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Cryptococcus neoformans is a fungal pathogen responsible for cryptococcosis and cryptococcal meningitis. The C. neoformans capsular polysaccharide and shed exopolysaccharide functions both as a key virulence factor and to protect the fungal cell from phagocytosis. Currently, a glycoconjugate of these polysaccharides is being explored as a vaccine to protect against C. neoformans infection. In this combined NMR and MD study, experimentally determined NOEs and J-couplings support a structure of the synthetic decasaccharide, GXM10-Ac3, obtained by MD. GXM10-Ac3 was designed as an extension of glucuronoxylomannan (GXM) polysaccharide motif (M2) which is common in the clinically predominant serotype A strains and is recognized by protective forms of GXM-specific monoclonal antibodies. The M2 motif is characterized by a 6-residue α-mannan backbone repeating unit, consisting of a triad of α-(1â3)-mannoses, modified by ß-(1â2)-xyloses on the first two mannoses and a ß-(1â2)-glucuronic acid on the third mannose. The combined NMR and MD analyses reveal that GXM10-Ac3 adopts an extended structure, with xylose/glucuronic acid branches alternating sides along the α-mannan backbone. O-acetyl esters also alternate sides and are grouped in pairs. MD analysis of a twelve M2-repeating unit polymer supports the notion that the GXM10-Ac3 structure is uniformly represented throughout the polysaccharide. This experimentally consistent GXM model displays high flexibility while maintaining a structural identity, yielding new insights to further explore intermolecular interactions between polysaccharides, interactions with anti-GXM mAbs, and the cryptococcal polysaccharide architecture.
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CLN3 disease (MIM# 204200), the most prevalent of the neuronal ceroid lipofuscinoses (NCL), is an autosomal recessive disorder with juvenile onset characterized by blindness, epilepsy, dementia, psychiatric manifestations, and motor deterioration. Problems related to behavior, emotions and thought are among the main features. Antidepressant and antipsychotic drugs have been employed with variable results. Neuroleptic malignant syndrome (NMS) has previously been described in two patients with NCL, one with CLN3 disease and one with adult onset NCL of unclear genetic origin. Our aims were to describe the occurrence of drug-induced hyperthermia in pediatric patients with CLN3 disease from West and South Sweden and to delineate the range of associated clinical features. Our study identified four patients presenting with seven episodes of severe drug-induced hyperthermia and either NMS-like or Serotonin syndrome (SS)-like features. Possibly provoking drugs were risperidone, clozapine, olanzapine, haloperidol, quetiapine, and sertraline. The course was atypical, frequently prolonged, associated with rhabdomyolysis and status dystonicus, and resulted in the death of three of the patients. Our study points to a vulnerability to drug-induced hyperthermia in patients with CLN3 disease which we believe could be underreported. Interestingly the proposed pathophysiological mechanisms behind NMS and SS on one hand and CLN3 on the other hand seem to converge in a common mechanism involving dysregulation of the sympathetic nervous system.
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Hipertermia Inducida , Lipofuscinosis Ceroideas Neuronales , Rabdomiólisis , Adulto , Niño , Humanos , Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Lipofuscinosis Ceroideas Neuronales/genética , Rabdomiólisis/inducido químicamente , Rabdomiólisis/complicacionesRESUMEN
The influenza A(H1N1)pdm09 vaccination campaign from 2009 to 2010 was associated with a sudden increase in the incidence of narcolepsy in several countries. Narcolepsy with cataplexy is strongly associated with the human leukocyte antigen (HLA) class II DQB1*06:02 allele, and protective associations with the DQB1*06:03 allele have been reported. Several non-HLA gene loci are also associated, such as common variants of the T-cell receptor-α (TRA), the purinergic receptor P2RY11, cathepsin H (CTSH) and TNFSF4/OX40L/CD252. In this retrospective multicenter study, we investigated if these predisposing gene loci were also involved in vaccination-associated narcolepsy. We compared HLA- along with single-nucleotide polymorphism genotypes for non-HLA regions between 42 Pandemrix-vaccinated narcolepsy cases and 1990 population-based controls. The class II gene loci associations supported previous findings. Nominal association (P-value<0.05) with TRA as well as suggestive (P-value<0.1) associations with P2RY11 and CTSH were found. These associations suggest a very strong gene-environment interaction, in which the influenza A(H1N1)pdm09 strain or Pandemrix vaccine can act as potent environmental triggers.
