Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 50
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
1.
Sci Rep ; 9(1): 14036, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575891

RESUMO

TRAPPC11 was identified as a component of the TRAPP III complex that functions in membrane trafficking and autophagy. Variants in TRAPPC11 have been reported to be associated with a broad spectrum of phenotypes but all affected individuals display muscular pathology. Identifying additional variants will further our understanding of the clinical spectrum of phenotypes and will reveal regions of the protein critical for its functions. Here we report three individuals from unrelated families that have bi-allellic TRAPPC11 variants. Subject 1 harbors a compound heterozygous variant (c.1287 + 5G > A and c.3379_3380insT). The former variant results in a partial deletion of the foie gras domain (p.Ala372_Ser429del), while the latter variant results in a frame-shift and extension at the carboxy terminus (p.Asp1127Valfs*47). Subjects 2 and 3 both harbour a homozygous missense variant (c.2938G > A; p.Gly980Arg). Fibroblasts from all three subjects displayed membrane trafficking defects manifested as delayed endoplasmic reticulum (ER)-to-Golgi transport and/or a delay in protein exit from the Golgi. All three individuals also show a defect in glycosylation of an ER-resident glycoprotein. However, only the compound heterozygous subject displayed an autophagic flux defect. Collectively, our characterization of these individuals with bi-allelic TRAPPC11 variants highlights the functional importance of the carboxy-terminal portion of the protein.

3.
Mol Genet Metab ; 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31378569

RESUMO

Late onset Pompe disease (LOPD) is a genetic disorder characterized by slowly progressive skeletal and respiratory muscle weakness. Symptomatic patients are treated with enzyme replacement therapy (ERT) with alglucosidase alpha (rhGAA). Although most of ERT treated patients develop antibodies against rhGAA, their influence on clinical progression is not completely known. We studied the impact of anti-rhGAA antibodies on clinical progression of 25 ERT treated patients. We evaluated patients at visit 0 and, after 1 year, at visit 1. We performed several muscle function tests, conventional spirometry and quantitative muscle MRI (qMRI) using 3-point Dixon analysis of thigh muscles at both visits. We also obtained serum samples at both visits and anti-rhGAA antibodies were quantified using ELISA. Antibody titers higher than 1:200 were identified in 18 patients (72%) of our cohort. Seven patients (28%) did not develop antibodies (0 to <1:200), 17 patients (68%) developed low to intermediate titers (1:200 to <1:31,200) and 1 patient (4%) developed high titers (>1:31,200). We analyzed the effect of low and intermediate antibody titers in clinical and radiological progression. There were no differences between the results of muscle function tests, spirometry or fat fraction analyzed using qMRI between patients with and without antibodies groups at baseline. Moreover, antibody titers did not influence muscle function test, spirometry results or qMRI results at year 1 visit. Most of the LOPD patients developed antibodies against ERT that persisted over time at low or intermediate levels. However, antibodies at these low and intermediate titers might not influence clinical response to the drug.

4.
J Inherit Metab Dis ; 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31339582

RESUMO

Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11-13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged-red/cytochrome c oxidase-negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q10 (CoQ10 ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum-Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ10 with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.

5.
Ann Neurol ; 86(2): 293-303, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31125140

RESUMO

OBJECTIVE: Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. We investigated the safety and efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies. METHODS: We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2-deficient patients under a compassionate use program. RESULTS: In 5 patients with early onset and severe disease, survival and motor functions were better than historically untreated patients. In 11 childhood and adult onset patients, clinical measures stabilized or improved. Three of 8 patients who were nonambulatory at baseline gained the ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 1 of 9 patients who required mechanical ventilation became able to breathe independently. In motor functional scales, improvements were observed in the 6-minute walk test performance in 7 of 8 subjects, Egen Klassifikation in 2 of 3, and North Star Ambulatory Assessment in all 5 tested. Baseline elevated serum growth differentiation factor 15 levels decreased with treatment in all 7 patients tested. A side effect observed in 8 of the 16 patients was dose-dependent diarrhea, which did not require withdrawal of treatment. Among 12 other TK2 patients treated with deoxynucleoside, 2 adults developed elevated liver enzymes that normalized following discontinuation of therapy. INTERPRETATION: This open-label study indicates favorable side effect profiles and clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies for TK2 deficiency. ANN NEUROL 2019;86:293-303.

