RESUMEN
Our objective was to investigate the frequency of KIF5A variants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants in KIF5A. Whole-exome sequence analysis was performed for a Japanese series of 43 families with FALS and 444 patients with sporadic ALS (SALS), in whom causative variants had not been identified. We compared the frequencies of rare variants (MAF < 0.01) in KIF5A, including missense and loss of function (LoF) variants, between ALS and control subjects (n = 1163). Clinical characteristics of patients with FALS carrying pathogenic variants in KIF5A were also described. LoF variants were identified only in the probands of two families with FALS, both of which were 3' splice-site variants leading to exon skipping and an altered C-terminal domain, located in the mutational hotspot causing FALS, and were considered to be pathogenic for FALS. Rare missense variants in KIF5A were identified in five patients with SALS (1.13%) and 11 control subjects (0.95%, carrier frequency), which were not significantly different. Consequently, the pathogenic LoF variants in KIF5A accounted for 2.1% of all FALS families in this study. These patients suffered from ALS characteristically associated with the predominant involvement of upper motor neuron. In conclusion, we identified two pathogenic splice-site variants in KIF5A in the probands in two Japanese families with FALS, which altered the C-terminal region of KIF5A. Our findings broaden the phenotype spectrum of ALS associated with variants in KIF5A in the Japanese series.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Predisposición Genética a la Enfermedad/genética , Cinesinas/genética , Mutación/genética , Adulto , Esclerosis Amiotrófica Lateral/diagnóstico , Pueblo Asiatico/genética , Femenino , Estudios de Asociación Genética , Humanos , Japón , Masculino , Persona de Mediana EdadRESUMEN
The mitogen-activated protein kinase (MAPK) module, composed of a MAPK, a MAPK kinase (MAPKK), and a MAPKK kinase (MAPKKK), is a cellular signaling device that is conserved throughout the eukaryotic world. In mammalian cells, various extracellular stresses activate two major subfamilies of MAPKs, namely, the Jun N-terminal kinases and the p38/stress-activated MAPK (SAPK). MTK1 (also called MEKK4) is a stress-responsive MAPKKK that is bound to and activated by the stress-inducible GADD45 family of proteins (GADD45alpha/beta/gamma). Here, we dissected the molecular mechanism of MTK1 activation by GADD45 proteins. The MTK1 N terminus bound to its C-terminal segment, thereby inhibiting the C-terminal kinase domain. This N-C interaction was disrupted by the binding of GADD45 to the MTK1 N-terminal GADD45-binding site. GADD45 binding also induced MTK1 dimerization via a dimerization domain containing a coiled-coil motif, which is essential for the trans autophosphorylation of MTK1 at Thr-1493 in the kinase activation loop. An MTK1 alanine substitution mutant at Thr-1493 has a severely reduced activity. Thus, we conclude that GADD45 binding induces MTK1 N-C dissociation, dimerization, and autophosphorylation at Thr-1493, leading to the activation of the kinase catalytic domain. Constitutively active MTK1 mutants induced the same events, but in the absence of GADD45.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , MAP Quinasa Quinasa Quinasa 4/metabolismo , Animales , Células COS , Chlorocebus aethiops , Dimerización , Activación Enzimática , Péptidos y Proteínas de Señalización Intracelular/genética , MAP Quinasa Quinasa Quinasa 4/genética , Mutación , Fosforilación , Unión Proteica , Estructura Terciaria de Proteína , Transducción de Señal , Tirosina/metabolismo , Proteinas GADD45RESUMEN
We provide the first report of amyopathic dermatomyositis combined with peripheral neuropathy. Our patient, a 49-year-old woman, initially experienced muscle weakness and tingling sensations in her legs, and nerve conduction study findings and the detection of antiganglioside antibodies indicated that she had autoimmune peripheral neuropathy. The unexpected presence of skin lesions, interstitial pneumonia and antibodies to melanoma differentiation-associated protein 5 prompted an additional diagnosis of amyopathic dermatomyositis. No previous report has described amyopathic dermatomyositis with peripheral neuropathy, and the present case provides evidence for the once-controversial concept of neuromyositis.
