RESUMEN
ATP1A3 encodes the α3 subunit of the sodium-potassium ATPase, one of two isoforms responsible for powering electrochemical gradients in neurons. Heterozygous pathogenic ATP1A3 variants produce several distinct neurological syndromes, yet the molecular basis for phenotypic variability is unclear. We report a novel recurrent variant, ATP1A3(NM_152296.5):c.2324C>T; p.(Pro775Leu), in nine individuals associated with the primary clinical features of progressive or non-progressive spasticity and developmental delay/intellectual disability. No patients fulfil diagnostic criteria for ATP1A3-associated syndromes, including alternating hemiplegia of childhood, rapid-onset dystonia-parkinsonism or cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss (CAPOS), and none were suspected of having an ATP1A3-related disorder. Uniquely among known ATP1A3 variants, P775L causes leakage of sodium ions and protons into the cell, associated with impaired sodium binding/occlusion kinetics favouring states with fewer bound ions. These phenotypic and electrophysiologic studies demonstrate that ATP1A3:c.2324C>T; p.(Pro775Leu) results in mild ATP1A3-related phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy. Cation leak provides a molecular explanation for this genotype-phenotype correlation, adding another mechanism to further explain phenotypic variability and highlighting the importance of biophysical properties beyond ion transport rate in ion transport diseases.
Asunto(s)
Ataxia Cerebelosa , Discapacidad Intelectual , Humanos , Mutación/genética , Síndrome , Discapacidad Intelectual/genética , Ataxia Cerebelosa/genética , Fenotipo , Espasticidad Muscular/genética , Cationes , ATPasa Intercambiadora de Sodio-Potasio/genéticaRESUMEN
Mutations in MORC2 lead to an axonal form of Charcot-Marie-Tooth (CMT) neuropathy type 2Z. To date, 31 families have been described with mutations in MORC2, indicating that this gene is frequently involved in axonal CMT cases. While the genetic data clearly establish the causative role of MORC2 in CMT2Z, the impact of its mutations on neuronal biology and their phenotypic consequences in patients remains to be clarified. We show that the full-length form of MORC2 is highly expressed in both embryonic and adult human neural tissues and that Morc2 expression is dynamically regulated in both the developing and the maturing murine nervous system. To determine the effect of the most common MORC2 mutations, p.S87L and p.R252W, we used several in vitro cell culture paradigms. Both mutations induced transcriptional changes in patient-derived fibroblasts and when expressed in rodent sensory neurons. These changes were more pronounced and accompanied by abnormal axonal morphology, in neurons expressing the MORC2 p.S87L mutation, which is associated with a more severe clinical phenotype. These data provide insight into the neuronal specificity of the mutated MORC2-mediated phenotype and highlight the importance of neuronal cell models to study the pathophysiology of CMT2Z.
Asunto(s)
Axones/metabolismo , Enfermedad de Charcot-Marie-Tooth/genética , Células Receptoras Sensoriales/metabolismo , Factores de Transcripción/genética , Animales , Axones/patología , Enfermedad de Charcot-Marie-Tooth/patología , Células Madre Embrionarias/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Regulación de la Expresión Génica/genética , Humanos , Mutación/genética , Células-Madre Neurales , Ratas , Células Receptoras Sensoriales/patologíaRESUMEN
Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.
Asunto(s)
Axones/patología , Enfermedad de Charcot-Marie-Tooth/genética , Mutación , Factores de Transcripción/genética , Adulto , Anciano , Animales , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/patología , Femenino , Expresión Génica/genética , Humanos , Lactante , Masculino , Ratones , Persona de Mediana Edad , Linaje , Fenotipo , Nervio Ciático/metabolismo , Nervio Sural/ultraestructura , Factores de Transcripción/biosíntesis , Adulto JovenRESUMEN
Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed whole-exome sequencing to determine the underlying defect in a group of individuals with an inherited limb-girdle pattern of myasthenic weakness. We identify DPAGT1 as a gene in which mutations cause a congenital myasthenic syndrome. We describe seven different mutations found in five individuals with DPAGT1 mutations. The affected individuals share a number of common clinical features, including involvement of proximal limb muscles, response to treatment with cholinesterase inhibitors and 3,4-diaminopyridine, and the presence of tubular aggregates in muscle biopsies. Analyses of motor endplates from two of the individuals demonstrate a severe reduction of endplate acetylcholine receptors. DPAGT1 is an essential enzyme catalyzing the first committed step of N-linked protein glycosylation. Our findings underscore the importance of N-linked protein glycosylation for proper functioning of the neuromuscular junction. Using the DPAGT1-specific inhibitor tunicamycin, we show that DPAGT1 is required for efficient glycosylation of acetylcholine-receptor subunits and for efficient export of acetylcholine receptors to the cell surface. We suggest that the primary pathogenic mechanism of DPAGT1 mutations is reduced levels of acetylcholine receptors at the endplate region. These individuals share clinical features similar to those of congenital myasthenic syndrome due to GFPT1 mutations, and their disorder might be part of a larger subgroup comprising the congenital myasthenic syndromes that result from defects in the N-linked glycosylation pathway and that manifest through impaired neuromuscular transmission.