6.
Am J Med Genet A ; 179(6): 915-926, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30868735

RESUMO

Mutations in the CHRNG gene cause autosomal recessive multiple pterygium syndrome (MPS). Herein we present a long-term follow-up of seven patients with CHRNG-related nonlethal MPS and we compare them with the 57 previously published patients. The objective is defining not only the clinical, histopathological, and molecular genetic characteristics, but also the type and degree of muscle involvement on whole-body magnetic resonance imaging (WBMRI). CHRNG mutations lead to a distinctive phenotype characterized by multiple congenital contractures, pterygium, and facial dysmorphism, with a stable clinical course over the years. Postnatal abnormalities at the neuromuscular junction were observed in the muscle biopsy of these patients. WBMRI showed distinctive features different from other arthrogryposis multiple congenita. A marked muscle bulk reduction is the predominant finding, mostly affecting the spinal erector muscles and gluteus maximus. Fatty infiltration was only observed in deep paravertebral muscles and distal lower limbs. Mutations in CHRNG are mainly located at the extracellular domain of the protein. Our study contributes to further define the phenotypic spectrum of CHRNG-related nonlethal MPS, including muscle imaging features, which may be useful in distinguishing it from other diffuse arthrogryposis entities.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30340910

RESUMO

INTRODUCTION: PLA2G6-associated neurodegeneration (PLAN) comprises a continuum of three phenotypes with overlapping clinical and radiologic features. METHODS: Observational clinical study in a cohort of infantile and childhood onset PLAN patients and genetic analysis of the PLA2G6 gene. We analysed chronological evolution in terms of age at onset and disease course through a 66-item questionnaire. We performed qualitative and quantitative assessment of MRI abnormalities and searched for clinical and radiological phenotype and genotype correlations. RESULTS: Sixteen PLAN patients (mean age: 10.2 years, range 3-33) were evaluated, with a median onset (years) of signs/symptoms as follows: neurological regression (1.5), oculomotor abnormalities (1.5), hypotonia (1.8), gait loss (2.2), pyramidal signs (3.0), axonal neuropathy (3.0), dysphagia (4.0), optic atrophy (4.0), psychiatric symptoms (4.0), seizures (5.9), joint contractures (6.0), dystonia (8.0), bladder dysfunction (13.0) and parkinsonism (15.0). MRI assessment identified cerebellar atrophy (19/19), brain iron deposition (10/19), clava hypertrophy (8/19) and T2/FLAIR hyperintensity of the cerebellar cortex (6/19). The mid-sagittal vermis relative diameter (MVRD) correlated with age at onset of clinical variants, meaning that the earlier the onset, the more severe the cerebellar atrophy. All patients harboured missense, nonsense and frameshift mutations in PLA2G6, including four novel variants. CONCLUSIONS: Cerebellar atrophy was a universal radiological sign in infantile and childhood onset PLAN, and correlated with the severity of the phenotype. Iron accumulation within the globus pallidum and substantia nigra was also a common and strikingly uniform feature regardless of the phenotype.