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Interacción Gen-Ambiente , Vacunas contra la Influenza/efectos adversos , Narcolepsia/inducido químicamente , Narcolepsia/genética , Cadenas beta de HLA-DQ/genética , Humanos , Subtipo H1N1 del Virus de la Influenza A , Estudios RetrospectivosRESUMEN
BACKGROUND AND PURPOSE: Most mitochondrial disorders with onset in early childhood are progressive and involve multiple organs. The m.3250T>C mutation in MTTL1 has previously been described in a few individuals with a possibly riboflavin-responsive myopathy and an association with sudden infant death syndrome was suspected. We describe a large family with this mutation and evaluate the effect of riboflavin treatment. METHODS: Medical data were collected with the help of a standardized data collection form. Sanger sequencing was used to screen for variants in mitochondrial DNA and the proportion of the mutation was analyzed in different tissues. Biochemical and muscle morphological investigations of muscle tissue were performed in two individuals. The effect of riboflavin treatment was evaluated in two individuals. RESULTS: Thirteen family members experienced exercise intolerance with fatigue and weakness. Inheritance was maternal with 100% penetrance. The course was either static or showed improvement over time. There was no evidence of other organ involvement except for a possible mild transient cardiac enlargement in one child. Muscle investigations showed isolated complex I deficiency and mitochondrial proliferation. The level of m.3250T>C was apparently 100%, i.e. homoplasmic, in all examined tissues. Riboflavin treatment showed no effect in any treated family member and there have been no cases of sudden infant death in this family. CONCLUSIONS: This study illustrates the importance of considering mitochondrial disorders in the work-up of individuals with exercise intolerance and provides a better understanding of the phenotype associated with the m.3250T>C mutation in MTTL1.
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ADN Mitocondrial/genética , Tolerancia al Ejercicio/genética , Miopatías Mitocondriales/genética , Mutación , ARN de Transferencia/genética , Adulto , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mitocondrias/genética , Miopatías Mitocondriales/tratamiento farmacológico , Linaje , Fenotipo , Riboflavina/uso terapéutico , Complejo Vitamínico B/uso terapéutico , Adulto JovenRESUMEN
AIM: To describe ophthalmological phenotypes in patients with mitochondrial disease and known genotypes. METHODS: A retrospective study was performed on 59 patients (29 male, 30 female) with a mean age of 11.8 years who had mitochondrial disease with known DNA mutations. Fifty-seven of the 59 subjects underwent a detailed ophthalmological examination including visual acuity (VA), eye motility, refraction, slit-lamp examination, ophthalmoscopy and, in almost one-half of the cases, a full-field electroretinogram (ERG). RESULTS: Forty-six (81%) of the patients had one or more ophthalmological findings such as ptosis (n = 16), reduced eye motility (n = 22) including severe external ophthalmoplegia (n = 9), strabismus (n = 4), nystagmus (n = 9), low VA (n = 21), refractive errors (n = 26), photophobia (n = 4), and partial or total optic atrophy (n = 25). Pigmentation in the macula and/or periphery was noted in 16 patients. In 10/27 investigated individuals with full field ERG, retinal dystrophy was recorded in six different genotypes representing Kearns-Sayre syndrome (n = 5), Leigh syndrome (n = 1), Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) (n = 1), Myoclonus epilepsy with red ragged fibres (MERRF) (n = 1), Leber hereditary optic neuropathy (n = 1) and mitochondrial myopathy (n = 1). CONCLUSION: The results show that a majority of patients with mitochondrial disorders have ophthalmological abnormalities. We recommend that an ophthalmological examination, including ERG, be performed on all children and adolescents who are suspected of having a mitochondrial disease.
