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OBJECTIVE: Duchenne muscular dystrophy (DMD) exon 45-55 deletion (del45-55) has been postulated as a model that could treat up to 60% of DMD patients, but the associated clinical variability and complications require clarification. We aimed to understand the phenotypes and potential modifying factors of this dystrophinopathy subset. METHODS: This cross-sectional, multicenter cohort study applied clinical and functional evaluation. Next generation sequencing was employed to identify intronic breakpoints and their impact on the Dp140 promotor, intronic long noncoding RNA, and regulatory splicing sequences. DMD modifiers (SPP1, LTBP4, ACTN3) and concomitant mutations were also assessed. Haplotypes were built using DMD single nucleotide polymorphisms. Dystrophin expression was evaluated via immunostaining, Western blotting, reverse transcription polymerase chain reaction (PCR), and droplet digital PCR in 9 muscle biopsies. RESULTS: The series comprised 57 subjects (23 index) expressing Becker phenotype (28%), isolated cardiopathy (19%), and asymptomatic features (53%). Cognitive impairment occurred in 90% of children. Patients were classified according to 10 distinct index-case breakpoints; 4 of them were recurrent due to founder events. A specific breakpoint (D5) was associated with severity, but no significant effect was appreciated due to the changes in intronic sequences. All biopsies showed dystrophin expression of >67% and traces of alternative del45-57 transcript that were not deemed pathogenically relevant. Only the LTBP4 haplotype appeared associated the presence of cardiopathy among the explored extragenic factors. INTERPRETATION: We confirmed that del45-55 segregates a high proportion of benign phenotypes, severe cases, and isolated cardiac and cognitive presentations. Although some influence of the intronic breakpoint position and the LTBP4 modifier may exist, the pathomechanisms responsible for the phenotypic variability remain largely unresolved. ANN NEUROL 2022;92:793-806.
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Distrofia Muscular de Duchenne , ARN Largo no Codificante , Humanos , Distrofina/genética , Distrofina/metabolismo , Estudios de Cohortes , Estudios Transversales , Exones/genética , Distrofia Muscular de Duchenne/metabolismo , Fenotipo , Actinina/genéticaRESUMEN
BACKGROUND AND PURPOSE: Patients with neuromuscular conditions are at increased risk of suffering perioperative complications related to anaesthesia. There is currently little specific anaesthetic guidance concerning these patients. Here, we present the European Neuromuscular Centre (ENMC) consensus statement on anaesthesia in patients with neuromuscular disorders as formulated during the 259th ENMC Workshop on Anaesthesia in Neuromuscular Disorders. METHODS: International experts in the field of (paediatric) anaesthesia, neurology, and genetics were invited to participate in the ENMC workshop. A literature search was conducted in PubMed and Embase, the main findings of which were disseminated to the participants and presented during the workshop. Depending on specific expertise, participants presented the existing evidence and their expert opinion concerning anaesthetic management in six specific groups of myopathies and neuromuscular junction disorders. The consensus statement was prepared according to the AGREE II (Appraisal of Guidelines for Research & Evaluation) reporting checklist. The level of evidence has been adapted according to the SIGN (Scottish Intercollegiate Guidelines Network) grading system. The final consensus statement was subjected to a modified Delphi process. RESULTS: A set of general recommendations valid for the anaesthetic management of patients with neuromuscular disorders in general have been formulated. Specific recommendations were formulated for (i) neuromuscular junction disorders, (ii) muscle channelopathies (nondystrophic myotonia and periodic paralysis), (iii) myotonic dystrophy (types 1 and 2), (iv) muscular dystrophies, (v) congenital myopathies and congenital dystrophies, and (vi) mitochondrial and metabolic myopathies. CONCLUSIONS: This ENMC consensus statement summarizes the most important considerations for planning and performing anaesthesia in patients with neuromuscular disorders.