Asunto(s)
Síndromes Miasténicos Congénitos/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , 4-Aminopiridina/análogos & derivados , 4-Aminopiridina/farmacología , Adulto , Amifampridina , Inhibidores de la Colinesterasa/uso terapéutico , Femenino , Glicosilación , Humanos , Extremidad Inferior , Masculino , Persona de Mediana Edad , Placa Motora/metabolismo , Mutación , Síndromes Miasténicos Congénitos/patología , Unión Neuromuscular/metabolismo , Receptores Colinérgicos/metabolismo , Transferasas (Grupos de Otros Fosfatos Sustitutos)/antagonistas & inhibidores , Tunicamicina/farmacologíaRESUMEN
BACKGROUND: SMA is a hereditary neuromuscular disease that causes progressive muscle weakness and atrophy. Several studies have shown that the burden of SMA is very high at many levels. Functional assessment tools currently used do not completely address the impact of the disease in patients' life. The objective of this qualitative study was to identify aspects of SMA that are relevant to patients and to design items useful for assessment purposes. RESULTS: Five focus group sessions were run during an annual SMA families meeting in Madrid, Spain. Focus groups were composed by parents of SMA type I children, sitter children type II-III, parents of sitter children type II-III, adult patients, and parents of walker children. Two trained facilitators conducted the focus groups using a semi-structured guideline to cover previously agreed topics based on the input of a Scientific and Patient Advisory Committee. The guideline was adapted for the different groups. According to what was communicated by participants, SMA entails a high burden of disease for both patients and their parents. Burden was perceived in physical, psychological, and social areas. Patient's physical domain was the most relevant for participants, especially for parents of non-ambulant children, followed by limitations of motor scales to capture all changes, parents psychological burden, treatment expectations and patient's psychological burden. Ten domains were the main areas identified as impacted by the disease: mobility and independence, fatigue and fatigability, infections and hospital consultations, scoliosis and contractures, vulnerability, pain, feeding, time spent in care, breathing, and sleep and rest. CONCLUSIONS: This study confirms the necessity of evaluating other aspects of the disease that are not assessed in the functional motor scale. Measures of other aspects of the disease, such as pain, fatigue, feeding, should be also considered. A patient-reported outcomes instrument measuring such aspects in a valid and reliable way would be very useful. This study generated a list of new items relevant to be systematically measured in the assessment of the impact of SMA on the patients' everyday life.
Asunto(s)
Cuidadores , Grupos Focales , Atrofia Muscular Espinal , Investigación Cualitativa , Calidad de Vida , Humanos , Calidad de Vida/psicología , Femenino , Masculino , Cuidadores/psicología , Niño , Adulto , Atrofia Muscular Espinal/psicología , Atrofia Muscular Espinal/terapia , Adolescente , Padres/psicología , España , Preescolar , Costo de Enfermedad , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: A newly defined congenital myasthenic syndrome (CMS) caused by DPAGT1 mutations has recently been reported. While many other CMS-associated proteins have discrete roles localised to the neuromuscular junction, DPAGT1 is ubiquitously expressed, modifying many proteins, and as such is an unexpected cause of isolated neuromuscular involvement. METHODS: We present detailed clinical characteristics of five patients with CMS caused by DPAGT1 mutations. RESULTS: Patients have prominent limb girdle weakness and minimal craniobulbar symptoms. Tubular aggregates on muscle biopsy are characteristic but may not be apparent on early biopsies. Typical myasthenic features such as pyridostigmine and 3, 4- diaminopyridine responsiveness, and decrement on repetitive nerve stimulation are present. CONCLUSIONS: These patients mimic myopathic disorders and are likely to be under-diagnosed. The descriptions here should facilitate recognition of this disorder. In particular minimal craniobulbar involvement and tubular aggregates on muscle biopsy help to distinguish DPAGT1 CMS from the majority of other forms of CMS. Patients with DPAGT1 CMS share similar clinical features with patients who have CMS caused by mutations in GFPT1, another recently identified CMS subtype.
