RESUMEN

In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.

Asunto(s)

Ácido Fólico/uso terapéutico , Leucovorina/uso terapéutico , Metilenotetrahidrofolato Deshidrogenasa (NADP)/deficiencia , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Anemia Megaloblástica/tratamiento farmacológico , Anemia Megaloblástica/genética , Anemia Megaloblástica/patología , Células Cultivadas , Resultado Fatal , Femenino , Deficiencia de Ácido Fólico/tratamiento farmacológico , Deficiencia de Ácido Fólico/genética , Deficiencia de Ácido Fólico/patología , Humanos , Hiperhomocisteinemia/tratamiento farmacológico , Hiperhomocisteinemia/genética , Hiperhomocisteinemia/patología , Lactante , Recién Nacido , Masculino , Antígenos de Histocompatibilidad Menor , Inmunodeficiencia Combinada Grave/tratamiento farmacológico , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/patología , Adulto Joven

RESUMEN

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.

Asunto(s)

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 Joven

RESUMEN

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.

Asunto(s)

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/patología

RESUMEN

We present clinical and laboratory data from 14 cases with an isolated deficiency of the mitochondrial ATP synthase (7-30% of control) caused by nuclear genetic defects. A quantitative decrease of the ATP synthase complex was documented by Blue-Native electrophoresis and Western blotting and was supported by the diminished activity of oligomycin/aurovertin-sensitive ATP hydrolysis in fibroblasts (10 cases), muscle (6 of 7 cases), and liver (one case). All patients had neonatal onset and elevated plasma lactate levels. In 12 patients investigated 3-methyl-glutaconic aciduria was detected. Seven patients died, mostly within the first weeks of life and surviving patients showed psychomotor and various degrees of mental retardation. Eleven patients had hypertrophic cardiomyopathy; other clinical signs included hypotonia, hepatomegaly, facial dysmorphism and microcephaly. This phenotype markedly differs from the severe central nervous system changes of ATP synthase disorders caused by mitochondrial DNA mutations of the ATP6 gene presenting mostly as NARP and MILS.

Asunto(s)

Predisposición Genética a la Enfermedad/genética , Enfermedades Mitocondriales/enzimología , Enfermedades Mitocondriales/genética , Encefalomiopatías Mitocondriales/enzimología , Encefalomiopatías Mitocondriales/genética , ATPasas de Translocación de Protón Mitocondriales/deficiencia , Adenosina Trifosfato/metabolismo , Adolescente , Edad de Inicio , Cardiomiopatía Hipertrófica Familiar/enzimología , Cardiomiopatía Hipertrófica Familiar/genética , Cardiomiopatía Hipertrófica Familiar/fisiopatología , Núcleo Celular/genética , Niño , Preescolar , Cara/anomalías , Femenino , Hepatomegalia/enzimología , Hepatomegalia/genética , Hepatomegalia/fisiopatología , Humanos , Lactante , Recién Nacido , Ácido Láctico/sangre , Masculino , Microcefalia/enzimología , Microcefalia/genética , Mitocondrias/enzimología , Mitocondrias/genética , Enfermedades Mitocondriales/fisiopatología , Encefalomiopatías Mitocondriales/fisiopatología , ATPasas de Translocación de Protón Mitocondriales/genética , Síndrome

RESUMEN

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.

Asunto(s)

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/fisiopatología

RESUMEN

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.

Asunto(s)

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 , Respiración

RESUMEN

We report a novel heteroplasmic T-->C mutation at nt position 582 within the mitochondrial tRNA(Phe) gene of a 70-year-old woman with mitochondrial myopathy. No other family members were affected, suggesting that our patient was a sporadic case. The muscle showed frequent ragged red fibers and 43% cytochrome c oxidase deficient fibers. The mutation alters a conserved base pairing in the aminoacyl acceptor stem. The mutation load was 70% in muscle homogenate and varied from 0 to 95% in individual muscle fiber segments. Cytochrome c oxidase-negative fibers showed significantly higher levels of mutated mtDNA (>75%) than Cytochrome c oxidase-positive fibers (<55%). This mutation adds to the previously described four pathogenic mutations in the tRNA(Phe) gene.