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Anestesia , Anestésicos , Enfermedades Musculares , Enfermedades Neuromusculares , Enfermedades de la Unión Neuromuscular , Humanos , NiñoRESUMEN
The causative mutation responsible for limb girdle muscular dystrophy 1F (LGMD1F) is one heterozygous single nucleotide deletion in the stop codon of the nuclear import factor Transportin 3 gene (TNPO3). This mutation causes a carboxy-terminal extension of 15 amino acids, producing a protein of unknown function (TNPO3_mut) that is co-expressed with wild-type TNPO3 (TNPO3_wt). TNPO3 has been involved in the nuclear transport of serine/arginine-rich proteins such as splicing factors and also in HIV-1 infection through interaction with the viral integrase and capsid. We analyzed the effect of TNPO3_mut on HIV-1 infection using PBMCs from patients with LGMD1F infected ex vivo. HIV-1 infection was drastically impaired in these cells and viral integration was reduced 16-fold. No significant effects on viral reverse transcription and episomal 2-LTR circles were observed suggesting that the integration of HIV-1 genome was restricted. This is the second genetic defect described after CCR5Δ32 that shows strong resistance against HIV-1 infection.
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Infecciones por VIH/prevención & control , VIH-1/fisiología , Distrofia Muscular de Cinturas/patología , Mutación , Replicación Viral/genética , beta Carioferinas/genética , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Infecciones por VIH/genética , Infecciones por VIH/virología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Distrofia Muscular de Cinturas/genética , Linaje , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Distal hereditary motor neuropathies (dHMNs) are a heterogeneous group of disorders characterized by degeneration of the motor component of peripheral nerves. Currently, only 15% to 32.5% of patients with dHMN are characterized genetically. Additionally, the prevalence of these genetic disorders is not well known. Recently, biallelic mutations in the sorbitol dehydrogenase gene (SORD) have been identified as a cause of dHMN, with an estimated frequency in undiagnosed cases of up to 10%. METHODS: In the present study, we included 163 patients belonging to 108 different families who were diagnosed with a dHMN and who underwent a thorough genetic screening that included next-generation sequencing and subsequent Sanger sequencing of SORD. RESULTS: Most probands were sporadic cases (62.3%), and the most frequent age of onset of symptoms was 2 to 10 years (28.8%). A genetic diagnosis was achieved in 37/108 (34.2%) families and 78/163 (47.8%) of all patients. The most frequent cause of distal hereditary motor neuropathies were mutations in HSPB1 (10.4%), GARS1 (9.8%), BICD2 (8.0%), and DNAJB2 (6.7%) genes. In addition, 3.1% of patients were found to be carriers of biallelic mutations in SORD. Mutations in another seven genes were also identified, although they were much less frequent. Eight new pathogenic mutations were detected, and 17 patients without a definite genetic diagnosis carried variants of uncertain significance. The calculated minimum prevalence of dHMN was 2.3 per 100,000 individuals. CONCLUSIONS: This study confirms the genetic heterogeneity of dHMN and that biallelic SORD mutations are a cause of dHMN in different populations.
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Enfermedad de Charcot-Marie-Tooth , Neuropatía Hereditaria Motora y Sensorial , Enfermedad de Charcot-Marie-Tooth/genética , Niño , Preescolar , Estudios de Asociación Genética , Pruebas Genéticas , Proteínas del Choque Térmico HSP40 , Heterocigoto , Humanos , Chaperonas Moleculares , MutaciónRESUMEN
BACKGROUND AND OBJECTIVE: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by an abnormal expansion of GCN triplets within the PABPN1 gene. Previous descriptions have focused on lower limb muscles in small cohorts of patients with OPMD, but larger imaging studies have not been performed. Previous imaging studies have been too small to be able to correlate imaging findings to genetic and clinical data. METHODS: We present cross-sectional, T1-weighted muscle MRI and CT-scan data from 168 patients with genetically confirmed OPMD. We have analysed the pattern of muscle involvement in the disease using hierarchical analysis and presented it as heatmaps. Results of the scans were correlated with genetic and clinical data. RESULTS: Fatty replacement was identified in 96.7% of all symptomatic patients. The tongue, the adductor magnus and the soleus were the most commonly affected muscles. Muscle pathology on MRI correlated positively with disease duration and functional impairment. CONCLUSIONS: We have described a pattern that can be considered characteristic of OPMD. An early combination of fat replacement in the tongue, adductor magnus and soleus can be helpful for differential diagnosis. The findings suggest the natural history of the disease from a radiological point of view. The information generated by this study is of high diagnostic value and important for clinical trial development.