Asunto(s)
Análisis Mutacional de ADN , Síndromes Miasténicos Congénitos/genética , N-Acetilglucosaminiltransferasas/genética , 4-Aminopiridina/análogos & derivados , 4-Aminopiridina/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 2 , Adulto , Edad de Inicio , Albuterol/uso terapéutico , Amifampridina , Biopsia , Inhibidores de la Colinesterasa/uso terapéutico , Diagnóstico Diferencial , Exoma , Femenino , Pruebas Genéticas , Glicosilación , Humanos , Masculino , Persona de Mediana Edad , Neuronas Motoras/fisiología , Músculo Esquelético/inervación , Músculo Esquelético/patología , Síndromes Miasténicos Congénitos/diagnóstico , Síndromes Miasténicos Congénitos/patología , Síndromes Miasténicos Congénitos/fisiopatología , Examen Neurológico , Unión Neuromuscular/fisiología , Fenotipo , Bloqueadores de los Canales de Potasio/uso terapéutico , Bromuro de Piridostigmina/uso terapéuticoRESUMEN
Minimal objective evidence exists regarding management of Friedreich's ataxia (FRDA). Antioxidant and recombinant human erythropoietin therapies have been considered potential treatments to slow progression of FRDA in a small number of studies. The primary objective of the current study was to test the efficacy, safety, and tolerability of triple therapy-darbepoetin alfa, idebenone, and riboflavin-in FRDA in a clinical pilot study. Patients included in this study were nine females, 16 to 45 years of age (average 28 ± 8), diagnosed with FRDA with confirmed GAA repeat expansion mutations in the FXN gene and a GAA repeat ≥400 on the shorter allele. Patients had a baseline score between 8 and 28.5 (average 20.7 ± 8.3) on the scale for the assessment and rating of ataxia and 94.3 ± 27.2 g/m(2) in left ventricular mass index (LVMI). Patients had been treated with triple therapy with 150 µg darbepoetin alfa every 2 or 3 weeks, 10-20 mg/kg/day idebenone, and 10-15 mg/kg/day riboflavin for 32 ± 19.4 months (range of 8-56 months). Triple therapy was tolerated. Although not statistically significant, improvement of ataxia was observed during the first six 4-month periods of the study. Furthermore, a small decrease in disease progression during the first 2 years of treatment was observed. Long-term statistically nonsignificant improvement of LVMI and stability of the echocardiographic parameters could be considered. Triple therapy may slow disease progression of FRDA.
Asunto(s)
Antioxidantes/uso terapéutico , Eritropoyetina/análogos & derivados , Ataxia de Friedreich/tratamiento farmacológico , Hematínicos/uso terapéutico , Riboflavina/uso terapéutico , Ubiquinona/análogos & derivados , Adolescente , Adulto , Antioxidantes/administración & dosificación , Darbepoetina alfa , Quimioterapia Combinada/métodos , Eritropoyetina/administración & dosificación , Eritropoyetina/uso terapéutico , Femenino , Ataxia de Friedreich/diagnóstico , Hematínicos/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Riboflavina/administración & dosificación , Ubiquinona/administración & dosificación , Ubiquinona/uso terapéutico , Adulto JovenRESUMEN
INTRODUCTION: Multiple endocrine neoplasia type 2 (MEN 2) is an uncommon autosomal dominant cancer syndrome which can be associated with nerve conduction abnormalities. METHODS: A 14-year-old boy with a family history of consanguinity developed progressive gait clumsiness, pes cavus, hypotonia, and mucosal tumors of the lips and tongue since the age of 3 years. At age 11 years, he was diagnosed with an hereditary motor neuropathy (Charcot-Marie-Tooth syndrome). RESULTS: Physical examination revealed a Marfanoid habitus, mucocutaneous verrucous tumors, thyroid nodules, and cervical adenopathy. Genetic testing demonstrated the p.M918T mutation in the RET gene, and blood tests showed elevated levels of calcitonin. CONCLUSIONS: Clinical suspicion in MEN2 is crucial for early diagnosis and subsequent therapy. Mucosal neuroma and a Marfanoid habitus are especially useful. Other neurologic manifestations should not disguise the endocrine disorder, because early diagnosis and treatment of medullary thyroid carcinoma determines the prognosis.