Asunto(s)

ADN Mitocondrial/genética , Mitocondrias/genética , Miopatías Mitocondriales/genética , Músculo Esquelético/metabolismo , Mutación Puntual/genética , ARN de Transferencia de Fenilalanina/genética , Anciano , Sustitución de Aminoácidos/genética , Aminoacil-ARNt Sintetasas/genética , Respiración de la Célula/genética , Análisis Mutacional de ADN , Complejo IV de Transporte de Electrones/metabolismo , Femenino , Humanos , Mitocondrias/metabolismo , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/patología , Músculo Esquelético/patología , Homología de Secuencia de Ácido Nucleico

RESUMEN

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.

Asunto(s)

Deficiencia de Citocromo-c Oxidasa/genética , Mutación/genética , Fenotipo , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Recién Nacido , Masculino

RESUMEN

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.

Asunto(s)

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 , Transfección

RESUMEN

UNLABELLED: In a male patient with hereditary tyrosinaemia type I (HTI), NTBC [2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexandion] treatment and a diet low in phenylalanine and tyrosine were started at the age of 4 wk. At the recommended average dosage (1 mg kg(-1)), liver failure improved transiently. After 4 mo of treatment, with increased body weight, the dose had decreased to 0.7 mg kg(-1), and diffuse cirrhotic changes in liver parenchyma and multiple nodules were visualized by ultrasonography. Multiple nodules in the liver parenchyma were differentiated from hepatocellular carcinoma by magnetic resonance imaging (MRI) using mangafodipir trisodium as a paramagnetic liver-specific contrast agent. Augmentation of NTBC dosage resulted in a decrease in serum alpha-fetoprotein levels and in significant regression of liver nodules on MRI. CONCLUSION: In HTI patients with a poor response to NTBC treatment and/or development of cirrhotic changes of liver parenchyma, augmentation of the recommended NTBC dosage may result in significant improvement of symptoms.

Asunto(s)

Ciclohexanonas/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/etiología , Regeneración Hepática/efectos de los fármacos , Nitrobenzoatos/uso terapéutico , Tirosinemias/complicaciones , Tirosinemias/tratamiento farmacológico , Humanos , Lactante , Recién Nacido , Cirrosis Hepática/patología , Masculino , Inducción de Remisión , Tirosinemias/patología

RESUMEN

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 Mitocondrial

RESUMEN

AIMS: To determine the frequency of cardiomyopathy in children with mitochondrial disease and describe their clinical course, prognosis and cardiological manifestations. METHODS AND RESULTS: Of 301 children with CNS and neuromuscular disease referred to our institution in 1984 to 1999, 101 had mitochondrial disease. Seventeen patients had cardiomyopathy, diagnosed by echo-Doppler investigations, all of the hypertrophic, non-obstructive type. The onset of symptomatic mitochondrial disease ranged from birth to 10 years of age. Eight children had cytochrome-c oxidase deficiency, while the remaining nine had various defects. Cardiomyopathy was diagnosed from birth to 27 years. Left ventricular posterior wall and septal thickness were both increased: z-scores +4.6+/-2.6 and +4.3+/-1.6 (mean+/-SD), respectively. The left ventricular diastolic diameter z-score, +1.3+/-3.4, and fractional shortening, 24+/-13%, displayed marked variations. Nine patients developed heart failure. Eleven patients with cardiomyopathy died, including all eight with cytochrome-c oxidase deficiency, and one patient underwent a heart transplantation. Mortality in children with mitochondrial disease was higher in those with cardiomyopathy (71%) than those without (26%) (P<0.001). CONCLUSIONS: In children with mitochondrial disease, cardiomyopathy was common (17%) and was associated with increased mortality. The prognosis for children with cytochrome-c oxidase deficiency and cardiomyopathy appeared to be particularly unfavorable.