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Músculo Esquelético/diagnóstico por imagen , Distrofia Muscular Oculofaríngea/diagnóstico por imagen , Adulto , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Distrofia Muscular Oculofaríngea/complicaciones , Distrofia Muscular Oculofaríngea/patología , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Mutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME. METHODS: We screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members. RESULTS: We found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease. CONCLUSION: MME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.
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Estudios de Asociación Genética , Patrón de Herencia , Metaloendopeptidasas/genética , Mutación , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/genética , Fenotipo , Adulto , Anciano , Alelos , Sustitución de Aminoácidos , Electromiografía , Fenómenos Electrofisiológicos , Femenino , Frecuencia de los Genes , Genes Recesivos , Genotipo , Humanos , Imagen por Resonancia Magnética , Masculino , Metaloendopeptidasas/metabolismo , Persona de Mediana Edad , LinajeRESUMEN
Charcot-Marie-Tooth disease type 4C (CMT4C) is a hereditary neuropathy with prominent unsteadiness. The objective of the current study is to determine whether the imbalance in CMT4C is caused only by reduced proprioceptive input or if vestibular nerve involvement is an additional factor. We selected 10 CMT4C patients and 10 age-matched and sex-matched controls. We performed a comprehensive evaluation of the vestibular system, including video Head Impulse Test, bithermal caloric test, galvanic stimulation test and skull vibration-induced nystagmus test. None of the patients experienced dizziness, spontaneous or gaze-evoked nystagmus, but all had significant vestibular impairment when tested when compared to controls. Seven had completely unexcitable vestibular systems and abnormal vestibuloocular reflex. There was no correlation between the degree of vestibulopathy and age or clinical severity. Significant vestibular impairment is a consistent finding in CMT4C and is present early in disease evolution. The profound imbalance that is so disabling in these patients may result from a combination of proprioceptive loss and vestibular neuropathy, and this would modify the recommended rehabilitation strategies.
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Enfermedad de Charcot-Marie-Tooth/fisiopatología , Enfermedades Vestibulares/fisiopatología , Adulto , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vestíbulo del Laberinto/fisiopatología , Adulto JovenRESUMEN
A single-nucleotide deletion in the stop codon of the nuclear import receptor transportin-3 (TNPO3), also involved in human immunodeficiency virus type 1 (HIV-1) infection, causes the ultrarare autosomal dominant disease limb-girdle muscular dystrophy D2 (LGMDD2) by extending the wild-type protein. Here, we generated a patient-derived in vitro model of LGMDD2 as an immortalized myoblast cell line carrying the TNP O 3 mutation. The cell model reproduced critical molecular alterations seen in patients, such as TNP O 3 overexpression, defects in terminal muscle markers, and autophagy overactivation. Correction of the TNP O 3 mutation via CRISPR-Cas9 editing caused a significant reversion of the pathological phenotypes in edited cells, including a complete absence of the mutant TNPO3 protein, as detected with a polyclonal antibody specific against the abnormal 15-aa peptide. Transcriptomic analyses found that 15% of the transcriptome was differentially expressed in model myotubes. CRISPR-Cas9-corrected cells showed that 44% of the alterations were rescued toward normal levels. MicroRNAs (miRNAs) analyses showed that around 50% of miRNAs with impaired expression because of the disease were recovered on the mutation edition. In summary, this work provides proof of concept of the potential of CRISPR-Cas9-mediated gene editing of TNP O 3 as a therapeutic approach and describes critical reagents in LGMDD2 research.
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Myosin heavy chains encoded by MYH7 and MYH2 are abundant in human skeletal muscle and important for muscle contraction. However, it is unclear how mutations in these genes disrupt myosin structure and function leading to skeletal muscle myopathies termed myosinopathies. Here, we used multiple approaches to analyze the effects of common MYH7 and MYH2 mutations in the light meromyosin (LMM) region of myosin. Analyses of expressed and purified MYH7 and MYH2 LMM mutant proteins combined with in silico modeling showed that myosin coiled coil structure and packing of filaments in vitro are commonly disrupted. Using muscle biopsies from patients and fluorescent ATP analog chase protocols to estimate the proportion of myosin heads that were super-relaxed, together with x-ray diffraction measurements to estimate myosin head order, we found that basal myosin ATP consumption was increased and the myosin super-relaxed state was decreased in vivo. In addition, myofiber mechanics experiments to investigate contractile function showed that myofiber contractility was not affected. These findings indicate that the structural remodeling associated with LMM mutations induces a pathogenic state in which formation of shutdown heads is impaired, thus increasing myosin head ATP demand in the filaments, rather than affecting contractility. These key findings will help design future therapies for myosinopathies.