Asunto(s)
Deformidades Congénitas de las Extremidades/etiología , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades de la Lengua/etiología , Adolescente , Humanos , Deformidades Congénitas de las Extremidades/genética , Masculino , Neoplasia Endocrina Múltiple Tipo 2b/complicaciones , Neoplasia Endocrina Múltiple Tipo 2b/genética , Neoplasia Endocrina Múltiple Tipo 2b/patología , Enfermedades del Sistema Nervioso Periférico/genéticaRESUMEN
X-linked myotubular myopathy (XLMTM; OMIM 310400) is a centronuclear congenital muscular disorder of X-linked recessive inheritance. Although female carriers are typically asymptomatic, affected heterozygous females have been described. Here, we describe the case of a sporadic female patient with suspicion of centronuclear myopathy and a heterozygous large deletion at Xq28 encompassing the MAMLD1, MTM1, MTMR1, CD99L2, and HMGB3 genes. The deletion was first detected using a custom next generation sequencing (NGS)-based multigene panel and finally characterized by comparative genomic hybridization array and multiplex ligation probe assay techniques. In this patient we have confirmed, by MTM1 mRNA quantification, a MTM1 gene expression less than the expected 50 percent in patient muscle. The significant 20% reduction in MTM1 mRNA expression in muscle, precludes low level of the normal myotubularin protein as the cause of the phenotype in this heterozygous female. We have also found that BIN1 expression in patient muscle biopsy was significantly increased, and postulate that BIN1 expression will be increased in XLMTM patient muscle as an attempt to maintain muscle function.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Deleción Cromosómica , Miopatías Estructurales Congénitas/genética , Proteínas Nucleares/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Proteínas Supresoras de Tumor/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adolescente , Cromosomas Humanos X/genética , Femenino , Heterocigoto , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miopatías Estructurales Congénitas/metabolismo , Miopatías Estructurales Congénitas/patología , Proteínas Nucleares/metabolismo , Proteínas Tirosina Fosfatasas no Receptoras/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
BACKGROUND: Hereditary Spastic Paraplegias (HSP) are characterized by progressive spasticity and weakness of the lower limbs. At least 45 loci have been identified in families with autosomal dominant (AD), autosomal recessive (AR), or X-linked hereditary patterns. Mutations in the SPAST (SPG4) and ATL1 (SPG3A) genes would account for about 50% of the ADHSP cases. METHODS: We defined the SPAST and ATL1 mutational spectrum in a total of 370 unrelated HSP index cases from Spain (83% with a pure phenotype). RESULTS: We found 50 SPAST mutations (including two large deletions) in 54 patients and 7 ATL1 mutations in 11 patients. A total of 33 of the SPAST and 3 of the ATL1 were new mutations. A total of 141 (31%) were familial cases, and we found a higher frequency of mutation carriers among these compared to apparently sporadic cases (38% vs. 5%). Five of the SPAST mutations were predicted to affect the pre-mRNA splicing, and in 4 of them we demonstrated this effect at the cDNA level. In addition to large deletions, splicing, frameshifting, and missense mutations, we also found a nucleotide change in the stop codon that would result in a larger ORF. CONCLUSIONS: In a large cohort of Spanish patients with spastic paraplegia, SPAST and ATL1 mutations were found in 15% of the cases. These mutations were more frequent in familial cases (compared to sporadic), and were associated with heterogeneous clinical manifestations.
Asunto(s)
Adenosina Trifosfatasas/genética , GTP Fosfohidrolasas/genética , Paraplejía Espástica Hereditaria/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Análisis Mutacional de ADN , Proteínas de Unión al GTP , Genotipo , Humanos , Lactante , Proteínas de la Membrana , Persona de Mediana Edad , Linaje , Fenotipo , Reacción en Cadena de la Polimerasa , Espastina , Población Blanca/genética , Adulto JovenRESUMEN
BACKGROUND: Tumours of the posterior fossa associated with neurofibromatosis type 1 (NF1) are very infrequent. Series studying this association are seldom reported. PERSONAL EXPERIENCE: In a series of 600 NF1 patients studied during 39 years (1965-2004) only five (0.83%) had posterior fossa tumours. They were studied clinically, radiologically by computerized tomography (CT) or magnetic resonance (MR) and histologically. Four of them had astrocytomas but only in one case was the tumour primarily cerebellar while the tumour was primarily of the brain stem with invasion of the adjacent regions of one or both cerebellar hemispheres in three patients. The fifth tumour was a medulloblastoma that had a survival of 3 years following treatment. The patient with primary cerebellar astrocytoma is apparently cured 7 years after the removal of the tumour. The patients with the brain stem tumours extending to the cerebellum, showed a chronic slowly progressive cerebellar disease, but remain alive at age of more than 20 years (one was lost to follow-up). DISCUSSION AND CONCLUSION: The aim of this study was to present five children (one male and four females) less than 16 years of age when they were initially seen in our service, who had NF1 associates with posterior fossa tumours. This location is very uncommon in patients with NF1, in contrast with those located in other regions, such as pathway optic tumours and brain stem tumours. Most of these tumours are histologically benign (low grade astrocytomas). Only one patient in this series had a medulloblastoma, an exceptionally rare tumour seldom reported in patients with NF1.
