials, and MRI root enhancement occurred in most CISP-plus and CISP cases. Eleven CISP-plus nerve biopsies showed loss of large myelinated fibers and onion-bulb formations, most prominent in rootlet biopsies. Immunotherapy resulted in marked improvement of gait ataxia in 84% (27/32) of patients with CISP-plus and 93% (13/14) of patients with CISP with return to normal neurologic examination in half (25/46). CONCLUSION: The recognition of CISP-plus expands the spectrum of CIDP by combining CISP-plus (predominant sensory polyradiculopathy with mild motor and sensory nerve involvement) with pure CISP (focal sensory polyradiculopathy) together as proximal sensory CIDP.
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Neuronas Motoras/patología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/patología , Células Receptoras Sensoriales/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/fisiopatología , Estudios Retrospectivos , Adulto JovenRESUMEN
The diagnosis and management of postoperative nerve injury can be a challenging and frustrating proposition for the patient, surgeon, and anesthesia provider. Unfortunately, in many cases, the true etiology is never elucidated and the injury is ascribed to positioning or a nerve block with "expectant management" being the order of the day, which can result in persistent disability for the patient. However, there is a rare subset of disorders affecting the nervous system that can masquerade as a peripheral nerve injury that warrants further investigation of risk factors and co-morbidities when other common causes of nerve injury are ruled out. We describe a patient with rheumatoid arthritis that underwent revision hip arthroplasty and presented almost immediately in the postoperative period with what was initially diagnosed as femoral nerve palsy. Further diagnostic workup later revealed that she had suffered from postoperative inflammatory neuropathy resulting in lumbosacral plexus injury and not a discrete nerve injury. Had the true cause been identified early enough, treatment with corticosteroids could have been initiated in an attempt to mitigate and perhaps reverse the progress of the neuropathy. We present this cautionary tale to remind practitioners to continue to be vigilant and consider more esoteric and unconventional diagnoses in the workup of perioperative neuropathies.
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OBJECTIVE: To investigate the following among patients with phrenic neuropathy: (1) occurrences of water immersion activity-induced dyspnea; (2) clinical, electrophysiologic, sonographic, and pulmonary function test abnormalities; and (3) frequency of documented counseling regarding the risks of water immersion activities. METHODS: We identified all patients with test-confirmed phrenic neuropathy seen from January 1, 2000, to December 31, 2018, at Mayo Clinic. RESULTS: Of 535 patients with phrenic neuropathy, documentation of dyspnea with water activities was identified in 4% (22/535). The risks of water immersion were only documented in patients having experienced this problem. The majority had isolated phrenic neuritis or neuralgic amyotrophy syndrome (77.3%), mean age was 55 years (range 31-79), and most patients were men (81.9%). Patients had right-sided (45.5%) or bilateral (54.5%) phrenic neuropathy. None had isolated left phrenic involvement. Near-fatal drowning occurred in 18.2% (4/22), with persons needing assistance to be rescued from the water, following diving into water. Dyspnea with water immersion was the only symptom in 4.5% (1/22) and the presenting respiratory symptom in 36.4% (8/22). A range of electrophysiologic, sonographic, and pulmonary function test abnormalities including mild abnormalities were seen and not found to be significantly different from those in patients in whom water-induced dyspnea was not recorded. CONCLUSION: Respiratory distress with water immersion activities is a serious complication of phrenic neuropathies. Physician-documented counseling is lacking. Isolated phrenic neuritis, neuralgic amyotrophy, and right-sided and bilateral phrenic involvement are most commonly implicated, but the range of severity and testing abnormalities suggest that all patients with neuralgic amyotrophy or phrenic neuropathy should be warned especially about diving into water.