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Enfermedades Musculares , Humanos , Enfermedades Musculares/patología , Miosinas/genética , Músculo Esquelético/metabolismo , Mutación , Adenosina TrifosfatoRESUMEN
LGMDD2 is a rare form of muscular dystrophy characterized by one of the three heterozygous deletions described within the TNPO3 gene that result in the addition of a 15-amino acid tail in the C-terminus.TNPO3 is involved in the nuclear import of splicing factors and acts as a host cofactor for HIV-1 infection by mechanisms not yet deciphered. Further characterization of the crosstalk between HIV-1 infection and LGMDD2 disease may contribute to a better understanding of both the cellular alterations occurring in LGMDD2 patients and the role of TNPO3 in the HIV-1 cycle. To this regard, transcriptome profiling of PBMCs from LGMDD2 patients carrying the deletion c.2771delA in the TNPO3 gene was compared to healthy controls. A total of 545 differentially expressed genes were detected between LGMDD2 patients and healthy controls, with a high representation of G protein-coupled receptor binding chemokines and metallopeptidases among the most upregulated genes in LGMDD2 patients. Plasma levels of IFN-ß and IFN-γ were 4.7- and 2.7-fold higher in LGMDD2 patients, respectively. An increase of 2.3-fold in the expression of the interferon-stimulated gene MxA was observed in activated PBMCs from LGMDD2 patients after ex vivo HIV-1 pseudovirus infection. Thus, the analysis suggests a pro-inflammatory state in LGMDD2 patients also described for other muscular dystrophies, that is characterized by the alteration of IL-17 signaling pathway and the consequent increase of metallopeptidases activity and TNF response. In summary, the increase in interferons and inflammatory mediators suggests an antiviral environment and resistance to HIV-1 infection but that could also impair muscular function in LGMDD2 patients, worsening disease evolution. Biomarkers of disease progression and therapeutic strategies based on these genes and mechanisms should be further investigated for this type of muscular dystrophy.
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Nemaline myopathy (NM) is one of the most common non-dystrophic genetic muscle disorders. NM is often associated with mutations in the NEB gene. Even though the exact NEB-NM pathophysiological mechanisms remain unclear, histological analyses of patients' muscle biopsies often reveal unexplained accumulation of glycogen and abnormally shaped mitochondria. Hence, the aim of the present study was to define the exact molecular and cellular cascade of events that would lead to potential changes in muscle energetics in NEB-NM. For that, we applied a wide range of biophysical and cell biology assays on skeletal muscle fibres from NM patients as well as untargeted proteomics analyses on isolated myofibres from a muscle-specific nebulin-deficient mouse model. Unexpectedly, we found that the myosin stabilizing conformational state, known as super-relaxed state, was significantly impaired, inducing an increase in the energy (ATP) consumption of resting muscle fibres from NEB-NM patients when compared with controls or with other forms of genetic/rare, acquired NM. This destabilization of the myosin super-relaxed state had dynamic consequences as we observed a remodeling of the metabolic proteome in muscle fibres from nebulin-deficient mice. Altogether, our findings explain some of the hitherto obscure hallmarks of NM, including the appearance of abnormal energy proteins and suggest potential beneficial effects of drugs targeting myosin activity/conformations for NEB-NM.
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Miopatías Nemalínicas , Animales , Ratones , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/patología , Mutación/genética , Miopatías Nemalínicas/genética , Miopatías Nemalínicas/patología , Miosinas/metabolismo , Proteoma/metabolismoRESUMEN
Human CMT2-FiPS4F1 cell line was generated from fibroblasts of a patient with Charcot-Marie-Tooth disease harbouring the following mutations in the GDAP1 gene in heterozygosis: p.Q163X/p.T288NfsX3. This patient did not present mutations in the PM22, MPZ or GJB genes. Human reprogramming factors OCT3/4, KLF4, SOX2 and C-MYC were delivered using a non-integrative methodology that involves the use of Sendai virus.