Asunto(s)
Fosa Craneal Posterior , Neurofibromatosis 1/cirugía , Neoplasias de la Base del Cráneo/cirugía , Adolescente , Adulto , Astrocitoma/diagnóstico , Astrocitoma/mortalidad , Astrocitoma/patología , Astrocitoma/cirugía , Neoplasias del Tronco Encefálico/diagnóstico , Neoplasias del Tronco Encefálico/mortalidad , Neoplasias del Tronco Encefálico/patología , Neoplasias del Tronco Encefálico/cirugía , Neoplasias Cerebelosas/diagnóstico , Neoplasias Cerebelosas/mortalidad , Neoplasias Cerebelosas/patología , Neoplasias Cerebelosas/cirugía , Niño , Preescolar , Fosa Craneal Posterior/patología , Femenino , Estudios de Seguimiento , Humanos , Lactante , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Meduloblastoma/diagnóstico , Meduloblastoma/mortalidad , Meduloblastoma/patología , Meduloblastoma/cirugía , Neurofibromatosis 1/diagnóstico , Neurofibromatosis 1/mortalidad , Neurofibromatosis 1/patología , Estudios Retrospectivos , Neoplasias de la Base del Cráneo/diagnóstico , Neoplasias de la Base del Cráneo/mortalidad , Neoplasias de la Base del Cráneo/patología , Tasa de Supervivencia , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Myotonia congenita (MC) is a Mendelian inherited genetic disease caused by the mutations in the CLCN1 gene, encoding the main skeletal muscle ion chloride channel (ClC-1). The clinical diagnosis of MC should be suspected in patients presenting myotonia, warm-up phenomenon, a characteristic electromyographic pattern, and/or family history. Here, we describe the largest cohort of MC Spanish patients including their relatives (up to 102 individuals). Genetic testing was performed by CLCN1 sequencing and multiplex ligation-dependent probe amplification (MLPA). Analysis of selected exons of the SCN4A gene, causing paramyotonia congenita, was also performed. Mutation spectrum and analysis of a likely founder effect of c.180+3A>T was achieved by haplotype analysis and association tests. Twenty-eight different pathogenic variants were found in the CLCN1 gene, of which 21 were known mutations and seven not described. Gross deletions/duplications were not detected. Four probands had a pathogenic variant in SCN4A. Two main haplotypes were detected in c.180+3A>T carriers and no statistically significant differences were detected between case and control groups regarding the type of haplotype and its frequencies. A diagnostic yield of 51% was achieved; of which 88% had pathogenic variants in CLCN1 and 12% in SCN4A. The existence of a c.180+3A>T founder effect remains unsolved.
Asunto(s)
Canales de Cloruro/genética , Miotonía Congénita/genética , Canal de Sodio Activado por Voltaje NAV1.4/genética , Estudios de Cohortes , Exones , Femenino , Efecto Fundador , Haplotipos , Humanos , Masculino , Músculo Esquelético/metabolismo , Mutación , Miotonía Congénita/diagnóstico , Polimorfismo de Nucleótido Simple , EspañaRESUMEN
Paramyotonia congenita (OMIM 168300) is a non-dystrophic myopathy caused by mutations in the SCN4A gene that sometimes can be confused with myotonia congenita. Another disease also caused by mutations in the gene SCN4A is called myotonia aggravated by potassium (OMIM 170500, 613345). It is estimated that more than 20% of patients with suspected myotonia congenita suffer paramyotonia congenita. The two related SCN4A phenotypes exhibit an autosomal dominant inheritance and are the result of mutations that cause an increase in the function of the protein coded by this gene. In this study we present a case of paramyotonia congenita in a family with several affected members and in which a mutation in the SCN4A gene was identified. Evolutionary conservation data and predictive algorithms of pathogenicity allow us to conclude that this DNA variant is the cause of the disease in this family.