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Disnea/etiología , Enfermedades del Sistema Nervioso Periférico/complicaciones , Nervio Frénico/patología , Deportes Acuáticos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Lipid droplets (LDs) are the major lipid storage organelles of eukaryotic cells and a source of nutrients for intracellular pathogens. We demonstrate that mammalian LDs are endowed with a protein-mediated antimicrobial capacity, which is up-regulated by danger signals. In response to lipopolysaccharide (LPS), multiple host defense proteins, including interferon-inducible guanosine triphosphatases and the antimicrobial cathelicidin, assemble into complex clusters on LDs. LPS additionally promotes the physical and functional uncoupling of LDs from mitochondria, reducing fatty acid metabolism while increasing LD-bacterial contacts. Thus, LDs actively participate in mammalian innate immunity at two levels: They are both cell-autonomous organelles that organize and use immune proteins to kill intracellular pathogens as well as central players in the local and systemic metabolic adaptation to infection.
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Bacterias/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata , Gotas Lipídicas/inmunología , Animales , Péptidos Catiónicos Antimicrobianos/metabolismo , Ácidos Grasos/metabolismo , GTP Fosfohidrolasas/metabolismo , Células HEK293 , Humanos , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Macrófagos/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/inmunología , CatelicidinasRESUMEN
OBJECTIVE: To define the clinicopathologic features of amphiphysin-immunoglobulin G (IgG)-mediated neuropathy. METHODS: Patients examined at our institution from January 1, 1995, to September 30, 2018, with amphiphysin-IgG by indirect immunofluorescence and Western blot, were reviewed. Their phenotypes were compared to cases of coexisting collapsin response-mediator protein-5 (CRMP5)-IgG or anti-neuronal nuclear antibody type 1 (ANNA1-IgG) and CRMP5-IgG autoimmunity. Improvement in modified Rankin Scale (mRS) (≥1) on follow-up was considered a favorable outcome. Amphiphysin RNA expression was assessed in healthy nerves. RESULTS: Fifty-three amphiphysin-IgG-positive cases were identified. Of 33 (60%) patients with neuropathy, 21 had amphiphysin-IgG alone, and 12 had coexisting autoantibodies (ANNA1-IgG, n = 8; CRMP5-IgG, n = 2; ANNA1-IgG and CRMP5-IgG, n = 2). The neuropathies in isolated amphiphysin-IgG autoimmunity included polyradiculoneuropathy (62%), diffuse sensory neuronopathy (35%), and facial neuropathy with gastroparesis (3%). Among these, pain (80%), breast cancer (63%), and CNS (57%) involvements commonly coexisted, and neuropathy frequently prompted breast cancer diagnosis (76%). Stiff-person spectrum disorder was the most common CNS accompaniment (45%). Nerve biopsies showed axonal loss (n = 6/6), subperineurial edema (n = 4/6), and CD4 predominant inflammation (n = 2/6). Median mRS score at last follow-up was 3.5; 58% of patients were immunotherapy-responsive. Patients with amphiphysin-IgG alone had more favorable immunotherapy response than patients with CRMP5-IgG polyneuropathy (n = 45) (44% vs 16%, p = 0.028, odds ratio 4.2, 95% confidence interval 1.1 to 15.5). Only 1/9 (11%) patients with amphiphysin-IgG with coexisting CRMP5-IgG or ANNA1-IgG had immunotherapy response. RNA amphiphysin expression occurred at low levels in nerve. CONCLUSION: Amphiphysin-IgG autoimmune neuropathy has a recognizable phenotype, is frequently immune responsive, and can prompt early diagnosis of breast cancer.