Asunto(s)
Dermatomiositis/complicaciones , Enfermedades del Sistema Nervioso Periférico/complicaciones , Adolescente , Anciano , Biopsia , Niño , Dermatomiositis/tratamiento farmacológico , Diagnóstico Diferencial , Femenino , Humanos , Inmunoterapia , Masculino , Persona de Mediana Edad , Enfermedades del Sistema Nervioso Periférico/terapia , Piel/patología , Tomografía Computarizada por Rayos XRESUMEN
The patient was a 64-year-old man presented with difficulty in walking, articulation, and swallowing, as well as cognitive impairment. He had refractory microcytic anemia and diabetes mellitus. His serum levels of iron, copper, and ceruloplasmin were low. Magnetic resonance imaging suggested iron deposition in the basal ganglia, thalami, cerebellar dentate nuclei, and cerebral and cerebellar cortices. He was diagnosed with aceruloplasminemia after a ceruloplasmin gene analysis. Iron chelation therapy with deferasirox improved his anemia and cerebellar symptoms, which included dysarthria and limb ataxia. The present study and previous reports indicate that cerebellar symptoms with aceruloplasminemia might respond to deferasirox in less than one year.
Asunto(s)
Anemia Ferropénica/tratamiento farmacológico , Ceruloplasmina/deficiencia , Deferasirox/uso terapéutico , Quelantes del Hierro/uso terapéutico , Trastornos del Metabolismo del Hierro/complicaciones , Trastornos del Metabolismo del Hierro/tratamiento farmacológico , Enfermedades Neurodegenerativas/complicaciones , Enfermedades Neurodegenerativas/tratamiento farmacológico , Adulto , Ceruloplasmina/análisis , Cobre/sangre , Femenino , Humanos , Hierro/sangre , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
RATIONALE: Neurological complications of varicella-zoster virus (VZV) infection include cerebral infarction, meningoencephalitis, segmental sensory disturbance, facial nerve palsy, and myelitis. Chronic myelitis is rarely reported. Diagnosis of VZV infection can be confirmed by elevated anti-VZV immunoglobulin G (IgG) antibody or detection of VZV DNA in the cerebrospinal fluid (CSF), the former reported to be superior. The detection rate of VZV DNA is generally thought to decrease with time after the onset of the condition. The utility of VZV DNA polymerase chain reaction (PCR) is thus thought to be limited to the acute phase of the disease. The presence of skin lesions also helps to render a diagnosis; however, cases of zoster sine herpete (ZSH), the occurrence of segmental symptoms without skin lesions, renders the diagnosis of VZV infection more difficult. Antiviral drugs, such as acyclovir, are the treatment of choice to resolve VZV infections. PATIENT CONCERNS: A 65-year-old Japanese man felt heaviness and a throbbing pain on the ulnar side of the right forearm. He was previously diagnosed with cervical spondylosis, and received nonsteroidal anti-inflammatory drugs with little improvement. Contrast cervical magnetic resonance imaging showed a swelling and an increased signal intensity of the spinal cord, and an enhancing lesion, all of which were suggestive of myelitis. DIAGNOSIS: We found no evidence for diagnoses of sarcoidosis, Behçet disease, multiple sclerosis, or neuromyelitis optica spectrum disorder. The CSF analysis revealed an elevation of the total protein concentration and that the patient was positive for VZV DNA, while anti-VZV IgG was not elevated. The patient was therefore diagnosed with ZSH myelitis. INTERVENTIONS: We administered acyclovir and valaciclovir as the first therapy. At the time of recurrence, we used high-dose acyclovir, vidarabine, and high-dose methylprednisolone pulse therapy. OUTCOMES: The patient's dysesthetic pain in the right upper limb improved following the first antiviral therapy. Two months later, he suffered a recurrence, but the second therapy significantly relieved his symptoms. LESSONS: VZV infection should be regarded as an important differential diagnosis of chronic myelitis. VZV DNA PCR should be performed even in the chronic phase of the condition to introduce the possibility of antiviral therapy as a treatment option.