Asunto(s)
Trastornos Miotónicos/genética , Canal de Sodio Activado por Voltaje NAV1.4/genética , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Linaje , Adulto JovenRESUMEN
Arterial ischemic strokes (AIS) are rare in childhood. Congenital and acquired heart diseases are one of the most important risk factors of AIS in children. OBJECTIVE: Study the outcome of children with heart disease that have suffered AIS and the factors that influence on prognosis. PATIENTS AND METHODS: We evaluated all children with heart disease who had suffered AIS between 2000 and 2014 in our hospital. RESULTS: Seventy-four children with heart disease suffered an arterial ischemic stroke. 20% of them died and 10% had new AIS during the study period. Fifty-two patients were evaluated an average of six years after AIS. According to the Paediatric Stroke Outcome Scale (PSOM), most of the patients had some degree of impairment, mainly in sensorimotor and in cognitive-behavioural areas. The modified Rankin scale (mRS) showed an unfavourable outcome in 70% of patients (including patients that have died). Upper limb was more functionally impaired than lower limb. Strokes in neonatal period and early life were associated with poor prognosis. Size of stroke, cortical and subcortical involvement and basal ganglia stroke were associated with an unfavourable outcome. Fever in the acute phase and hemiparesis at presentation were also poor prognostic factors. Epilepsy at time of evaluation was also associated with unfavourable outcome. On the other hand, a normal electroencephalogram was associated with favourable outcome. CONCLUSIONS: AIS in children with heart disease had an unfavourable outcome, with impairment in different areas. Epilepsy happened in one third of the patients.
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Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiología , Cardiopatías/complicaciones , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Adolescente , Niño , Preescolar , Electroencefalografía , Epilepsia/complicaciones , Femenino , Cardiopatías/mortalidad , Humanos , Lactante , Masculino , Actividad Motora , Evaluación de Resultado en la Atención de Salud , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: Charcot-Marie-Tooth 1A (CMT1A) disease is the most common inherited neuropathy that lacks of therapy and of molecular markers to assess disease severity. Herein, we have pursued the identification of potential biomarkers in plasma samples and skin biopsies that could define the phenotype of CMT1A patients at mild (Mi), moderate (Mo) and severe (Se) stages of disease as assessed by the CMT neuropathy score to contribute to the understanding of CMT pathophysiology and eventually inform of the severity of the disease. METHODS: We have used: (i) a high-throughput untargeted metabolomic approach of plasma samples in a cohort of 42 CMT1A patients and 15 healthy controls (CRL) using ultrahigh liquid chromatography coupled to mass spectrometry and (ii) reverse phase protein microarrays to quantitate the expression of some proteins of energy metabolism and of the antioxidant response in skin biopsies of a cohort of 70 CMT1A patients and 13 healthy controls. RESULTS: The metabolomic approach identified 194 metabolites with significant differences among the four groups (Mi, Mo, Se, CRL) of samples. A multivariate Linear Discriminant Analysis model using 12 metabolites afforded the correct classification of the samples. These metabolites indicate an increase in protein catabolism and the mobilization of membrane lipids involved in signaling inflammation with severity of CMT1A. A concurrent depletion of leucine, which is required for the biogenesis of the muscle, is also observed in the patients. Protein expression in skin biopsies indicates early loss of mitochondrial and antioxidant proteins in patients' biopsies. CONCLUSION: The findings indicate that CMT1A disease is associated with a metabolic state resembling inflammation and sarcopenia suggesting that it might represent a potential target to prevent the nerve and muscle wasting phenotype in these patients. The observed changes in metabolites could be useful as potential biomarkers of CMT1A disease after appropriate validation in future longitudinal studies.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/sangre , Enfermedad de Charcot-Marie-Tooth/metabolismo , Metaboloma , Proteínas/análisis , Piel/patología , Adulto , Biomarcadores/análisis , Biomarcadores/sangre , Biomarcadores/metabolismo , Enfermedad de Charcot-Marie-Tooth/patología , Metabolismo Energético , Humanos , Metabolómica , Persona de Mediana Edad , Estudios Prospectivos , Proteínas/metabolismo , Piel/metabolismoRESUMEN
Charcot-Marie-Tooth disease is characterized by broad genetic heterogeneity with >50 known disease-associated genes. Mutations in some of these genes can cause a pure motor form of hereditary motor neuropathy, the genetics of which are poorly characterized. We designed a panel comprising 56 genes associated with Charcot-Marie-Tooth disease/hereditary motor neuropathy. We validated this diagnostic tool by first testing 11 patients with pathological mutations. A cohort of 33 affected subjects was selected for this study. The DNAJB2 c.352+1G>A mutation was detected in two cases; novel changes and/or variants with low frequency (<1%) were found in 12 cases. There were no candidate variants in 18 cases, and amplification failed for one sample. The DNAJB2 c.352+1G>A mutation was also detected in three additional families. On haplotype analysis, all of the patients from these five families shared the same haplotype; therefore, the DNAJB2 c.352+1G>A mutation may be a founder event. Our gene panel allowed us to perform a very rapid and cost-effective screening of genes involved in Charcot-Marie-Tooth disease/hereditary motor neuropathy. Our diagnostic strategy was robust in terms of both coverage and read depth for all of the genes and patient samples. These findings demonstrate the difficulty in achieving a definitive molecular diagnosis because of the complexity of interpreting new variants and the genetic heterogeneity that is associated with these neuropathies.