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Autoanticuerpos/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Proteínas del Tejido Nervioso/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antinucleares/inmunología , Anticuerpos Antineoplásicos , Enfermedades Autoinmunes del Sistema Nervioso/epidemiología , Enfermedades Autoinmunes del Sistema Nervioso/patología , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Biopsia , Neoplasias de la Mama/epidemiología , Comorbilidad , Enfermedades del Nervio Facial/epidemiología , Enfermedades del Nervio Facial/inmunología , Enfermedades del Nervio Facial/patología , Enfermedades del Nervio Facial/fisiopatología , Femenino , Humanos , Hidrolasas/inmunología , Inmunoglobulina G/inmunología , Masculino , Proteínas Asociadas a Microtúbulos/inmunología , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Dolor , Nervios Periféricos/inmunología , Nervios Periféricos/metabolismo , Nervios Periféricos/patología , Polirradiculoneuropatía/epidemiología , Polirradiculoneuropatía/inmunología , Polirradiculoneuropatía/patología , Polirradiculoneuropatía/fisiopatología , Síndrome de la Persona Rígida/epidemiología , SíndromeRESUMEN
OBJECTIVE: To identify novel genes involved in the etiology of intracranial aneurysms (IAs) or subarachnoid hemorrhages (SAHs) using whole-exome sequencing. METHODS: We performed whole-exome sequencing in 13 individuals from 3 families with an autosomal dominant IA/SAH inheritance pattern to look for candidate genes for disease. In addition, we sequenced PCNT exon 38 in a further 161 idiopathic patients with IA/SAH to find additional carriers of potential pathogenic variants. RESULTS: We identified 2 different variants in exon 38 from the PCNT gene shared between affected members from 2 different families with either IA or SAH (p.R2728C and p.V2811L). One hundred sixty-four samples with either SAH or IA were Sanger sequenced for the PCNT exon 38. Five additional missense mutations were identified. We also found a second p.V2811L carrier in a family with a history of neurovascular diseases. CONCLUSION: The PCNT gene encodes a protein that is involved in the process of microtubule nucleation and organization in interphase and mitosis. Biallelic loss-of-function mutations in PCNT cause a form of primordial dwarfism (microcephalic osteodysplastic primordial dwarfism type II), and ≈50% of these patients will develop neurovascular abnormalities, including IAs and SAHs. In addition, a complete Pcnt knockout mouse model (Pcnt -/-) published previously showed general vascular abnormalities, including intracranial hemorrhage. The variants in our families lie in the highly conserved PCNT protein-protein interaction domain, making PCNT a highly plausible candidate gene in cerebrovascular disease.
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Antígenos/genética , Predisposición Genética a la Enfermedad/genética , Aneurisma Intracraneal/genética , Hemorragia Subaracnoidea/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Mutación Puntual , Secuenciación del Exoma , Adulto JovenAsunto(s)
Carnitina O-Palmitoiltransferasa/deficiencia , Errores Innatos del Metabolismo/diagnóstico , Debilidad Muscular/diagnóstico , Mialgia/diagnóstico , Procedimientos Ortopédicos/efectos adversos , Complicaciones Posoperatorias/diagnóstico , Rabdomiólisis/diagnóstico , Carnitina O-Palmitoiltransferasa/genética , Humanos , Masculino , Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/etiología , Errores Innatos del Metabolismo/genética , Persona de Mediana Edad , Debilidad Muscular/etiología , Debilidad Muscular/genética , Mialgia/etiología , Mialgia/genética , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/genética , Rabdomiólisis/etiología , Rabdomiólisis/genéticaRESUMEN
INTRODUCTION: The term CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) refers to a hereditary systemic microangiopathy caused by mutations of the NOTCH3 gene located on chromosome 19. It typically presents in young people with migraine attacks and recurrent ischemic strokes, leading to a progressive subcortical cognitive decline over several years. AIM: To describe the symptoms of onset and clinical manifestations in 11 CADASIL patients diagnosed by genetic testing or skin biopsy. PATIENTS AND METHODS: Detailed physical and neurological examinations, vital signs, electrocardiogram, laboratory investigations (including glucose levels, lipid profile, coagulation studies and homocysteine levels, among others), brain MRI, Mini-Mental Test and Trail Making Test A and B were done. In addition, some patients with complaints related to depressive symptoms or impaired cognition received the Montgomery and Åsberg Depression Rating Scale and a battery of neuropsychological examinations (the Stroop Color and Word Test and the V-ADAS-cog that includes the Maze Test). RESULTS AND CONCLUSIONS: Our patients presented with a clinical course and a radiological pattern similar to those described previously in the literature. We found a delay in the detection of this pathology and previous diagnostic errors in some patients and their relatives. Multiple sclerosis was the most frequent misdiagnosis. The course of the disease was barely modified by therapeutic interventions introduced to control the progression of the symptoms. Cognitive complaints in patients with advanced stages were common and the executive abilities were found to be impaired in many cases.