9.
EMBO Mol Med ; 10(11)2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30201738

RESUMO

OXA1, the mitochondrial member of the YidC/Alb3/Oxa1 membrane protein insertase family, is required for the assembly of oxidative phosphorylation complexes IV and V in yeast. However, depletion of human OXA1 (OXA1L) was previously reported to impair assembly of complexes I and V only. We report a patient presenting with severe encephalopathy, hypotonia and developmental delay who died at 5 years showing complex IV deficiency in skeletal muscle. Whole exome sequencing identified biallelic OXA1L variants (c.500_507dup, p.(Ser170Glnfs*18) and c.620G>T, p.(Cys207Phe)) that segregated with disease. Patient muscle and fibroblasts showed decreased OXA1L and subunits of complexes IV and V. Crucially, expression of wild-type human OXA1L in patient fibroblasts rescued the complex IV and V defects. Targeted depletion of OXA1L in human cells or Drosophila melanogaster caused defects in the assembly of complexes I, IV and V, consistent with patient data. Immunoprecipitation of OXA1L revealed the enrichment of mtDNA-encoded subunits of complexes I, IV and V. Our data verify the pathogenicity of these OXA1L variants and demonstrate that OXA1L is required for the assembly of multiple respiratory chain complexes.

10.
J Inherit Metab Dis ; 2018 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-29974349

RESUMO

Mitochondrial diseases are a group of genetic disorders leading to the dysfunction of mitochondrial energy metabolism pathways. We aimed to assess the clinical phenotype and the biochemical cerebrospinal fluid (CSF) biogenic amine profiles of patients with different diagnoses of genetic mitochondrial diseases. We recruited 29 patients with genetically confirmed mitochondrial diseases harboring mutations in either nuclear or mitochondrial DNA (mtDNA) genes. Signs and symptoms of impaired neurotransmission and neuroradiological data were recorded. CSF monoamines, pterins, and 5-methyltetrahydrofolate (5MTHF) concentrations were analyzed using high-performance liquid chromatography with electrochemical and fluorescence detection procedures. The mtDNA mutations were studied by Sanger sequencing, Southern blot, and real-time PCR, and nuclear DNA was assessed either by Sanger or next-generation sequencing. Five out of 29 cases showed predominant dopaminergic signs not attributable to basal ganglia involvement, harboring mutations in different nuclear genes. A chi-square test showed a statistically significant association between high homovanillic acid (HVA) values and low CSF 5-MTHF values (chi-square = 10.916; p = 0.001). Seven out of the eight patients with high CSF HVA values showed cerebral folate deficiency. Five of them harbored mtDNA deletions associated with Kearns-Sayre syndrome (KSS), one had a mitochondrial point mutation at the mtDNA ATPase6 gene, and one had a POLG mutation. In conclusion, dopamine deficiency clinical signs were present in some patients with mitochondrial diseases with different genetic backgrounds. High CSF HVA values, together with a severe cerebral folate deficiency, were observed in KSS patients and in other mtDNA mutation syndromes.

11.
J Med Genet ; 55(8): 515-521, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29602790

RESUMO

BACKGROUND: Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. OBJECTIVE: To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. METHODS: The study was conducted by 42 investigators across 31 academic medical centres. RESULTS: We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion. CONCLUSIONS: In TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder.

12.
Rev. neurol. (Ed. impr.) ; 66(4): 121-124, 16 feb., 2018.
Artigo em Espanhol | IBECS | ID: ibc-172120

RESUMO

Introducción. La enfermedad de Pompe infantil es una glucogenosis por deficiencia de la enzima alfa-glucosidasa ácida. Antes de disponer del tratamiento enzimático sustitutivo (TES) específico, la forma clásica era mortal antes de los 2 años de vida. El TES aumenta la supervivencia y mejora la función cardíaca, respiratoria y motora. Casos clínicos. Caso 1: lactante de 2 meses con hipotonía de predominio axial y portadora de sonda nasogástrica por dificultades en la succión y la deglución. Se evidenció miopatía y miocardiopatía hipertrófica. Se diagnosticó enfermedad de Pompe, se inició TES y se observó una mejoría de la función cardíaca y motora. Sin embargo, presentó infecciones respiratorias recurrentes que finalmente obligaron a una traqueostomía. Actualmente continúa con TES, camina con un andador y presenta una disfunción ventricular leve. Caso 2: lactante de 3 semanas que acudió a revisión rutinaria por su pediatra. En la exploración se apreció un soplo sistólico e hipotonía axial y proximal. En las pruebas cardiológicas se evidenció una miocardiopatía hipertrófica. Se envió al paciente a un centro de referencia donde se diagnosticó enfermedad de Pompe y un estado del material inmunológico con reactividad cruzada negativo. El paciente recibió tratamiento inmunomodulador y TES. La evolución fue favorable, aunque presentó infecciones respiratorias frecuentes. En la actualidad ha conseguido la deambulación autónoma, pero la marcha es inestable. Conclusiones. Ambos casos ilustran el nuevo fenotipo de la enfermedad de Pompe infantil tratada con TES. A pesar de las limitaciones motoras y la afectación respiratoria que presentan los pacientes, la supervivencia y la autonomía han aumentado (AU)