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Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Neuropatía Hereditaria Motora y Sensorial/diagnóstico , Neuropatía Hereditaria Motora y Sensorial/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Estudios de Casos y Controles , Femenino , Proteínas del Choque Térmico HSP40/genética , Haplotipos , Humanos , Masculino , Chaperonas Moleculares/genética , Mutación , Reproducibilidad de los ResultadosRESUMEN
Early-onset hereditary motor and sensory neuropathies are rare diseases representing a broad clinical and genetic spectrum. Without a notable familial history, the clinical diagnosis is complicated because acquired causes of peripheral neuropathy, such as inflammatory neuropathies, neuropathies with toxic causes, and nutritional deficiencies, must be considered. We examined the clinical, electrophysiological, and pathologic manifestations of a boy with an initial diagnosis of chronic inflammatory demyelinating polyneuropathy. The progression of the disease despite treatment led to a suspicion of hereditary motor and sensory neuropathy. Genetic testing revealed the presence of the MPZ p.D90E mutation in heterozygosis. To clarify the pathogenicity of this mutation and achieve a conclusive diagnosis, we investigated the MPZ p.D90E mutation through in silico and cellular approaches. This study broadens the clinical phenotype of hereditary motor and sensory neuropathy due to MPZ mutation and emphasises the difficulty of achieving an accurate genetic diagnosis in a sporadic patient to provide an appropriate pharmacologic treatment.
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Neuropatía Hereditaria Motora y Sensorial/genética , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , Proteína P0 de la Mielina/genética , Preescolar , Progresión de la Enfermedad , Células HeLa , Neuropatía Hereditaria Motora y Sensorial/patología , Humanos , Masculino , Mutación , Proteína P0 de la Mielina/metabolismo , Fenotipo , Nervio Sural/patología , Nervio Sural/fisiopatologíaRESUMEN
Although treatment with alglucosidase alfa has helped improve the prognosis of patients with late-onset Pompe disease, both the development of the disease and the effectiveness of the treatment need to be monitored on a regular basis. This is the reason that has led a committee of Spanish experts to draw up a series of guidelines on how to follow up these patients. The committee proposes a model of follow-up tests for late-onset Pompe disease. First of all, the nutritional status and swallowing function must be evaluated. Second, and due to the variability of the clinical features, the committee recommends the simultaneous use of several scales to measure different functions and parameters. Thus, muscular force is assessed with the Medical Research Council scale; motor functioning, with the six-minute walk test and timed tests; disability, with the Rasch-built Pompe-specific Activity scale; respiratory functioning, with measurement of the forced vital capacity and oxygen saturation; and fatigue, with the fatigue intensity scale. Lastly, the safety and tolerability of enzyme replacement therapy are controlled by registering and treating the potential side effects and measurement of the anti-alglucosidase alfa antibodies. A number of different general recommendations are also included.
TITLE: Guia para el seguimiento de la enfermedad de Pompe de inicio tardio.Aunque el tratamiento con alglucosidasa alfa ha contribuido a mejorar el pronostico de los pacientes con enfermedad de Pompe de inicio tardio, es necesario hacer un seguimiento periodico de la evolucion de la enfermedad y de la eficacia del tratamiento. Por este motivo, un comite de expertos españoles ha elaborado una guia para el seguimiento de estos pacientes. El comite propone un modelo de pruebas de seguimiento para la enfermedad de Pompe de inicio tardio. En primer lugar, ha de valorarse el estado nutricional y la funcion deglutoria. En segundo lugar, y debido a la variabilidad del cuadro clinico, el comite recomienda el uso simultaneo de varias escalas que midan distintas funciones y parametros. De este modo, la fuerza muscular se evalua con la escala del Medical Research Council; la funcion motora, con la prueba de la marcha en seis minutos y pruebas cronometradas; la discapacidad, con la escala de actividad especifica de la enfermedad de Pompe construida segun el analisis de Rasch; la funcion respiratoria, con la medida de la capacidad vital forzada y la saturacion de oxigeno; y la fatiga, con la escala de intensidad de la fatiga. Por ultimo, la seguridad y la tolerabilidad del tratamiento enzimatico sustitutivo se controlan con el registro y tratamiento de los potenciales efectos adversos y la medicion de los anticuerpos antialglucosidasa alfa. Se incluyen tambien diversas recomendaciones generales.