Asunto(s)
Mielitis/etiología , Zoster Sine Herpete/complicaciones , Zoster Sine Herpete/diagnóstico , Anciano , Antivirales/uso terapéutico , ADN Viral/análisis , Antebrazo , Herpesvirus Humano 3/aislamiento & purificación , Humanos , Imagen por Resonancia Magnética , Masculino , Mielitis/diagnóstico por imagen , Reacción en Cadena de la Polimerasa , Recurrencia , Zoster Sine Herpete/líquido cefalorraquídeo , Zoster Sine Herpete/tratamiento farmacológicoRESUMEN
RATIONALE: Intravascular large B-cell lymphoma (IVLBCL) is a type of malignant lymphoma in which neoplastic B cells proliferate selectively within the lumina of small- and medium-sized vessels. Patients with IVLBCL frequently develop neurological manifestations during their disease course. Patients are known to often develop various neurological manifestations, but there are only a few reports of IVLBCL whose initial symptoms are deafness and/or disequilibrium. PATIENT CONCERNS: A 66-year-old Japanese man was provisionally diagnosed with sudden sensorineural hearing loss. Administration of prednisolone did not improve his symptoms, and then he experienced amaurosis fugax. Magnetic resonance imaging (MRI) showed multiple brain infarcts, so he was administered antithrombotic drugs. Nevertheless, he experienced recurrent strokes, became irritable, and had visual hallucinations. He was emergently admitted to our hospital with disturbance of consciousness. DIAGNOSIS: Blood tests showed elevation of lactose dehydrogenase and soluble interleukin-2 receptor. Cranial MR diffusion-weighted imaging showed multiple lesions bilaterally in the cerebral white matter and cortex, posterior limbs of the internal capsule, and cerebellar hemispheres, which were hypointense on apparent diffusion coefficient maps. Hyperintense lesions were detected bilaterally in the cerebral white matter and basal ganglia on both T2-weighted imaging and fluid-attenuated inversion recovery imaging. Contrast-enhanced brain MRI demonstrated contrast-enhancing high-signal lesions along the cerebral cortex. Brain biopsy revealed a diagnosis of IVLBCL. INTERVENTIONS: The patient could not receive chemotherapy because of his poor general condition. Therefore, we administered high-dose methylprednisolone (mPSL) pulse therapy. OUTCOMES: There was little improvement in consciousness levels after the high-dose mPSL pulse therapy. On the forty-ninth day of hospitalization, he was transferred to another hospital to receive supportive care. LESSONS: IVLBCL should be regarded as an important differential diagnosis of hearing loss and dizziness. Most importantly, if the symptoms are fluctuant and steroid therapy is not effective, biopsy should be considered as early as possible.
Asunto(s)
Mareo/etiología , Pérdida Auditiva/etiología , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/fisiopatología , Anciano , Imagen de Difusión por Resonancia Magnética , Humanos , Masculino , Oxidorreductasas/sangre , Receptores de Interleucina-2/sangre , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/etiologíaRESUMEN
BACKGROUND: Cortical damage in areas such as the frontal lobe is reported in amyotrophic lateral sclerosis (ALS). However, aside from executive dysfunction, the pathological significance of this cortical damage has yet to be clarified. The present study investigated the effects of cortical damage on vestibular function in ALS. METHODS: Subjects comprised 18 ALS patients and 18 age- and sex-matched healthy controls. Cold air caloric stimulation was performed in all subjects to induce vestibular nystagmus, which was analysed to evaluate vestibular function. Visual suppression testing to investigate the suppressive effects of visual stimuli on vestibular nystagmus was expressed as suppression rate (SR, %). Executive function was tested using the frontal assessment battery (FAB). RESULTS: Suppression rate and FAB score were significantly lower in the ALS group than in the control group (pâ¯<â¯0.01 each). A positive correlation was also observed between SR and FAB score (Râ¯=â¯0.65, pâ¯=â¯0.023). CONCLUSION: Visual suppression testing showed significant damage to the central nervous system vestibular control mechanisms, which utilize visual information in the ALS group and a positive correlation between SR and FAB score suggest a relationship between frontal lobe damage and impaired vestibular control. A simple vestibular function test may be useful as a tool to objectively monitor the progression of cerebral lesions in ALS.
