RESUMEN
BACKGROUND: This cross-sectional study was undertaken to evaluate the existence and distribution of comorbid disorders among myasthenia gravis (MG) patients according to subgroups and to identify the effects of the comorbid diseases of MG patients on clinical outcomes. METHODS: The patients were divided into six subgroups according to serum antibodies, age at onset, and thymoma presence. All patients were treated in line with the International Consensus Guidance for Management of Myasthenia Gravis. To assess the clinical outcome after treatment for MG, we used the MGFA Post-intervention Status. In generalized MG patients, the good prognosis group included patients who were classified as having minimal-manifestation status or better. In ocular MG patients, the remission subgroup included patients who were classified as having complete stable remission or pharmacological remission status. RESULTS: Our study included 168 MG patients, 85 were female while 83 were male. Comorbid diseases were present in 124 (73.8%) MG cases. After at least 1 year of follow-up, 106 (86.8%) of the generalized MG patients were in the good prognosis group and 16 (13.2%) generalized MG patients were in the poor prognosis group. 27 (58.6%) ocular MG patients were in the remission group and 19 (41.3%) ocular MG patients were in the non-remission group. Hypertension increased the risk of poor prognosis by 3.55-fold among patients with generalized MG and type 2 DM increased the risk of not achieving remission by 9.32-fold among patients with ocular MG. CONCLUSION: Hypertension and type 2 DM had negative effects on the clinical outcomes of MG.
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Miastenia Gravis , Timoma , Neoplasias del Timo , Humanos , Masculino , Femenino , Estudios Transversales , Miastenia Gravis/complicaciones , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/epidemiología , Neoplasias del Timo/etiología , Anticuerpos/uso terapéutico , Timectomía/efectos adversos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To find out if Charcot-Marie-Tooth (CMT) patients, who have peripheral vestibular as well as peripheral somatosensory impairment, have worse postural balance than those who do not. METHODS: We studied 32 patients with various CMT phenotypes and genotypes. Vestibular function was measured with the video head impulse test (vHIT) which tests vestibulo-ocular reflex (VOR) gain from each of the six semicircular canals in response to rapid head rotations. Postural balance was evaluated with a battery of four postural tests with emphasis on the modified clinical test of sensory integration in balance (mCTSIB). RESULTS: Half of the 32 patients had some impairment of vestibular function ranging from mild, affecting only 1-2 semicircular canals, to almost total affecting all 6 semicircular canals. Their mCTSIB scores correlated with VOR gain from the vertical rather than from the lateral semicircular canals. The worse the vertical VOR gain the worse the mCTSIB score. CONCLUSION: We propose that any CMT patient could have clinically inapparent vestibular impairment that can be easily measured with the vHIT. This vestibular impairment could be contributing to their imbalance and could respond to a focused vestibular rehabilitation program.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth , Vestíbulo del Laberinto , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/genética , Prueba de Impulso Cefálico , Humanos , Reflejo Vestibuloocular , Canales SemicircularesRESUMEN
Autosomal-recessive mutations in the Alsin Rho guanine nucleotide exchange factor (ALS2) gene may cause specific subtypes of childhood-onset progressive neurodegenerative motor neuron diseases (MND). These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile-onset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next-generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with ALS2-related MND. We identified five novel homozygous pathogenic variants in ALS2 at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.Tyr348Ter), c.1718C>A (p.Ala573Glu), c.3161T>C (p.Leu1054Pro), and c.1471+1G>A (NM_020919.3, NP_065970.2). In our cohort, disease onset was in infancy or early childhood with rapid onset of motor neuron signs. Muscle weakness, spasticity, severe dysarthria, dysphagia, and facial weakness were common features in the first decade of life. Frameshift and nonsense mutations clustered in the N-terminal Alsin domains are most prevalent. We enriched the mutational spectrum of ALS2-related disorders with five novel pathogenic variants. Our study indicates a high detection rate of ALS2 mutations in patients with a clinically well-characterized early onset MND. Intrafamilial and even interfamilial diversity in patients with identical pathogenic variants suggest yet unknown modifiers for phenotypic expression.