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Terapia de Reemplazo Enzimático , Glucano 1,4-alfa-Glucosidasa/uso terapéutico , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Adolescente , Edad de Inicio , Biomarcadores , Niño , Enfermedades del Sistema Digestivo/etiología , Evaluación de la Discapacidad , Manejo de la Enfermedad , Monitoreo de Drogas , Glucano 1,4-alfa-Glucosidasa/deficiencia , Enfermedad del Almacenamiento de Glucógeno Tipo II/clasificación , Enfermedad del Almacenamiento de Glucógeno Tipo II/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo II/epidemiología , Humanos , Imagen por Resonancia Magnética , Fuerza Muscular , Estado Nutricional , Proteínas Recombinantes/uso terapéutico , Índice de Severidad de la Enfermedad , Capacidad VitalRESUMEN
We present a 7-year-old boy in whom cutaneous hemangioma and intramedullary and paraspinal arteriovenous malformations were associated. Magnetic resonance arteriography revealed the presence of the two arterovenous malformations, and the selective intercostal arteriography demonstrated that the intraspinal and paraspinal arteriovenous malformations were supplied by the same intercostal arteries. Rubbing the back was required to detect the cutaneous changes, which were only suspected by casual inspection.
Asunto(s)
Anomalías Múltiples , Malformaciones Arteriovenosas/complicaciones , Hemangioma Capilar/etiología , Neoplasias Cutáneas/etiología , Médula Espinal/irrigación sanguínea , Niño , Humanos , Angiografía por Resonancia Magnética , Masculino , SíndromeRESUMEN
AIM. To present the clinic, imaging and evolutive characteristics of a series of patients with neurofibromatosis 1 with voluminous plexiform neurofibromas in the neck (VPNFN) during childhood. PATIENTS AND METHODS. Nine patients (five females and four males) who were diagnosed as VPNFN at ages between 3 and 15 years. The VPNFN widespread to the posterior fossa or the upper thoracic region in some cases. The diagnosis was based on the clinical, imaging and histological findings. RESULTS. One of the tumors was intralaryngeal and caused respiratory difficulties. The other eight patients had the origin of the tumor in several spinal roots of one or both sides and could growth to the posterior fossa and to the upper thoracic region in some cases with displacement of the surrounding organs, especially in three patients, all girls, in whom the tumor reached a voluminous size on one side, that was observed only until 10 to 11 years when the growth ceased. CONCLUSIONS. The VPNFN are histologically benign tumors. Those located in the larynx must be removed because of the respiratory problems, but it is not necessary in cases with other locations despite the voluminous size that can reach in some patients with great displacement of the surrounding organs. The analysis of the results of our series may demonstrate that al least the extralaryngeal tumors only grow to 11-12 years of age. This possibility may make recommendable to retard the surgical treatment as much as possible in cases that it is not necessary.
TITLE: Neurofibromas plexiformes voluminosos de cuello en la neurofibromatosis tipo 1.Objetivo. Presentar las caracteristicas clinicas, de imagen y evolutivas de una serie de pacientes con neurofibromatosis tipo 1 que desarrollaron durante la infancia neurofibromas plexiformes voluminosos en el cuello (NFPVC). Pacientes y metodos. Nueve pacientes (cinco mujeres y cuatro varones) con edades entre 3 y 15 años en el momento del diagnostico de los tumores, que podian extenderse tambien a la fosa posterior y a la zona toracica superior. El diagnostico estuvo basado fundamentalmente en la clinica, la imagen y la histologia. Resultados. Un tumor era intralaringeo y causaba problemas respiratorios. Los otros ocho casos tenian su origen en varias raices espinales de uno o de ambos lados y podian crecer tambien hacia el interior de la fosa posterior y de la region toracica en algunos pacientes, y desplazaban a las estructuras anatomicas vecinas, especialmente en tres casos, todos niñas, en las que el tumor crecio hasta alcanzar gran volumen, especialmente por un lado, parandose el crecimiento entre los 11 y 12 años y no volviendo a crecer mas tarde. Conclusiones. Los NFPVC son tumores histologicamente benignos. La extirpacion es necesaria cuando estan localizados en la laringe por los problemas respiratorios que causan, pero no en los de las otras regiones, pese a que el voluminoso tamaño que alcanzan en algunos casos puede causar exagerados desplazamientos de las estructuras vecinas. El estudio de nuestra serie parece indicar que al menos los tumores extralaringeos solo crecen hasta los 11-12 años. Puede ser recomendable retrasar la cirugia tanto como sea posible si no existe sintomatologia aguda que la haga necesaria.