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Oftalmopatías/etiología , Enfermedades Mitocondriales/complicaciones , Adolescente , Adulto , Blefaroptosis/etiología , Niño , Preescolar , ADN Mitocondrial/genética , Electrorretinografía , Femenino , Genotipo , Humanos , Hiperpigmentación/etiología , Lactante , Masculino , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Mutación , Trastornos de la Motilidad Ocular/etiología , Atrofia Óptica/etiología , Fenotipo , Errores de Refracción/etiología , Estudios Retrospectivos , Adulto JovenRESUMEN
Metal-olefin bond dissociation enthalpies have been calculated for the series of complexes M(CO)5(C2H(4-n)Cln), M = Cr, Mo, W; n = 0-4 using density functional theory. Experimental values of the bond enthalpies have been measured for M(CO)5(C2H(4-n)Cln) M = Cr, Mo, W; n = 2 (vinyl chloride), 3, and 4 using laser photoacoustic calorimetry in n-hexane solution. Experimental and calculated values indicate that the trend in metal-olefin bond energies is opposite to the electron-withdrawing ability of the olefin, which is counter to expectations based on the Dewar-Chatt-Duncanson model for metal-olefin bonding. An in-depth analysis of the metal-olefin interaction using a bond energy decomposition scheme implies that the observed and calculated decreasing trend is influenced by the increase in steric interactions and olefin reorganizational energy which is concomitant to the increase of the number of electron-withdrawing halogen atoms.
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OBJECTIVE: Mutations in the beta-tropomyosin gene (TPM2) are a rare cause of congenital myopathies with features of nemaline myopathy and cap disease and may also cause distal arthrogryposis syndromes without major muscle pathology. We describe the muscle biopsy findings in three patients with cap disease and novel heterozygous mutations in TPM2. METHODS: Three unrelated patients with congenital myopathy were investigated by muscle biopsy and genetic analysis. RESULTS: All three patients had early-onset muscle weakness of variable severity and distribution. Muscle biopsy demonstrated in all three patients near uniformity of type 1 fibers and an unusual irregular and coarse-meshed intermyofibrillar network. By electron microscopy, the myofibrils were broad and partly split, and the Z lines appeared jagged. In one of the patients caps structures were identified only by electron microscopy, and in one patient they were identified only in a second biopsy at adulthood. Three novel, de novo, heterozygous mutations in TPM2 were identified: a three-base pair deletion in-frame (p.Lys49del), a three-base pair duplication in-frame (p.Gly52dup), and a missense mutation (p.Asn202Lys). CONCLUSIONS: Mutations in TPM2 seem to be a frequent cause of cap disease. Because cap structures may be sparse, other prominent features, such as a coarse-meshed intermyofibrillar network and jagged Z lines, may be clues to correct diagnosis and also indicate that the pathogenesis involves defective assembly of myofilaments.
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Músculo Esquelético/patología , Mutación , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/patología , Tropomiosina/genética , Adulto , Niño , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Microscopía Electrónica de Transmisión , Músculo Esquelético/fisiopatología , Músculo Esquelético/ultraestructura , Miopatías Estructurales Congénitas/fisiopatología , NAD/metabolismo , Fotograbar , Sales de TetrazolioRESUMEN
Complex I of the oxidative phosphorylation system is composed of at least 45 subunits, seven of which are encoded by mitochondrial DNA (mtDNA). In this study we have investigated two children with complex I deficiency in muscle mitochondria. Patient 1 had cerebellar ataxia from early infancy and an abnormal MRI of the brain compatible with Leigh syndrome (LS). The course was rapidly progressive with frequent exacerbations and death at 2 years and 10 months of age. Patient 2 had a lactic acidosis in the newborn period and had a severe psychomotor developmental retardation. In her teens she developed hypertrophic cardiomyopathy and died at 26 years of age because of cardiac insufficiency. Sequencing analysis of mitochondrial encoded ND genes (MTND) showed two DE NOVO mutations in MTND1 in both patients. Patient 1 had a novel heteroplasmic G3890A mutation, R195Q. Patient 2 had a heteroplasmic G3481A mutation, E59K. The G3890A mutation in patient 1 is the first identified mutation in MTND1 in association with LS and complex I deficiency. The findings in this patient as well as in patient 2 demonstrate new clinical expressions of mutations in MTND1. The findings in patient 2 also illustrates that MTND mutations may be pathogenic even at a low percentage.