Introduction. Infantile-onset Pompe disease is a kind of glycogenosis resulting from a deficit of the enzyme acid alphaglucosidase. Before specific enzyme replacement therapy (ERT) became available, the classic form was fatal during the first two years of life. ERT increases survival and improves cardiac, respiratory and motor functioning. Case reports. Case 1: 2-month-old infant with predominantly axial hypotonia who required the use of a nasogastric tube as a result of difficulties in sucking and swallowing. Myopathy and hypertrophic cardiomyopathy were observed. The patient was diagnosed with Pompe disease, ERT was established and improved heart and motor functioning were noted. Nevertheless, she presented recurring respiratory infections that finally made it necessary to perform a tracheostomy. She is currently still undergoing ERT, walks with a walker and presents a mild ventricular dysfunction. Case 2: 3-week-old infant who was taken to see his paediatrician for a routine check-up. The examination revealed a systolic bruit and axial and proximal hypotonia. Cardiology tests revealed hypertrophic cardiomyopathy. The patient was sent to a referral centre, where he was diagnosed with Pompe disease and a cross-reactive immunological material-negative status. The patient received immunomodulator treatment and ERT. Progress was favourable, although he presented frequent respiratory infections. The patient is currently capable of walking by himself, although the gait is unsteady. Conclusions. Both cases illustrate the new phenotype of infantile-onset Pompe disease treated with ERT. Despite the motor limitations and respiratory involvement presented by the patients, both survival and autonomy have increased (AU)


Assuntos
Humanos , Feminino , Recém-Nascido , Lactente , Doença de Depósito de Glicogênio Tipo II/terapia , Terapia de Reposição de Enzimas/métodos , Hipotonia Muscular/etiologia , alfa-Glucosidases/uso terapêutico , Fenótipo , Fatores Imunológicos/uso terapêutico , Transtornos de Deglutição/etiologia , Transtornos Motores/etiologia , Traqueostomia , Cardiomiopatia Hipertrófica/diagnóstico , Insuficiência Respiratória/terapia
13.
Front Aging Neurosci ; 9: 268, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28848425

RESUMO

Mutations in human collagen VI genes cause a spectrum of musculoskeletal conditions in children and adults collectively termed collagen VI-related myopathies (COL6-RM) characterized by a varying degree of muscle weakness and joint contractures and which include Ullrich Congenital Muscular Dystrophy (UCMD) and Bethlem Myopathy (BM). Given that collagen VI is one of the most abundant extracellular matrix proteins in adipose tissue and its emerging role in energy metabolism we hypothesized that collagen VI deficiency might be associated with alterations in adipose tissue distribution and adipokines serum profile. We analyzed body composition by means of dual-energy X-ray absorptiometry in 30 pediatric and adult COL6-RM myopathy patients representing a range of severities (UCMD, intermediate-COL6-RM, and BM). We found a distinctive pattern of regional adipose tissue accumulation which was more evident in children at the most severe end of the spectrum. In particular, the accumulation of fat in the android region was a distinguishing feature of UCMD patients. In parallel, there was a decrease in lean mass compatible with a state of sarcopenia, particularly in ambulant children with an intermediate phenotype. All children and adult patients that were sarcopenic were also obese. These changes were significantly more pronounced in children with collagen VI deficiency than in children with Duchenne Muscular Dystrophy of the same ambulatory status. High molecular weight adiponectin and leptin were significantly increased in sera from children in the intermediate and BM group. Correlation analysis showed that the parameters of fat mass were negatively associated with motor function according to several validated outcome measures. In contrast, lean mass parameters correlated positively with physical performance and quality of life. Leptin and adiponectin circulating levels correlated positively with fat mass parameters and negatively with lean mass and thus may be relevant to the disease pathogenesis and as circulating markers. Taken together our results indicate that COL6-RM are characterized by specific changes in total fat mass and distribution which associate with disease severity, motor function, and quality of life and which are clinically meaningful and thus should be taken into consideration in the management of these patients.