Asunto(s)

Cardiomiopatía Hipertrófica/etiología , Enfermedades Mitocondriales/complicaciones , Adolescente , Adulto , Cardiomiopatía Hipertrófica/patología , Niño , Preescolar , Ecocardiografía Doppler/métodos , Electrocardiografía/métodos , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Enfermedades Mitocondriales/patología , Pronóstico , Análisis de Supervivencia

RESUMEN

In this study we present incidence, point prevalence, and mortality figures of mitochondrial encephalomyopathies in a population-based study of children from western Sweden. Through the screening of registers and review of medical records, we identified 32 patients under 16 years of age from the study population who were diagnosed between January 1, 1984, and December 31, 1998. The incidence of mitochondrial encephalomyopathies in preschool children (<6 years of age) was 1 out of 11,000. The preschool incidence of Leigh's syndrome was 1 out of 32,000, and the preschool incidences of both Alper's syndrome and infantile mitochondrial myopathy with cytochrome C oxidase deficiency were 1 out of 51,000. The point prevalence January 1, 1999) of mitochondrial encephalomyopathies in children under 16 years of age was 1 out of 21,000. The median survival for patients with infantile onset was until 12 years of age. We identified 4 cases with mitochondrial DNA point mutations, 2 cases with mitochondrial DNA deletions, and 2 cases with nuclear mutations in the SURF1 gene. We conclude that mitochondrial encephalomyopathies are relatively common neurometabolic disorders in childhood.

Asunto(s)

Encefalomiopatías Mitocondriales/epidemiología , Edad de Inicio , Niño , Preescolar , Femenino , Humanos , Incidencia , Lactante , Masculino , Encefalomiopatías Mitocondriales/fisiopatología , Análisis de Supervivencia

RESUMEN

Tyrosinemia type I is an autosomal recessive inherited disorder caused by deficient fumarylacetoacetase activity. Treatment with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC), an inhibitor of 4-hydroxyphenylpyruvate dioxygenase, has successfully been applied for the last few years. Our aim was to evaluate the clinical and biochemical response to treatment with NTBC of a 18-year-old patient with a chronic form of tyrosinemia type I, whose main clinical feature was vitamin D-resistant rickets leading to severe osteoporosis with multiple bone fractures and skeletal deformities. After treatment, toxic metabolites became undetectable and porphobilinogen synthase activity returned to normal. Renal function improved, blood hemoglobin returned to normal and alfa-fetoprotein decreased. The patient's general condition greatly improved. However, the alfa-fetoprotein concentration slowly increased during the second year of NTBC treatment and hepatocellular carcinoma developed. NTBC treatment should be considered even in advanced cases of tyrosinemia type I, although only as a palliative therapy.

Asunto(s)

4-Hidroxifenilpiruvato Dioxigenasa/antagonistas & inhibidores , Carcinoma Hepatocelular/etiología , Ciclohexanonas/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Neoplasias Hepáticas/etiología , Nitrobenzoatos/uso terapéutico , Tirosinemias/tratamiento farmacológico , Adolescente , Humanos , Masculino , Cuidados Paliativos , Tirosinemias/complicaciones

RESUMEN

PURPOSE: The purpose of the study was to investigate the core temperature responses to the induction of electrical exercise and to clarify whether an increase in temperature could be responsible for some of the observed reactions to acute and repeated exposure to electrical muscle stimulation. METHODS: The paralyzed thigh and gluteal muscles were stimulated electrically with surface electrodes in seven persons with transection of the spinal cord. By this means, they were able to pedal a lower extremity ergometer at 50 revolutions per minute for 30 min. Skin surface, esophageal (Tes), rectal (Tre), and muscle temperature in m. quadriceps were measured with thermocouples. RESULTS: The average rate of oxygen consumption was 0.91 +/- 0.16 L.min-1, and the heart rate after 20 min was 123 +/- 9 bpm during the electrically induced exercise. The involuntary, induced exercise led to increases in core temperature, whereas skin surface temperature was the same before and after exercise. Average Tes and Tre both rose 0.7 degrees C from, respectively, 36.6 +/- 0.2 and 36.9 +/- 0.1 degrees C, and muscle temperature increased even more: 2.9 degrees C from 33.9 +/- 0.3 degrees C. CONCLUSION: It is suggested that these increased temperatures may act as stimuli, directly or, through resulting release of humoral factors, and elicit the changes in heart rate, as well as the previously observed adaptive changes after electrically induced exercise, e.g., in muscle fiber size, and capillarization.