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Complejo I de Transporte de Electrón/deficiencia , Complejo I de Transporte de Electrón/genética , Encefalomiopatías Mitocondriales/genética , Mutación Missense , NADH Deshidrogenasa/genética , Acidosis Láctica/etiología , Acidosis Láctica/patología , Adulto , Secuencia de Bases , Niño , Preescolar , Análisis Mutacional de ADN/métodos , ADN Mitocondrial/química , ADN Mitocondrial/genética , Discapacidades del Desarrollo/etiología , Discapacidades del Desarrollo/patología , Complejo I de Transporte de Electrón/metabolismo , Resultado Fatal , Femenino , Humanos , Lactante , Recién Nacido , Encefalomiopatías Mitocondriales/complicaciones , Encefalomiopatías Mitocondriales/enzimología , Fosforilación Oxidativa , Trastornos Psicomotores/etiología , Trastornos Psicomotores/patologíaAsunto(s)
Miosinas Cardíacas/genética , Cardiomiopatías/genética , Corazón/fisiopatología , Músculo Esquelético/fisiopatología , Enfermedades Musculares/genética , Mutación Missense/genética , Cadenas Pesadas de Miosina/genética , Miosinas Cardíacas/química , Cardiomiopatías/diagnóstico , Cardiomiopatías/fisiopatología , Niño , Análisis Mutacional de ADN , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , Músculo Esquelético/patología , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/fisiopatología , Miocardio/patología , Cadenas Pesadas de Miosina/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Miosinas Ventriculares/química , Miosinas Ventriculares/genéticaRESUMEN
Limb-girdle muscular dystrophy (LGMD) type 2I, caused by mutations in the fukutin-related protein gene (FKRP), is one of the most common forms of LGMD in childhood. We describe two patients with LGMD2I and a Duchenne-like phenotype. In addition to the common L276I mutation, both patients had a new mutation in FKRP, L169P and P89L, respectively. Clinical onset was triggered by viral upper respiratory tract infections. In addition to the common dystrophic pattern with a weak immune histochemical staining for alpha-dystroglycan, muscle biopsy showed inflammatory changes. This was especially striking in one of the patients with up-regulation of MHC class 1 antigen, suggestive of myositis. Both patients showed a good clinical response to treatment with prednisolone, which was initiated at daily dosage of 0.35 mg/kg/day. Our results provide evidence for an inflammatory involvement in the pathological expression of LGMD2I and open up the possibility that this disorder could be treatable with corticosteroids.
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Inflamación/tratamiento farmacológico , Distrofia Muscular de Cinturas/tratamiento farmacológico , Esteroides/uso terapéutico , Adolescente , Niño , Análisis Mutacional de ADN , Distroglicanos/metabolismo , Humanos , Inflamación/etiología , Inflamación/genética , Inflamación/patología , Estudios Longitudinales , Masculino , Distrofia Muscular de Cinturas/complicaciones , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Mutación , Pentosiltransferasa , Proteínas/genéticaRESUMEN
We describe a second patient with the 583G>A mutation in the tRNA(phe) gene of mitochondrial DNA (mtDNA). This 17-year-old girl had a mitochondrial myopathy with exercise intolerance and an asymptomatic retinopathy. Muscle investigations showed occasional ragged red fibers, 30% cytochrome c oxidase (COX)-negative fibers, and reduced activities of complex I+IV in the respiratory chain. The mutation was heteroplasmic (79%) in muscle but undetectable in other tissues. Analysis of single muscle fibers revealed a significantly higher level of mutated mtDNA in COX-negative fibers. Our study indicates that the 583G>A mutation is pathogenic and expands the clinical spectrum of this mutation.