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Reprogramación Celular , Enfermedad de Charcot-Marie-Tooth/patología , Células Madre Pluripotentes Inducidas/citología , Proteínas del Tejido Nervioso/genética , Secuencia de Bases , Diferenciación Celular , Línea Celular , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/metabolismo , Análisis Mutacional de ADN , Fibroblastos/citología , Fibroblastos/metabolismo , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Heterocigoto , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Cariotipo , Factor 4 Similar a Kruppel , Masculino , Microscopía Fluorescente , Polimorfismo de Nucleótido Simple , Virus Sendai/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Mutations in the GDAP1 gene can cause Charcot-Marie-Tooth disease. These mutations are quite rare in most Western countries but not so in certain regions of Spain or other Mediterranean countries. This cross-sectional retrospective multicenter study analyzed the clinical and genetic characteristics of patients with GDAP1 mutations across Spain. 99 patients were identified, which were distributed across most of Spain, but especially in the Northwest and Mediterranean regions. The most common genotypes were p.R120W (in 81% of patients with autosomal dominant inheritance) and p.Q163X (in 73% of autosomal recessive patients). Patients with recessively inherited mutations had a more severe phenotype, and certain clinical features, like dysphonia or respiratory dysfunction, were exclusively detected in this group. Dominantly inherited mutations had prominent clinical variability regarding severity, including 29% of patients who were asymptomatic. There were minor clinical differences between patients harboring specific mutations but not when grouped according to localization or type of mutation. This is the largest clinical series to date of patients with GDAP1 mutations, and it contributes to define the genetic distribution and genotype-phenotype correlation in this rare form of CMT.
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Enfermedad de Charcot-Marie-Tooth/genética , Estudios de Asociación Genética , Mutación , Proteínas del Tejido Nervioso/genética , Adolescente , Adulto , Anciano , Enfermedad de Charcot-Marie-Tooth/metabolismo , Niño , Preescolar , Estudios Transversales , Femenino , Geografía Médica , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , España , Adulto JovenRESUMEN
We aimed to identify new cell-membrane antigens implicated in opsoclonus-myoclonus with neuroblastoma. The sera of 3 out of 14 patients showed IgG electron-microscopy immunogold reactivity on SH-SY5Y neuroblastoma cells. Immunoprecipitation experiments using rat brain synaptosomes and SH-SY5Y cells led to the identification of: (1) thirty-one nuclear/cytoplasmic proteins (including antigens HuB, HuC); (2) seven neuronal membrane proteins, including the Shaw-potassium channel Kv3.3 (KCNC3), whose genetic disruption in mice causes ataxia and generalized muscle twitching. Although cell-based assays did not demonstrate direct antigenicity, our findings point to Shaw-related subfamily of the potassium voltage-gated channels complexed proteins as hypothetical antigenic targets.
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Neoplasias Encefálicas , Sistema Nervioso Central/metabolismo , Neuroblastoma , Síndrome de Opsoclonía-Mioclonía , Animales , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Moléculas de Adhesión Celular Neuronal/metabolismo , Línea Celular Tumoral , Sistema Nervioso Central/ultraestructura , Niño , Bases de Datos Factuales/estadística & datos numéricos , Encefalitis/complicaciones , Encefalitis/inmunología , Femenino , Células HEK293 , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/ultraestructura , Neuroblastoma/complicaciones , Neuroblastoma/inmunología , Neuroblastoma/patología , Proteínas Nucleares/metabolismo , Proteínas Nucleares/ultraestructura , Síndrome de Opsoclonía-Mioclonía/complicaciones , Síndrome de Opsoclonía-Mioclonía/inmunología , Síndrome de Opsoclonía-Mioclonía/patología , Ratas , Ratas Wistar , Canales de Potasio Shaw/inmunología , Canales de Potasio Shaw/metabolismo , Canales de Potasio Shaw/ultraestructura , Sinaptosomas/metabolismo , Sinaptosomas/ultraestructura , Timoma/complicacionesRESUMEN
BACKGROUND AND OBJECTIVE: The use of transcranial doppler (TD) for the assessment of critical neurological patients and brain death (BD) is steadily growing. In this study we describe the daily clinical practice around BD diagnosis and compare the usefulness of TD, including advantages and shortcomings, with that of other tests. PATIENTS AND METHOD: A series of 100 patients diagnosed of brain death is presented including the demographic and clinical data as well as the results of ancillary tests (CE). RESULTS: Fifty eight patients were males with a mean age of 46. The most frequent etiology of coma was spontaneous cerebral hemorrhage. Central nervous system depressants had been administered to 62 patients within a few hours prior to the diagnosis. When ancillary tests were performed, only 55% patients fulfilled the currently accepted clinical criteria for brain death. TD was performed in 44 patients and 80% of them showed a pattern supporting a brain death diagnosis. Definitive diagnostic tests were electroencephalogram (EEG) in 53% patients and TD in 35% of them. In ten cases, discrepancies were observed between the results offered by these tests. CONCLUSIONS: Transcraneal Doppler stands out as a safe, fast, inexpensive and bloodless method of assessment of the critical neurological patient and for BD diagnosis. It is the choice test in the presence of central nervous system depressant drugs, abuse of substances or coma of unknown etiology. The main limitations of this technique are the presence of extensive craniotomies and the absence of an adequate acoustic window.