14.
Sci Rep ; 7(1): 6677, 2017 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-28751717

RESUMO

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.

15.
Neuromuscul Disord ; 27(2): 188-192, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28040389

RESUMO

We report the case of a newborn with arthrogryposis multiplex congenita and severe axial hypotonia without cardiac involvement in which, using a customized targeted next-generation sequencing assay for 64 myopathy-associated genes, we detected a novel homozygous truncating mutation, c.38661_38665del, in exon 197 of the TTN gene that is expressed only in the fetal skeletal isoform. Its pathogenicity is supported by evidence of maternal isodisomy for chromosome 2. Muscle pathology showed fibers with core-like areas devoid of oxidative staining and cytoplasmic bodies. Electron microscopy showed the replacement of the sarcomeric structure with filamentous material. Identification of this mutation expands the phenotypic spectrum of the TTN gene and shows for the first time that a mutation not found in adult TTN isoforms is involved in the development of a neuromuscular disorder. TTN mutations should be considered in all severe congenital myopathies with arthrogryposis without cardiac involvement.


Assuntos
Artrogripose/genética , Conectina/genética , Doenças Musculares/genética , Humanos , Recém-Nascido , Doenças Musculares/congênito , Mutação , Isoformas de Proteínas
16.
Neuromuscul Disord ; 27(1): 15-23, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27979502

RESUMO

Circulating microRNAs (miRs/miRNAs) are being used as non-invasive biomarkers for diagnosis, prognosis and efficiency of clinical trials. However, to exploit their potential it is necessary to improve and standardize their detection. In a previous study, we identified two microRNAs, miR-30c and miR-181a, that appear to be key regulators of muscular dystrophy. We hypothesized that they could represent useful biomarkers of Duchenne and Becker muscular dystrophies (DMD and BMD). The objective of this study was to assess the absolute levels of miR-30c and miR-181a in sera of DMD and BMD patients using digital PCR (a robust technique for precise and direct quantification of small amounts of nucleic acids without standard curves and external references), and investigate the correlation between miR-30c and miR-181a expressions and several clinical parameters. Our results show that the serum levels of miR-30c and miR-181a increased 7- and 6-fold respectively in DMD patients (n = 21, 2-14 years, ambulant), and 7-fold in BMD patients (n = 5, 9-15 years) compared to controls (n = 22, 2-14 years). No association between miRNA levels and age or corticosteroid treatment was detected in DMD. However, there was a trend towards higher levels of miR-30c in DMD patients with better preserved motor function according to various motor scales and timed tests. We demonstrate that digital PCR is a useful technique for accurate absolute quantification of microRNAs in sera of DMD/BMD patients. We propose miR-30c and miR-181a as reliable serum diagnostic biomarkers for DMD and BMD and miR-30c as a potential novel biomarker to assess disease severity in DMD.