Asunto(s)
Esclerosis Amiotrófica Lateral/complicaciones , Función Ejecutiva/fisiología , Lóbulo Frontal/fisiopatología , Enfermedades Vestibulares/etiología , Anciano , Esclerosis Amiotrófica Lateral/fisiopatología , Esclerosis Amiotrófica Lateral/psicología , Pruebas Calóricas , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Enfermedades Vestibulares/fisiopatologíaRESUMEN
We herein report the case of an 84-year-old woman with transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP-ATTR Val30Met), representing a very old case. The patient had muscle weakness and sensory disturbances in her extremities caused by severe peripheral neuropathy. She also had vitreous opacity and orthostatic hypotension, and pyrophosphate scintigraphy showed a myocardial accumulation. Esophagogastroduodenoscopy revealed mucosal amyloid deposits, positive in anti-TTR antibody staining. A TTR gene analysis isolated the Val30Met mutation. More than a few cases of FAP-ATTR develop late, like our own, and their familial histories are often obscure in non-endemic areas, which might make a diagnosis difficult.
Asunto(s)
Neuropatías Amiloides Familiares/diagnóstico , Anciano de 80 o más Años , Amiloide/análisis , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/genética , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Oftalmopatías/etiología , Femenino , Humanos , Hipotensión Ortostática/etiología , Mutación , Prealbúmina/genética , Cintigrafía , Cuerpo VítreoRESUMEN
GDF-15, a member of the transforming growth factor beta superfamily, regulates inflammatory and apoptotic pathways in various diseases, such as heart failure, kidney dysfunction, and cancer. We aimed to clarify potentially confounding variables affecting GDF-15 and demonstrate its utility as a mitochondrial biomarker using serum samples from 15 patients with mitochondrial diseases (MD), 15 patients with limbic encephalitis (LE), 10 patients with multiple sclerosis/neuromyelitis optica spectrum disorders (MS/NMOSD), and 19 patients with amyotrophic lateral sclerosis (ALS). GDF-15 and FGF-21 were significantly elevated in MD. GDF-15 and FGF-21 showed a good correlation in MD but not in LE, MS, and ALS. GDF-15 was potentially influenced by age in LE, MS/NMOSD, and ALS but not in MD. FGF-21 was not correlated with age in MS/NMOSD, ALS, LE, and MD. GDF-15 was not correlated with clinical features in LE or BMI or body weight in ALS. GDF-15 positively correlated with the Expanded Disability Status Scale (EDSS) in MS/NMOSD, while EDSS showed no correlation with age. In conclusion, the results revealed that GDF-15 may be influenced by EDSS in MS/NMOPSD and by age in LE, MS/NMOSD, and ALS but not in MD. Mitochondrial damage in MS/NMOSD is a potentially confounding variable affecting GDF-15.
Asunto(s)
Factores de Crecimiento de Fibroblastos/sangre , Factor 15 de Diferenciación de Crecimiento/sangre , Enfermedades Mitocondriales/sangre , Esclerosis Múltiple/sangre , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/sangre , Biomarcadores/sangre , Evaluación de la Discapacidad , Femenino , Humanos , Encefalitis Límbica/sangre , Masculino , Persona de Mediana Edad , Neuromielitis Óptica/sangre , Adulto JovenRESUMEN
RATIONALE: Antiepileptic drugs (AEDs) are one of the causative drugs of drug-induced hypothyroidism. In most cases, AED-induced hypothyroidism is subclinical and indicated only by abnormalities of free thyroxine (T4) and/or thyroid-stimulating hormone (TSH) levels. Severe symptomatic hypothyroidism following AEDs is rarely reported in the literature. PATIENT CONCERNS: A 75-year-old man experienced neurologic symptoms including memory impairment, ataxic gait, sensory polyneuropathy and myopathy, lethargy, and edema of the face and lower extremities. He had been administered phenytoin and gabapentin for the treatment of symptomatic traumatic epilepsy 8 years before. DIAGNOSES: The patient had low free T4 (0.21âng/dL) and high TSH (113.2âµIU/mL), which indicated hypothyroidism. Negative thyroid-related autoantibody tests and the lack of goiter excluded the possibility of Hashimoto disease. Phenytoin and/or gabapentin were strongly suspected as causing his hypothyroidism. INTERVENTION: The patient was treated with replacement therapy (levothyroxine 25âµg/day). OUTCOMES: His symptoms markedly and promptly improved alongside continued antiepileptic therapy. LESSONS: In this case, the patient's hypothyroidism was assumed to result from different mechanisms of the 2 AEDs leading to thyroid hormone reduction. AEDs can not only cause asymptomatic thyroid hormone abnormalities but also clinically observable hypothyroidism. Therefore, clinicians should be aware of the association between anticonvulsants and symptomatic hypothyroidism.
Asunto(s)
Aminas/efectos adversos , Anticonvulsivantes/efectos adversos , Ácidos Ciclohexanocarboxílicos/efectos adversos , Hipotiroidismo/inducido químicamente , Fenitoína/efectos adversos , Ácido gamma-Aminobutírico/efectos adversos , Anciano , Epilepsia/tratamiento farmacológico , Gabapentina , Humanos , Hipotiroidismo/tratamiento farmacológico , Masculino , Tiroxina/uso terapéuticoRESUMEN
We herein report the case of a patient who developed peripheral neuropathy of the bilateral lower legs that later became complicated with isolated oculomotor nerve disorder and was finally diagnosed as systemic lupus erythematosus (SLE). Based on the findings for oculomotor nerve paralysis and contrast-enhanced magnetic resonance imaging findings for the oculomotor nerve in the prepontine cistern, the isolated oculomotor nerve disorder was considered to be a manifestation of peripheral neuropathy. This oculomotor nerve disorder may contribute to the diagnosis of SLE and can be effectively treated with steroid pulse therapy. Reports of SLE manifesting as isolated oculomotor nerve paralysis are rare.
Asunto(s)
Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Enfermedades del Nervio Oculomotor/etiología , Enfermedades del Sistema Nervioso Periférico/etiología , Antiinflamatorios/administración & dosificación , Encéfalo/diagnóstico por imagen , Medios de Contraste , Femenino , Humanos , Extremidad Inferior/inervación , Lupus Eritematoso Sistémico/tratamiento farmacológico , Imagen por Resonancia Magnética , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Enfermedades del Nervio Oculomotor/diagnóstico por imagen , Enfermedades del Nervio Oculomotor/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Quimioterapia por PulsoRESUMEN
BACKGROUND: No studies to date have attempted to evaluate frontotemporal lobar degeneration from the perspective of the vestibular system. OBJECTIVE: The present study examined vestibular function in patients with frontotemporal dementia (FTD) clinical syndrome and evaluated whether vestibular disorders are involved in the clinical symptoms due to FTD. METHODS: Fourteen patients with FTD syndrome, as well as healthy elderly controls without dementia, were included in the present study. All subjects underwent vestibular function tests using electronystagmography, such as caloric tests and visual suppression (VS) tests, in which the induced caloric nystagmus was suppressed by visual stimuli. The association between clinical symptoms and vestibular function in the FTD syndrome group was further examined. RESULTS: In the FTD syndrome group, caloric nystagmus was not necessarily suppressed during VS tests. Furthermore, VS was observed to be significantly impaired in FTD syndrome patients with gait disturbance as compared to those without such disturbance. CONCLUSION: The present study revealed that impairment of VS in patients with FTD results in an inability to regulate vestibular function by means of visual perception, regardless of multiple presumed neuropathological backgrounds. This could also be associated with gait disturbance in patients with FTD syndrome.