Asunto(s)
Predisposición Genética a la Enfermedad , Factores de Intercambio de Guanina Nucleótido/genética , Enfermedad de la Neurona Motora/genética , Adolescente , Adulto , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Niño , Preescolar , Codón sin Sentido/genética , Femenino , Mutación del Sistema de Lectura/genética , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Enfermedad de la Neurona Motora/clasificación , Enfermedad de la Neurona Motora/patología , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/patología , Adulto JovenRESUMEN
Background Recently, urinary excretion of the tetrasaccharide 6-α-D-glucopyranosyl-maltotriose (Glc4) has been proposed as a marker for the diagnosis and monitoring of Pompe disease (PD). We aimed to determine the reference intervals and reliable decision-making levels of urine tetrasaccharide concentrations for the diagnosis of infantile- and late-onset Pompe patients in the Turkish population. Methods In this study, nine patients with PD (five of them with late-onset PD [LOPD]) and 226 healthy individuals (aged 0-64 years) were included. Urine Glc4 concentrations were determined using the ultra-high-performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS) method. Results Our data showed that the urine tetrasaccharide levels decreased with age in healthy individuals (p < 0.001, r = -0.256). It was higher especially during the first year of life compared to that in the elder subjects. The tetrasaccharide level of Pompe patients was higher compared to that of healthy controls of the same age: 99 ± 68 mmol/mol creatinine for infantile onset vs. 4.0 ± 3.0 mmol/mol creatinine for healthy controls of the same age group and 12.1 ± 17.4 mmol/mol creatinine for late onset vs. 1.7±1.2 mmol/mol creatinine for healthy controls of the same age group. Conclusions The results of this study showed that the reference intervals of tetrasaccharide in urine changed over time; therefore, it is critically important to define age-based decision levels for the diagnosis of LOPD.
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Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo II/orina , Oligosacáridos/orina , Adolescente , Adulto , Edad de Inicio , Envejecimiento/metabolismo , Biomarcadores/orina , Niño , Preescolar , Toma de Decisiones Clínicas , Creatinina/sangre , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Turquía , Adulto JovenRESUMEN
The aim of this study was to search for the frequency of late onset Pompe disease (LOPD) among patients who had a myopathy with unknown diagnosis registered in the pre-diagnostic part of a novel registry for LOPD within a collaborative study of neurologists working throughout Turkey. Included in the study were 350 patients older than 18 years who have a myopathic syndrome without a proven diagnosis by serum creatine kinase (CK) levels, electrodiagnostic studies, and/or muscle pathology, and/or genetic tests for myopathies other than LOPD. Acid alpha glucosidase (GAA) in dried blood spot was measured in each patient at two different university laboratories. LOPD was confirmed by mutation analysis in patients with decreased GAA levels from either both or one of the laboratories. Pre-diagnostic data, recorded by 45 investigators from 32 centers on 350 patients revealed low GAA levels in a total of 21 patients; from both laboratories in 6 and from either one of the laboratories in 15. Among them, genetic testing proved LOPD in 3 of 6 patients and 1 of 15 patients with decreased GAA levels from both or one of the laboratories respectively. Registry was transferred to Turkish Neurological Association after completion of the study for possible future use and development. Our collaborative study enabled collection of a considerable amount of data on the registry in a short time. GAA levels by dried blood spot even from two different laboratories in the same patient may not prove LOPD. LOPD seemed to be rarer in Turkey than in Europe.
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Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Edad de Inicio , Creatina Quinasa/sangre , Bases de Datos Factuales , Enfermedad del Almacenamiento de Glucógeno Tipo II/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo II/diagnóstico , Humanos , Tamizaje Masivo , Prevalencia , Sistema de Registros , Turquía/epidemiologíaRESUMEN
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a common, treatable, autoimmune peripheral neuropathy considered to produce imbalance by weakness and proprioceptive impairment rather than vestibular impairment. We measured semicircular canal vestibular function in 21 CIDP patients (15M/6F) by the video head impulse test and postural stability with a battery comprising the modified Clinical Test of Sensory Integration and Balance, the Berg Balance Scale, the Dynamic Gait Index, the Fall Efficiency Scale, and the International Cooperative Ataxia Rating Scale. Of the 21 patients, 16 had vestibular impairment, ranging from mild-affecting just a single semicircular canal, to severe-affecting all 6 canals. Although the severity of the vestibular impairment did not correlate either with the severity of the postural imbalance or of the peripheral neuropathy, our data show that vestibular impairment is an additional challenge to balance that some CIDP patients will face.
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Nervios Craneales/fisiopatología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/complicaciones , Enfermedades Vestibulares/etiología , Femenino , Prueba de Impulso Cefálico , Humanos , Masculino , Conducción Nerviosa/fisiología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Equilibrio Postural/fisiología , Estadísticas no Paramétricas , Enfermedades Vestibulares/diagnóstico , Pruebas de Función VestibularRESUMEN
Myosin storage myopathy (MSM) is a protein aggregate myopathy caused by the accumulation of myosin in muscle fibres and results from MYH7 mutation. Although MYH7 mutation is also an established cause of variable cardiomyopathy with or without skeletal myopathy, cardiomyopathy with MSM is a rare combination. Here, we update the clinical findings in the two brothers that we previously reported as having recessively inherited MSM characterized by scapuloperoneal distribution of weakness and typical hyaline-like bodies in type 1 muscle fibres. One of the patients, weak from childhood but not severely symptomatic until 28 years of age, had an unusual combination of MSM, severe dilated cardiomyopathy, and respiratory impairment at the age of 44 years. We identified homozygous missense mutation c.5458C>T (p.R1820W) in exon 37 in these patients as the second recessive MYH7 mutation reported to date.
Asunto(s)
Miosinas Cardíacas/genética , Enfermedades Musculares/congénito , Mutación Missense , Cadenas Pesadas de Miosina/genética , Adulto , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/fisiopatología , Cardiomiopatía Dilatada/terapia , Progresión de la Enfermedad , Familia , Humanos , Masculino , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , Debilidad Muscular/terapia , Enfermedades Musculares/genética , Enfermedades Musculares/fisiopatología , Enfermedades Musculares/terapiaRESUMEN
We describe a 34-year old man presenting with subacute generalized myasthenic symptoms. His clinical features and laboratory investigations demonstrated both myasthenia gravis and myotonic dystrophy type 1. The computerized tomography of chest revealed anterior mediastinal mass. The lymphocyte-rich thymoma was removed surgically and he received radiotherapy. Recent observations suggested that the patients with myotonic dystrophy may have an increased risk of benign and malignant tumours but its coexistence with thymoma is very rare. The risk of thymoma associated with myotonic dystrophy is unknown.
Asunto(s)
Miastenia Gravis/diagnóstico , Distrofia Miotónica/diagnóstico , Timoma/diagnóstico , Neoplasias del Timo/diagnóstico , Adulto , Humanos , Masculino , Miastenia Gravis/complicaciones , Distrofia Miotónica/complicaciones , Factores de Riesgo , Timoma/complicaciones , Neoplasias del Timo/complicacionesRESUMEN
Congenital myopathies are severe muscle disorders affecting adults as well as children in all populations. The diagnosis of congenital myopathies is constrained by strong clinical and genetic heterogeneity. Moreover, the majority of patients present with unspecific histological features, precluding purposive molecular diagnosis and demonstrating the need for an alternative and more efficient diagnostic approach. We used exome sequencing complemented by histological and ultrastructural analysis of muscle biopsies to identify the causative mutations in eight patients with clinically different skeletal muscle pathologies, ranging from a fatal neonatal myopathy to a mild and slowly progressive myopathy with adult onset. We identified RYR1 (ryanodine receptor) mutations in six patients and NEB (nebulin) mutations in two patients. We found novel missense and nonsense mutations, unraveled small insertions/deletions and confirmed their impact on splicing and mRNA/protein stability. Histological and ultrastructural findings of the muscle biopsies of the patients validated the exome sequencing results. We provide the evidence that an integrated strategy combining exome sequencing with clinical and histopathological investigations overcomes the limitations of the individual approaches to allow a fast and efficient diagnosis, accelerating the patient's access to a better healthcare and disease management. This is of particular interest for the diagnosis of congenital myopathies, which involve very large genes like RYR1 and NEB as well as genetic and phenotypic heterogeneity.