Asunto(s)

Ciclismo/fisiología , Temperatura Corporal , Músculo Esquelético/fisiología , Paraplejía/fisiopatología , Traumatismos de la Médula Espinal/fisiopatología , Adaptación Fisiológica , Adulto , Estimulación Eléctrica , Femenino , Frecuencia Cardíaca , Humanos , Masculino , Consumo de Oxígeno

RESUMEN

La tirosinemia tipo I es una enfermedad hereditaria autosómica recesiva causada por la actividad deficiente de la enzima fumarilacetoacetasa. El tratamiento con 2-(2-nitro-4-trifluorometilbenzoil)-1,3-ciclohexadiona (NTBC), un inhibidor del 4-hidroxifenilpiruvato dioxigenasa, ha sido usado con éxito en los últimos años. Se ha evaluado la respuesta clínica y bioquímica al tratamiento con NTBC en un paciente de 18 años con una forma crónica de tirosinemia tipo I, con hallazgos clínicos de raquitismo por vitamina D resistente junto con osteoporosis y múltiples fracturas y deformidades esqueléticas. Con el tratamiento los metabolitos tóxicos llegaron a ser indetectables con actividad enzimática de la porfobilinógeno sintetasa normalizada. La función renal mejoró, la hemoglobina se normalizó y la concentración de alfafetoproteína disminuyó. Su estado general mejoró de manera espectacular. Sin embargo, durante el segundo año de tratamiento, la concentración de alfafetoproteína aumentó considerablemente y el paciente desarrolló un carcinoma hepatocelular. El tratamiento con NTBC debe considerarse, incluso en casos de tirosinemia tipo I avanzados, como terapia paliativa (AU)

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Asunto(s)

Adolescente , Masculino , Humanos , 4-Hidroxifenilpiruvato Dioxigenasa , Cuidados Paliativos , Nitrobenzoatos , Tirosinemias , Ciclohexanonas , Carcinoma Hepatocelular , Inhibidores Enzimáticos , Neoplasias Hepáticas

RESUMEN

The association of a particular mitochondrial DNA (mtDNA) mutation with different clinical phenotypes is a well-known feature of mitochondrial diseases. A simple genotype-phenotype correlation has not been found between mutation load and disease expression. Tissue and intercellular mosaicism as well as mtDNA copy number are thought to be responsible for the different clinical phenotypes. As disease expression of mitochondrial tRNA mutations is mostly in postmitotic tissues, studies to elucidate disease mechanisms need to be performed on patient material. Heteroplasmy quantitation and copy number estimation using small patient biopsy samples has not been reported before, mainly due to technical restrictions. In order to resolve this problem, we have developed a robust assay that utilizes Molecular Beacons to accurately quantify heteroplasmy levels and determine mtDNA copy number in small samples carrying the A8344G tRNA(Lys) mutation. It provides the methodological basis to investigate the role of heteroplasmy and mtDNA copy number in determining the clinical phenotypes.

Asunto(s)

ADN Mitocondrial/genética , Síndrome MERRF/genética , Reacción en Cadena de la Polimerasa/métodos , Línea Celular , Fluorescencia , Dosificación de Gen , Humanos , Síndrome MERRF/patología , Mutación Puntual , Sensibilidad y Especificidad

RESUMEN

Tyrosinaemia type III is a rare disorder caused by a deficiency of 4-hydroxyphenylpyruvate dioxygenase, the second enzyme in the catabolic pathway of tyrosine. The majority of the nine previously reported patients have presented with neurological symptoms after the neonatal period, while others detected by neonatal screening have been asymptomatic. All have had normal liver and renal function and none has skin or eye abnormalities. A further four patients with tyrosinaemia type III are described. It is not clear whether a strict low tyrosine diet alters the natural history of tyrosinaemia type III, although there remains a suspicion that treatment may be important, at least in infancy.