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CADASIL/fisiopatología , Adulto , Anciano , CADASIL/diagnóstico , CADASIL/genética , CADASIL/patología , Cromosomas Humanos Par 19 , Trastornos del Conocimiento/genética , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Receptor Notch3 , Receptores Notch/genética , Estudios RetrospectivosRESUMEN
Introducción. El término CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) hace referencia a una microangiopatía sistémica hereditaria que se presenta en individuos jóvenes con migraña e ictus isquémicos recurrentes y que conduce a un deterioro cognitivo de tipo subcortical en pocos años. Objetivo. Describir el patrón de presentación y la evolución clínica de 11 pacientes con diagnóstico de CADASIL confirmado por biopsia de piel o estudio genético. Pacientes y métodos. Se sometió a todos los pacientes a una exploración física y neurológica detallada, electrocardiograma, analítica completa (incluyendo glucemia, perfil lipídico, estudio de coagulación y niveles de homocisteína, entre otros), resonancia magnética cerebral, test minimental y test del trazo A y B. En pacientes con alteraciones del estado de ánimo o quejas cognitivas se llevó a cabo además una valoración de la sintomatología depresiva mediante la escala de Montgomery y Åsberg y una batería de tests neuropsicológicos: el test de colores y palabras para valorar el efecto Stroop y la subescala de evaluación cognitiva vascular (V-ADAS-cog), que incluye el test del laberinto. Resultados y conclusiones. Nuestros pacientes presentaron un patrón clínico y radiológico similar a los descritos en la bibliografía. Los errores diagnósticos y la demora en la detección de esta patología fueron frecuentes; la esclerosis múltiple resultó uno de los diagnósticos erróneos más comunes. Los tratamientos iniciados para el control de los síntomas apenas modificaron el curso de la enfermedad. En estadios avanzados las quejas cognitivas fueron habituales, y se halló una notable disminución en las habilidades ejecutivas en la mayoría de los pacientes (AU)
Introduction. The term CADASIL (cerebral autosomal dominant arteriopathy with subcortical infartcs and leukoencephalopathy) refers to a hereditary systemic microangiopathy caused by mutations of the NOTCH3 gene located on chromosome 19. It typically presents in young people with migraine attacks and recurrent ischemic strokes, leading to a progressive subcortical cognitive decline over several years. Aim. To describe the symptoms of onset and clinical manifestations in 11 CADASIL patients diagnosed by genetic testing or skin biopsy. Patients and methods. Detailed physical and neurological examinations, vital signs, electrocardiogram, laboratory investigations (including glucose levels, lipid profile, coagulation studies and homocysteine levels, among others), brain MRI, Mini-Mental Test and Trail Making Test A & B were done. In addition, some patients with complaints related to depressive symptoms or impaired cognition received the Montgomery & Åsberg Depression Rating Scale and a battery of neuropsychological examinations (the Stroop Color and Word Test and the V-ADAS-cog that includes the Maze Test). Results and conclusions. Our patients presented with a clinical course and a radiological pattern similar to those described previously in the literature. We found a delay in the detection of this pathology and previous diagnostic errors in some patients and their relatives. Multiple sclerosis was the most frequent misdiagnosis. The course of the disease was barely modified by therapeutic interventions introduced to control the progression of the symptoms. Cognitive complaints in patients with advanced stages were common and the executive abilities were found to be impaired in many cases (AU)