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Miopatías Mitocondriales/genética , Mutación/genética , ARN de Transferencia de Fenilalanina/genética , ARN/genética , Enfermedades de la Retina/genética , Adolescente , Análisis Mutacional de ADN , Transporte de Electrón/genética , Complejo IV de Transporte de Electrones/metabolismo , Tolerancia al Ejercicio/genética , Femenino , Humanos , Miopatías Mitocondriales/complicaciones , Miopatías Mitocondriales/fisiopatología , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patología , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , ARN Mitocondrial , Retina/patología , Retina/fisiopatología , Arteria Retiniana/patología , Arteria Retiniana/fisiopatología , Enfermedades de la Retina/complicaciones , Enfermedades de la Retina/fisiopatologíaRESUMEN
The purpose of this study was to measure and compare the amount of stress produced by GT ProFile (GT) and ProFile (PF) rotary files lubricated with either RC Prep (RCP) or saline (S) on the walls of prepared simulated canals. Twenty-four 10-mm long canals with a 10 mm radius of curvature were prepared in PL-2 photoelastic acrylic blocks which were lubricated with either RCP or S. The files were inserted into a Nouvag handpiece mounted to an Instron 4502 universal testing machine and lowered into the canal at a rate of 60 mm/min and a rotational speed of 300 RPM. The following four GTs and four PFs were sequentially introduced into predetermined depths of each canal: 20/.10, 20/.08, 20/.06, 20/.04, 40/.04, 35/.04, 30/.04, and 25/.04. Total areas of stress created by each file were captured by digital video images and measured using Image J software. Statistical analysis of the data was performed using a two-way ANOVA (p < 0.05, n = 24). The GT/RCP group demonstrated a significant average of 64.22% less stress than GT/S group. The PF (25, 30, and 35)/RCP groups demonstrated a significant average of 27.02% less stress than the same S groups. PF (40) produced a negligible amount of stress regardless of the lubricant type. The results reveal that using RCP as a lubricant when instrumenting curved canals with GT and PF results in less stress when compared to saline.
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Instrumentos Dentales , Análisis del Estrés Dental , Ácido Edético , Peróxidos , Preparación del Conducto Radicular/instrumentación , Urea , Ceras , Resinas Acrílicas , Análisis de Varianza , Cavidad Pulpar/fisiología , Elasticidad , Falla de Equipo , Lubrificación , Cloruro de Sodio , Estrés Mecánico , TorqueRESUMEN
In this study we have analyzed the mtDNA encoded ATPase 6 and 8 genes ( MTATP6 and MTATP8) in two children with Leigh syndrome (LS) and reduced Mg (2+) ATPase activity in muscle mitochondria. In patient 1, with a mild and reversible phenotype, mutational analysis revealed a heteroplasmic T --> C mutation at nt position 9185 (T9185C) in the MTATP6. The mutation resulted in substitution of a highly conserved leucine to proline at codon 220. The proportion of the mutation was > 97 % in the patient's blood and muscle and 85 % in blood of his asymptomatic mother. Patient 2, with severe clinical phenotype and death at 2 years of age, exhibited a novel heteroplasmic T9191C missense mutation in the MTATP6, which converted a highly conserved leucine to a proline at position 222 of the polypeptide. The proportion of the mutation was 90 % in fibroblasts and 94 % muscle tissue. This mutation was absent in the patient's parents and sister suggesting that the mutation was de novo. Our findings expand the spectrum of mutations causing LS and emphasize the role of MTATP6 gene mutations in pathogenesis of LS.
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Enfermedad de Leigh/genética , ATPasas de Translocación de Protón Mitocondriales/genética , Mutación , Secuencia de Aminoácidos/fisiología , Niño , Preescolar , Análisis Mutacional de ADN/métodos , ADN Mitocondrial/genética , Humanos , Enfermedad de Leigh/fisiopatología , RespiraciónRESUMEN
Myosin, a molecular motor, converts chemical energy into mechanical force. The motor domain of myosin heavy chain (MyHC) includes an ATP binding region with ATPase activity and an actin-binding region. Motor function is achieved by conformational changes, at hydrolysis, of ATP causing a shift in the angle between the actin binding head and the rod region of the molecule. The elongated alpha-helical coiled-coil rod region of MyHC molecules constitutes the major part of the thick filaments of the sarcomere. Three major MyHC isoforms are expressed in human skeletal muscle (type I, MYH7, expressed in type 1 fibres; IIa, MYH2, expressed in 2A fibres; IIx, MYH1, expressed in 2B fibres). While mutations in slow/beta cardiac MyHC (MYH7) are a common cause of familial hypertrophic cardiomyopathy, no skeletal myopathies have, until recently, been associated with mutations in MyHC. A heterozygous mutation, Glu706Lys, in the core of the head of MyHC IIa is associated with a familial congenital myopathy, which, in most instances, has shown mild phenotypic expression in children but progressive course in some adults. There is a relationship between the level of expression of mutated MyHC IIa and muscle pathology. Some adults with a progressive course show muscle fibres with rimmed vacuoles and filaments of the type seen in inclusion body myositis/myopathy (IBM). Endurance training in a group of affected patients caused a shift in the expression of myosin from fast (IIx) to slow (I) isoforms but no reduction in the expression of MyHC IIa. A heterozygous mutation, Arg1845Trp, in the distal rod region of slow myosin (type I, MYH7) is associated with familial congenital myopathy, with large deposits of MyHC I in the subsarcolemmal region of type 1 muscle fibres, "Myosin storage myopathy". These patients showed slowly progressive muscle weakness but no overt cardiomyopathy. These two muscle diseases, which are caused by mutations in MyHC, form the basis of a novel entity: "Myosin myopathies".
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Enfermedades Musculares/genética , Mutación , Cadenas Pesadas de Miosina/genética , Animales , Ejercicio Físico/fisiología , Humanos , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/fisiopatologíaRESUMEN
Nemaline myopathy has been associated with mutations in five different genes, which all encode protein components of the sarcomeric thin filaments. We report follow-up studies in two children with mutations not previously described in skeletal muscle alpha-actin (ACTA1). Case 1 was a male patient who after birth suffered from pronounced muscle weakness and hypotonia. Muscle biopsy showed small fibers with numerous rods. He failed to achieve any motor milestones. At the age of 17 he required 24 h ventilator support. He could not lift his arms against gravity, but he could use his hands to control his electric wheelchair. The muscle biopsy showed marked replacement of muscle tissue by fat and connective tissue. Only few fibers showed nemaline rods. He had a de novo, heterozygous mutation, G268D in ACTA1. Case 2 was a female patient with feeding difficulties and mild hypotonia in the neonatal period. Muscle biopsy showed hypoplastic muscle fibers and numerous rods. At 11 years of age she walked and moved unhindered and could run fairly well. She had a de novo, heterozygous mutation, K373E, in ACTA1. These two patients illustrate the marked variability in the clinical features of nemaline myopathy in spite of similar muscle pathology in early childhood. The severe muscle atrophy with replacement of fat and connective tissue in case 1 demonstrates the progressive nature of nemaline myopathy in some cases. The described two mutations add to the previously reported mutations in ACTA1 associated with nemaline myopathy.
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Actinas/genética , Músculo Esquelético , Mutación , Miopatías Nemalínicas/genética , Ácido Aspártico/genética , Análisis Mutacional de ADN/métodos , Exones , Femenino , Estudios de Seguimiento , Tamización de Portadores Genéticos , Ácido Glutámico/metabolismo , Glicina/genética , Heterocigoto , Humanos , Lisina/genética , Masculino , Microscopía Electrónica/métodos , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Miopatías Nemalínicas/patologíaRESUMEN
OBJECTIVE: To evaluate muscle performance and its consequences in eight individuals with a hereditary myopathy and the effects of an 8-week endurance training program. MATERIAL AND METHODS: Handgrip, muscle strength and endurance and oxygen consumption by breath-by-breath analysis during a stepless bicycle ergonometer test were evaluated. Walking, balance test and activities of daily living (ADL) were assessed, and a questionnaire for activity level and perceived symptoms was used. The design was a before-after trial in comparison with data from a control population, bicycling at 70% of maximal workload, 30 min/day, 5 days/week for 8 weeks. RESULTS: The subjects were weaker than age-matched controls. After training, the peak watt increased by almost 20% (P < 0.05). Muscle strength (flexion/extension) and isometric endurance (40% of maximum at 60 degrees ) did not change significantly. The average self-selected walking speed increased significantly (P < 0.05) from 1.25 to 1.45 m/s. Compliance was excellent and no serious adverse events occurred. CONCLUSION: Endurance training seems to function for this myopathy.
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Terapia por Ejercicio , Enfermedades Musculares/genética , Enfermedades Musculares/rehabilitación , Miosina Tipo IIA no Muscular/genética , Resistencia Física , Adulto , Prueba de Esfuerzo , Femenino , Fuerza de la Mano/fisiología , Humanos , Contracción Isométrica/fisiología , Masculino , Persona de Mediana Edad , Músculo Esquelético/fisiopatología , Enfermedades Musculares/fisiopatología , Resultado del TratamientoRESUMEN
Cytochrome c oxidase (COX) deficiency has been associated with a wide spectrum of clinical features and may be caused by mutations in different genes of both the mitochondrial and the nuclear DNA. In an attempt to correlate the clinical phenotype with the genotype in 16 childhood cases, mtDNA was analysed for deletion, depletion, and mutations in the three genes encoding COX subunits and the 22 tRNA genes. Furthermore, nuclear DNA was analysed for mutations in the SURF1, SCO2, COX10, and COX17 genes and cases with mtDNA depletion were analysed for mutations in the TK2 gene. SURF1-mutations were identified in three out of four cases with Leigh syndrome while a mutation in the mitochondrial tRNA (trp) gene was identified in the fourth. One case with mtDNA depletion had mutations in the TK2 gene. In two cases with leukoencephalopathy, one case with encephalopathy, five cases with fatal infantile myopathy and cardiomyopathy, two cases with benign infantile myopathy, and one case with mtDNA depletion, no mutations were identified. We conclude that COX deficiency in childhood should be suspected in a wide range of clinical settings and although an increasing number of genetic defects have been identified, the underlying mutations remain unclear in the majority of the cases.
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Deficiencia de Citocromo-c Oxidasa/genética , Mutación/genética , Fenotipo , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
Leigh syndrome (LS) is one of the most frequent forms of mitochondrial disease in infancy and childhood. Mutations in SURF1 have been shown to be an important cause of LS with cytochrome c oxidase (COX) deficiency. The authors have identified four pathogenic mutations including a novel, in-frame, 15-bp tandem duplication (806-820) in exon 8 and a novel 751+1G>A splice site mutation in SURF1 in three cases of LS with COX deficiency.
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Deficiencia de Citocromo-c Oxidasa/genética , Enfermedad de Leigh/enzimología , Enfermedad de Leigh/genética , Proteínas/genética , Western Blotting , Encéfalo/patología , Células Cultivadas , Niño , Preescolar , Deficiencia de Citocromo-c Oxidasa/complicaciones , Análisis Mutacional de ADN , Femenino , Fibroblastos/metabolismo , Humanos , Lactante , Recién Nacido , Enfermedad de Leigh/complicaciones , Imagen por Resonancia Magnética , Masculino , Proteínas de la Membrana , Proteínas Mitocondriales , Mutación , Proteínas/análisis , TransfecciónRESUMEN
We report a nine-year-old boy with the features of Leigh syndrome (LS) and a severe cytochrome-c oxidase (COX) deficiency with a single thymidine insertion at nucleotide position 5537 (T 5537i) in the tRNA Trp gene of mitochondrial DNA. During infancy the boy was irritable and hypotonus was noticed. Early motor development was delayed, although mental development seemed normal until eight months of age. Early neurological signs were nystagmus, hypertonus and optic atrophy. Severe seizures and mental retardation developed subsequently. Major findings on neuroradiological investigation were from the brainstem, thalami and white matter compatible with LS. Spectrophotometric analysis of skeletal muscle mitochondria showed a profound COX deficiency and a marked complex I deficiency. Enzyme-histochemical analysis showed reduced COX activity in the majority of the muscle fibres. There were no ragged red fibres. The T 5537i mutation was found in a high proportion (> 95 %) in blood, liver and muscle tissue of the patient and in blood of the patient's mother (81 %). This mutation has previously been described in one family in which one child had a very high proportion of the T 5537i mutation and clinical features of LS. We conclude that, although mtDNA mutations are considered to be rare in LS with COX deficiency, the T 5537i mutation should be screened for in cases of LS with COX deficiency when SURF1 gene mutations have been excluded, especially when complex I activity is also decreased.
Asunto(s)
Deficiencia de Citocromo-c Oxidasa/complicaciones , Deficiencia de Citocromo-c Oxidasa/genética , Enfermedad de Leigh/complicaciones , Enfermedad de Leigh/genética , Mutagénesis Insercional/genética , ARN de Transferencia de Triptófano/genética , ARN/genética , Nucleótidos de Timina/genética , Niño , Deficiencia de Citocromo-c Oxidasa/diagnóstico , Humanos , Enfermedad de Leigh/diagnóstico , Masculino , ARN MitocondrialRESUMEN
BACKGROUND: The authors recently described a new autosomal dominant myopathy (OMIM 605637 inclusion body myopathy 3) associated with a missense mutation in the myosin heavy chain (MyHC) IIa gene (MyHC IIa, Human Gene Map [HGM] locus MYH2). Young patients showed minor changes in their muscle biopsies, although dystrophic alterations and rimmed vacuoles with 15- to 20-nm tubulofilaments identical to those in sporadic inclusion body myositis (s-IBM) were observed in some of the adult (especially older) patients. The current study was undertaken to investigate the relation between expression of the mutant MyHC IIa and pathologic changes in muscle. METHODS: The expression of MyHC IIa in nine muscle specimens from six individuals carrying the mutation was analyzed by immunohistochemistry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and a new reverse transcriptase--PCR method to measure the relative abundance of the various MyHC transcripts. RESULTS: Young patients with muscle weakness and minor pathologic changes in muscle expressed MyHC IIa at undetectable levels. MyHC IIa was expressed at high levels in adults with a progressive clinical course and dystrophic muscle changes. In these cases, a large number of muscle fibers were hybrids with expression of more than one MyHC isoform. Both MyHC IIa alleles were equally expressed. The relative level of MyHC IIa transcripts exceeded that of the corresponding protein, indicating an increased turnover of mutated protein. MyHC IIa expression was a consistent finding in muscle fibers with rimmed vacuoles. CONCLUSIONS: The clear correlation between pathologic changes and expression of MyHC IIa indicates that defects in MyHC may lead not only to muscle weakness but also to muscle degeneration. The consistent expression of MyHC IIa in muscle fibers with rimmed vacuoles indicates that the breakdown of sarcomeric proteins is a key element in the pathogenesis of rimmed vacuoles of s-IBM type.