Asunto(s)

Tirosinemias/dietoterapia , Tirosinemias/etiología , 4-Hidroxifenilpiruvato Dioxigenasa/deficiencia , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Inteligencia , Masculino , Tamizaje Neonatal , Resultado del Tratamiento , Tirosina/sangre , Tirosinemias/diagnóstico , Tirosinemias/psicología

RESUMEN

Tyrosinemia type III (OMIM 276710) is an autosomal recessive disorder caused by the deficiency of 4-hydroxyphenylpyruvate dioxygenase (HPD), the second enzyme in the tyrosine catabolic pathway. The enzyme deficiency results in an accumulation and increased excretion of tyrosine and phenolic metabolites. Only a few cases with the disorder have been described, and the clinical spectrum of the disorder is unknown. Reported patients have presented with mental retardation or neurological symptoms or have been picked up by neonatal screening. We have identified four presumed pathogenic mutations (two missense and two nonsense mutations) in the HPD gene in three unrelated families encompassing four homozygous individuals and one compound heterozygous individual with tyrosinemia type III. Furthermore, a number of polymorphic mutations have been identified in the HPD gene. No correlation of the severity of the mutation and enzyme deficiency and mental function has been found; neither do the recorded tyrosine levels correlate with the clinical phenotype.

Asunto(s)

4-Hidroxifenilpiruvato Dioxigenasa/genética , Mutación Missense/genética , Tirosinemias/genética , 4-Hidroxifenilpiruvato Dioxigenasa/metabolismo , Adolescente , Sustitución de Aminoácidos , Sitios de Unión/genética , Niño , Análisis Mutacional de ADN , Exones , Femenino , Homocigoto , Humanos , Lactante , Intrones , Riñón/enzimología , Hígado/enzimología , Masculino , Reacción en Cadena de la Polimerasa , Mapeo Restrictivo , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Tirosina/sangre , Tirosinemias/sangre , Tirosinemias/diagnóstico , Tirosinemias/enzimología

RESUMEN

Mutations in human mitochondrial tRNA genes are associated with a number of multisystemic disorders. Using an assay that combines tRNA oxidation and circularization we have determined the relative amounts and states of aminoacylation of mutant and wild-type tRNAs in tissue samples from patients with MELAS syndrome (mito- chondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) and MERRF syndrome (myoclonus epilepsy with ragged red fibers), respectively. In most, but not all, biopsies from MELAS patients carrying the A3243G substitution in the mitochondrial tRNA(Leu(UUR))gene, the mutant tRNA is under-represented among processed and/or aminoacylated tRNAs. In contrast, in biopsies from MERRF patients harboring the A8344G substitution in the tRNA(Lys)gene neither the relative abundance nor the aminoacylation of the mutated tRNA is affected. Thus, whereas the A3243G mutation may contribute to the pathogenesis of MELAS by reducing the amount of aminoacylated tRNA(Leu), the A8344G mutation does not affect tRNA(Lys)function in the same way.

Asunto(s)

Síndrome MELAS/genética , Encefalomiopatías Mitocondriales/genética , Mutación Puntual , ARN de Transferencia de Leucina/genética , Acilación , Adulto , Línea Celular , Preescolar , Femenino , Humanos , Células Híbridas , Síndrome MELAS/metabolismo , Masculino , Persona de Mediana Edad , Encefalomiopatías Mitocondriales/metabolismo , Oxidación-Reducción , ARN/metabolismo , ARN Circular , Aminoacil-ARN de Transferencia/metabolismo , ARN de Transferencia de Aspártico/metabolismo , ARN de Transferencia de Leucina/metabolismo