Asunto(s)
Enfermedades Musculares/congénito , Enfermedades Musculares/diagnóstico , Adulto , Secuencia de Bases , Biopsia , Análisis Mutacional de ADN , Exoma/genética , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Músculos/patología , Músculos/ultraestructura , Enfermedades Musculares/genética , Mutación/genética , Linaje , Fenotipo , Análisis de Secuencia de ADNRESUMEN
Familial parkinson's disease is both clinically and genetically heterogeneous. By mapping the disease locus with a lod score of 5.13 to a < 3.5 Mbp region at 1p31.3 in a consanguineous family and subsequent exome sequencing analysis, we identified homozygous truncating mutation p.Q734X in DNAJC6. Four members of the family were afflicted with juvenile parkinsonism that presented with mental retardation, pyramidal signs and epilepsy, as well as varying degrees of a progressive neurological disease. Recently a splicing mutation in the same gene was reported in two brothers with juvenile parkinsonism that was not L-Dopa responsive and not accompanied by pyramidal signs or mental retardation. Also, an 80-kb deletion that included DNAJC6 sequences was identified in a boy reported as having obesity, epilepsy and mental retardation but not any signs of parkinsonism. The phenotype of our study family resembles both of those families, which among themselves do not share any clinical features. Our findings further establish DNAJC6 as a juvenile parkinsonism gene, and expand the spectrums of the parkinsonism phenotype and DNAJC6 mutation. DNAJC6 encodes the neuronal co-chaperone auxilin. We found that its transcript is highly significantly more abundant in brain as compared to the non-neural tissues assayed.
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Predisposición Genética a la Enfermedad/genética , Proteínas del Choque Térmico HSP40/genética , Trastornos Parkinsonianos/genética , Adolescente , Adulto , Consanguinidad , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Masculino , Mutación , Linaje , Fenotipo , Adulto JovenRESUMEN
Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.
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Dinamina II/genética , Genes Dominantes , Estudios de Asociación Genética , Mutación , Miopatías Estructurales Congénitas/genética , Secuencia de Aminoácidos , Dinamina II/química , Humanos , Datos de Secuencia Molecular , Miopatías Estructurales Congénitas/diagnóstico , Polimorfismo Genético , Alineación de SecuenciaRESUMEN
Sydenham chorea is an immune-mediated neuropsychiatric disorder associated with group A beta-hemolytic streptococci infection. The authors present a 12-year-old female patient with Sydenham chorea and Hashimoto thyroiditis. Although Hashimoto thyroiditis has been associated with other autoimmune disorders, the association of Sydenham chorea and Hashimoto thyroiditis has not been previously reported. Immunological processes are suggested to be implicated in the pathogenesis of this association; however, the exact mechanism remains unclear.