Assuntos
MicroRNAs/sangue , Distrofia Muscular de Duchenne/sangue , Distrofia Muscular de Duchenne/fisiopatologia , Índice de Gravidade de Doença , Adolescente , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase em Tempo Real
17.
Mitochondrion ; 30: 51-8, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27374853

RESUMO

We evaluated the coenzyme Q10 (CoQ) levels in patients who were diagnosed with mitochondrial oxidative phosphorylation (OXPHOS) and non-OXPHOS disorders (n=72). Data from the 72 cases in this study revealed that 44.4% of patients showed low CoQ concentrations in either their skeletal muscle or skin fibroblasts. Our findings suggest that secondary CoQ deficiency is a common finding in OXPHOS and non-OXPHOS disorders. We hypothesize that cases of CoQ deficiency associated with OXPHOS defects could be an adaptive mechanism to maintain a balanced OXPHOS, although the mechanisms explaining these deficiencies and the pathophysiological role of secondary CoQ deficiency deserves further investigation.


Assuntos
Doenças Mitocondriais/patologia , Fosforilação Oxidativa , Ubiquinona/análogos & derivados , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Músculos/patologia , Prevalência , Pele/patologia , Ubiquinona/deficiência , Adulto Jovem
18.
Pediatr. catalan ; 76(1): 18-20, ene.-mar. 2016. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-154567

RESUMO

Introducción. La distrofia muscular de Duchenne es la distrofia muscular más común en la población pediátrica. Estos pacientes presentan una mineralización ósea deficiente y las fracturas son frecuentes. El síndrome de embolia grasa es una de las posibles complicaciones de difícil diagnóstico si no existe una alta sospecha, dado que muchas veces se presenta de forma subclínica. Observación clínica. Se presentan dos pacientes de 12 y 15 años con enfermedad de Duchenne que tras caída presentan a las 3 y 16 horas, respectivamente, un cuadro de inicio súbito de dificultad respiratoria. En ambos casos las radiografías muestran fractura de fémur y se orientan como un síndrome de embolia grasa. Comentarios. La embolia grasa es la obstrucción de un vaso por un émbolo graso, secundario en la mayoría de ocasiones a fracturas de huesos largos, que contienen trioleínas; estas penetran con facilidad al torrente sanguíneo provocando microinfartos y hemorragias. Entre el 15 y el 44% de los niños afectos de Duchenne padecen fracturas. En algunos casos esas fracturas darán lugar a un síndrome de embolia grasa. Dado que en la mayoría de ocasiones se presenta de forma subclínica, es una entidad a tener en cuenta en estos pacientes cuando presenten síntomas respiratorios y/o neurológicos tras traumatismos con fracturas, incluso no desplazadas (AU)


Introduction. Duchenne muscular dystrophy is the most common muscular dystrophy in the pediatric population. Patients with Duchenne dystrophy have poor bone mineralization, and fractures are frequent. Fat embolism syndrome is one of the possible complications; it commonly presents subclinically and in the absence of high level of suspicion, the diagnosis is difficult. Clinical observation. We present two patients aged 12 and 15 years with Duchenne dystrophy who presented with acute onset of respiratory distress hours after a fall. In both cases the X-rays showed femur fractures and were diagnosed as having a fat embolism syndrome. Comments. Fat embolism is the obstruction of a vessel due to fat emboli, which occurs as result of a long bone fracture. Long bones are rich in trioleines, which in the setting of a fracture can easily reach the blood stream and cause micro infarctions and hemorrhages. Between 15% and 44% of children with Duchenne dystrophy suffer from bone fractures, which in some cases could lead to the development of fat embolism syndrome. Since it usually presents subclinically, fat embolism syndrome needs to be considered in patients with Duchenne dystrophy presenting with acute respiratory or neurological symptoms after a trauma with a fracture (AU)