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Muerte Encefálica/diagnóstico por imagen , Ultrasonografía Doppler Transcraneal , Adolescente , Adulto , Anciano , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVES: To determine the genetic distribution and the phenotypic correlation of an extensive series of patients with Charcot-Marie-Tooth disease in a geographically well-defined Mediterranean area. METHODS: A thorough genetic screening, including most of the known genes involved in this disease, was performed and analyzed in this longitudinal descriptive study. Clinical data were analyzed and compared among the genetic subgroups. RESULTS: Molecular diagnosis was accomplished in 365 of 438 patients (83.3%), with a higher success rate in demyelinating forms of the disease. The CMT1A duplication (PMP22 gene) was the most frequent genetic diagnosis (50.4%), followed by mutations in the GJB1 gene (15.3%), and in the GDAP1 gene (11.5%). Mutations in 13 other genes were identified, but were much less frequent. Sixteen novel mutations were detected and characterized phenotypically. CONCLUSIONS: The relatively high frequency of GDAP1 mutations, coupled with the scarceness of MFN2 mutations (1.1%) and the high proportion of recessive inheritance (11.6%) in this series exemplify the particularity of the genetic distribution of Charcot-Marie-Tooth disease in this region.
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Enfermedad de Charcot-Marie-Tooth , Conexinas/genética , Mutación/genética , Proteínas de la Mielina/genética , Proteínas del Tejido Nervioso/genética , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/epidemiología , Enfermedad de Charcot-Marie-Tooth/genética , Análisis Mutacional de ADN , Femenino , Deformidades del Pie/etiología , Humanos , Estudios Longitudinales , Masculino , Fuerza Muscular/fisiología , Atrofia Muscular/etiología , Estudios Retrospectivos , Trastornos de la Sensación/etiología , España/epidemiología , Proteína beta1 de Unión ComunicanteRESUMEN
FUNDAMENTO Y OBJETIVO: El Doppler transcraneal (DTC) se está extendiendo para la monitorización del paciente neurocrítico y el diagnóstico de muerte encefálica (ME). Nuestro objetivo es describir las condiciones clínicas en que se diagnostica la ME y establecer la utilidad del DTC, sus limitaciones y ventajas frente a otras técnicas. PACIENTES Y MÉTODO: Presentamos una serie de 100 pacientes diagnosticados de ME, de los que se recogen y analizan datos demográficos, clínicos, resultados de las exploraciones complementarias y las discordancias entre ellas. RESULTADOS: El 58 por ciento eran varones y la edad media de 46 años; la causa más frecuente del coma fue la hemorragia cerebral. En 62 pacientes se habían administrado depresores del sistema nervioso central en las horas previas. Sólo 55 cumplían todos los criterios clínicos de ME cuando se solicitó una exploración complementaria. Se realizó DTC en 44 pacientes con un 80 por ciento de patrones compatibles con ME. La confirmación se realizó en el 53 por ciento con electroencefalograma y en 35 por ciento con DTC. Existía discordancia en los resultados de las exploraciones complementarias en 10 pacientes. CONCLUSIONES: El DTC es rápido, barato e incruento en la monitorización del paciente neurocrítico y en el diagnóstico de ME. Es de elección en comas de causa desconocida, tóxicos o depresores. Sus principales limitaciones son las aperturas craneales extensas y la mala ventana (AU)