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Corea/complicaciones , Corea/diagnóstico , Enfermedad de Hashimoto/complicaciones , Autoanticuerpos/inmunología , Niño , Corea/inmunología , Femenino , Enfermedad de Hashimoto/inmunología , Humanos , Factores de RiesgoRESUMEN
We present the case of a 14-year-old female who had many characteristics of neuroleptic malignant syndrome (NMS) without pyrexia following a single depot injection of 200 mg of zuclopenthixol. The patient presented with a change in mental status that had progressed over the preceding 48 hours. Subsequently, she became increasingly agitated and confused, and developed diffuse muscular rigidity, mutism, tremor, tachycardia, diaphoresis, sialorrhea, and incontinence. Results of laboratory tests showed elevated CPK levels, leukocytosis, and a low serum iron level. Bromocriptine and diazepam were used as initial treatment of a probable NMS and provided significant improvement. During the next seven days, she clinically improved but continued to exhibit emotional lability, logorrhea, elevated mood, and increased psychomotor activity. Therefore, bromocriptine and diazepam were discontinued and lorazepam and lithium were administered as treatment of a bipolar disorder. Four weeks later, she was discharged in stable condition. The presentation of this case report suggests that the primary psychiatric diagnosis is important in antipsychotic usage in the pediatric population, and that young patients receiving neuroleptic treatment should be monitored for the early signs of NMS. Using the diagnostic criteria of a neuroleptic toxicity spectrum may result in greater clinical awareness and earlier recognition of NMS.
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Antipsicóticos/envenenamiento , Clopentixol/envenenamiento , Síndrome Neuroléptico Maligno/fisiopatología , Adolescente , Ansiolíticos/uso terapéutico , Antídotos/uso terapéutico , Antipsicóticos/administración & dosificación , Bromocriptina/uso terapéutico , Clopentixol/administración & dosificación , Preparaciones de Acción Retardada , Diazepam/uso terapéutico , Agonistas de Dopamina/uso terapéutico , Femenino , Humanos , Hipnóticos y Sedantes/uso terapéutico , Inyecciones Intramusculares , Compuestos de Litio/uso terapéutico , Lorazepam/uso terapéutico , Síndrome Neuroléptico Maligno/tratamiento farmacológico , Síndrome Neuroléptico Maligno/etiología , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate atypical electroencephalographic features in subacute sclerosing panencephalitis (SSPE) and to detect its relation to clinical features. METHODS: Twenty-two patients aged 2-17 years (mean 9.4 years) with definite diagnosis of SSPE were studied. Their clinical data and EEG records were reviewed retrospectively. All EEG records were analysed for features of periodic complexes (PCs) in relation to age, age at onset, clinical stage and the rate of progression as well as duration of the disease. RESULTS: Classical periodic complexes of SSPE were found in EEGs of 13 patients (group I). Atypical patterns were observed in EEGs of nine patients (group II). Two new atypical findings were identified: prolonged discharges which include sharp waves and slow waves for 4-7 s followed by suppression for 1-4s; and periodic complexes which consist of four or five sharp waves in every 2 s. We observed atypical EEG patterns were more frequently in Stage III, acute form, and the disease duration was longer than in the typical group. CONCLUSIONS: Atypical EEG patterns in SSPE might be related to the progression of the disease, but this theory needs further longitudinal studies. SIGNIFICANCE: We suggest atypical EEG patterns might be observed more frequently in patients with severe neurologic disability, more rapidly progressive disease and longer duration of disease.
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Electroencefalografía , Panencefalitis Esclerosante Subaguda/patología , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
We carried out molecular deletion analysis on 142 patients with Duchenne/Becker muscular dystrophy which covered 25 exons of the dystrophin gene. We also evaluated the results by comparing with the clinical findings and examples in the literature. A deletion ratio of 63.7% was achieved. Exon 46 was the most frequently affected region. Interestingly we also observed four cases with muscle promoter (Mp) region deletions which have been rarely reported in the literature.
Asunto(s)
Distrofina/genética , Eliminación de Gen , Distrofia Muscular de Duchenne/genética , Adolescente , Adulto , Niño , Exones/genética , Salud de la Familia , Genotipo , Humanos , Intrones/genética , Distrofia Muscular de Duchenne/patología , FenotipoRESUMEN
Hyaline body myopathy is a rare congenital disease with distinctive histopathological features. We performed homozygosity mapping in a family with two affected sibs and identified a gene locus with a maximum homozygosity region of 5.35 centi Morgans or 5.59 Megabases at chromosome 3p22.2-p21.32. The best candidate responsible for the disease is a novel gene that exhibits homology to the myosin heavy chain.