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Embolia Gordurosa/complicações , Embolia Gordurosa/terapia , Distrofias Musculares/complicações , Distrofias Musculares/fisiopatologia , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne , Fraturas do Fêmur/complicações , Fraturas do Fêmur/fisiopatologia , Ventilação não Invasiva/métodos , Ventilação não Invasiva , Fraturas do Fêmur , Trioleína/análise , Infarto/sangue , Infarto/complicações , Insuficiência Respiratória/complicações , Insuficiência Respiratória/diagnóstico , Ventilação não Invasiva/instrumentação
19.
PLoS One ; 11(2): e0148709, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26867126

RESUMO

BACKGROUND: We previously described increased levels of growth and differentiation factor 15 (GDF-15) in skeletal muscle and serum of patients with mitochondrial diseases. Here we evaluated GDF-15 as a biomarker for mitochondrial diseases affecting children and compared it to fibroblast-growth factor 21 (FGF-21). To investigate the mechanism of GDF-15 induction in these pathologies we measured its expression and secretion in response to mitochondrial dysfunction. METHODS: We analysed 59 serum samples from 48 children with mitochondrial disease, 19 samples from children with other neuromuscular diseases and 33 samples from aged-matched healthy children. GDF-15 and FGF-21 circulating levels were determined by ELISA. RESULTS: Our results showed that in children with mitochondrial diseases GDF-15 levels were on average increased by 11-fold (mean 4046pg/ml, 1492 SEM) relative to healthy (350, 21) and myopathic (350, 32) controls. The area under the curve for the receiver-operating-characteristic curve for GDF-15 was 0.82 indicating that it has a good discriminatory power. The overall sensitivity and specificity of GDF-15 for a cut-off value of 550pg/mL was 67.8% (54.4%-79.4%) and 92.3% (81.5%-97.9%), respectively. We found that elevated levels of GDF-15 and or FGF-21 correctly identified a larger proportion of patients than elevated levels of GDF-15 or FGF-21 alone. GDF-15, as well as FGF-21, mRNA expression and protein secretion, were significantly induced after treatment of myotubes with oligomycin and that levels of expression of both factors significantly correlated. CONCLUSIONS: Our data indicate that GDF-15 is a valuable serum quantitative biomarker for the diagnosis of mitochondrial diseases in children and that measurement of both GDF-15 and FGF-21 improves the disease detection ability of either factor separately. Finally, we demonstrate for the first time that GDF-15 is produced by skeletal muscle cells in response to mitochondrial dysfunction and that its levels correlate in vitro with FGF-21 levels.


Assuntos
Biomarcadores/sangue , Fatores de Crescimento de Fibroblastos/sangue , Fator 15 de Diferenciação de Crescimento/sangue , Doenças Mitocondriais/sangue , Músculo Esquelético/metabolismo , Adolescente , Animais , Estudos de Casos e Controles , Linhagem Celular , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Masculino , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Mioblastos/metabolismo , Doenças Neuromusculares/sangue , RNA Mensageiro/metabolismo , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
20.
Semin Pediatr Neurol ; 23(4): 290-305, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-28284391

RESUMO

Mitochondrial diseases exhibit significant clinical and genetic heterogeneity. Mitochondria are highly dynamic organelles that are the major contributor of adenosine triphosphate, through oxidative phosphorylation. These disorders may be developed at any age, with isolated or multiple system involvement, and in any pattern of inheritance. Defects in the mitochondrial respiratory chain impair energy production and almost invariably involve skeletal muscle and peripheral nerves, causing exercise intolerance, cramps, recurrent myoglobinuria, or fixed weakness, which often affects extraocular muscles and results in droopy eyelids (ptosis), progressive external ophthalmoplegia, peripheral ataxia, and peripheral polyneuropathy. This review describes the main neuromuscular symptomatology through different syndromes reported in the literature and from our experience. We want to highlight the importance of searching for the "clue clinical signs" associated with inheritance pattern as key elements to guide the complex diagnosis process and genetic studies in mitochondrial diseases.


Assuntos
Doenças Mitocondriais/complicações , Doenças Neuromusculares/fisiopatologia , Criança , Humanos , Doenças Neuromusculares/etiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA