RESUMEN
We studied the extent and nature of renal involvement in a cohort of 117 adult patients with mitochondrial disease, by measuring urinary retinol-binding protein (RBP) and albumin; established markers of tubular and glomerular dysfunction, respectively. Seventy-five patients had the m.3243A>G mutation and the most frequent phenotypes within the entire cohort were 14 with MELAS, 33 with MIDD, and 17 with MERRF. Urinary RBP was increased in 29 of 75 of m.3243A>G patients, whereas albumin was increased in 23 of the 75. The corresponding numbers were 16 and 14, respectively, in the 42 non-m.3243A>G patients. RBP and albumin were higher in diabetic m.3243A>G patients than in nondiabetics, but there were no significant differences across the three major clinical phenotypes. The urine proteome (mass spectrometry) and metabonome (nuclear magnetic resonance) in a subset of the m.3243A>G patients were markedly different from controls, with the most significant alterations occurring in lysosomal proteins, calcium-binding proteins, and antioxidant defenses. Differences were also found between asymptomatic m.3243A>G carriers and controls. No patients had an elevated serum creatinine level, but 14% had hyponatremia, 10% had hypophosphatemia, and 14% had hypomagnesemia. Thus, abnormalities in kidney function are common in adults with mitochondrial disease, exist in the absence of elevated serum creatinine, and are not solely explained by diabetes.
Asunto(s)
Enfermedades Renales/orina , Metaboloma , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/orina , Proteoma , ARN de Transferencia , Adolescente , Adulto , Anciano , Albuminuria/orina , Antioxidantes/metabolismo , Biomarcadores/orina , Proteínas de Unión al Calcio/orina , Estudios de Casos y Controles , Creatinina/sangre , Creatinina/orina , Estudios Transversales , Sordera/complicaciones , Sordera/genética , Sordera/orina , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/orina , Heterocigoto , Humanos , Hiponatremia/etiología , Hipofosfatemia/etiología , Enfermedades Renales/complicaciones , Síndrome MELAS/complicaciones , Síndrome MELAS/genética , Síndrome MELAS/orina , Síndrome MERRF/complicaciones , Síndrome MERRF/genética , Síndrome MERRF/orina , Magnesio/sangre , Persona de Mediana Edad , Enfermedades Mitocondriales/complicaciones , Mutación , Proteínas/metabolismo , Proteínas de Unión al Retinol/orina , Adulto JovenRESUMEN
OBJECTIVE: To explore the expression and significance of respiratory chain enzyme of cells in urine sediment in mitochondrial encephalopathy myopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. METHODS: Through enzyme histochemistry, the authors analyzed the changes of respiratory chain enzyme in urine sediment in 20 MELAS patients due to mitochondrial A3243G mutation (MELAS group) and 20 health peoples (control group). And the impact on the expression of protein encoded by nuclear DNA (A21347) and mitochondrial DNA (A6404) was detected by immunochemistry. Image pro Plus 6.0 software was used for analysis of absorbance (A) of staining images as staining intensity. The data were expressed as M (Q1, Q3) and analyzed through statistical software. RESULTS: The staining intensity of complexes Iin the MELAS group was lower than that in the control group (0.06(0.01, 0.12) vs 0.12(0.01, 0.62), P = 0.010). The intergroup staining intensity of complex II showed no marked difference. Increased density of blue particle and cytoplasmic gathering was found in 13 cased (65%) of the MELAS group under light microscope. The staining intensity of complexes IV was expressed at a low level in the MELAS group (0.14(0.03, 0.32) vs 0.23(0.06, 0.43), P = 0.038). The expression of protein encoded by nuclear DNA (A21347) was lower than that in the control group (0.05(0.02, 0.45) vs 0.17(0.03, 0.70), P = 0.000). The expression of protein encoded by mitochondrial DNA (A6404) was also lower than that in the control group (0.03(0.01, 0.07) vs 0.15 (0.09, 0.23), P = 0.000). CONCLUSION: Abnormal change of respiratory chain enzyme in urine sediment in MELAS due to mitochondrial A3243G mutation and a low expression of proteins encoded by two kinds of DNA in complexes IV can help to confirm the genetic diagnosis of mitochondrial encephalomyopathies so that different subtypes may be classified and its pathogenesis elucidated.
Asunto(s)
Complejo IV de Transporte de Electrones/orina , Síndrome MELAS/enzimología , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Núcleo Celular/genética , Niño , Preescolar , ADN Mitocondrial/genética , Transporte de Electrón , Complejo IV de Transporte de Electrones/genética , Femenino , Humanos , Síndrome MELAS/metabolismo , Síndrome MELAS/orina , Masculino , Persona de Mediana Edad , Membranas Mitocondriales/metabolismo , Mutación , Adulto JovenRESUMEN
A patient with a known family history of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) due to the MT-TL1 m.3243A>G mutation presented with mild myalgia and very minor upper limb proximal muscle weakness. Muscle histology revealed low levels of cytochrome oxidase-negative fibres and non-specific myositis. Using the last "hot cycle" polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP), the MELAS MT-TL1 m.3243A>G mutation was only detected in urine, and not in hair, blood or skeletal muscle. This report highlights the need to screen various tissues to achieve an accurate mitochondrial genetic diagnosis and suggests the likelihood of myositis arising secondary to the MELAS MT-TL1 m.3243A>G mutation.
Asunto(s)
Cabello/química , Síndrome MELAS/genética , Síndrome MELAS/orina , Músculo Esquelético/química , Biopsia , ADN Mitocondrial/genética , Femenino , Humanos , Síndrome MELAS/diagnóstico , Persona de Mediana Edad , Músculo Esquelético/patología , Mutación , Polimorfismo de Longitud del Fragmento de Restricción , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVE: To identify a better non-invasive method to detect the carrier of mitochondrial A3243G mutation, a cause of mitochondrial encephalopathy-lactic acidosis-stroke like episode (MELAS) syndrome. METHODS: DNA was extracted from the peripheral blood, urine, hair follicle, and saliva of 25 MELAS syndrome patients carrying A3243G mutation and their mothers and other maternal relatives, 33 persons in number, and the muscle tissues from 5 patients obtained by biopsy. A3243G mutation was detected by PCR-RFLP method, and the A3243G mutation ratio was identified by measuring the density of each band and calculation with the software AlphaEase 5.0. RESULTS: A3243G mutations were detected in all tissues of the 25 MELAS patients. The A3243G mutation ratio in urine was 62% +/- 9%, significantly higher than that in the blood [(36% +/- 10%), t = -11.13, P < 0.01]. A3243G mutations were detected in at least one tissue of the 28 maternal relatives. The A3243G mutation rates in their urine samples was 33.0% (5.0% - 70.4%), significantly higher than that in their blood samples [8.0% (0 - 33.3%), z = -4.197, P < 0.01]. There was no significant difference in A3243G mutation ratio among the samples of hair follicle, saliva, and blood. CONCLUSION: The A3243G mutation ratio in urine is significantly higher than those in blood samples of the patients and their maternal relatives. A noninvasive method, A3243G mutation ratio analysis of urine is superior to that in blood.
Asunto(s)
ADN Mitocondrial/genética , Síndrome MELAS/diagnóstico , Síndrome MELAS/genética , Adolescente , Adulto , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Síndrome MELAS/orina , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Various organ involvements and endocrinologic abnormalities associated with electrolyte imbalance, including hyponatremia, are seen in patients with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS); however, the clinical significance of hyponatremia in these patients is rarely reported. We analyzed the serum sodium concentration profiles and clinical and laboratory data of seven patients with MELAS. We found that hyponatremia occurred episodically in four of the seven patients from an early stage of the disease. We identified excessive sodium loss in urine to be associated with the hyponatremic episodes and the causes of hyponatremia in two patients as relative adrenal insufficiency, acute renal failure, and serious paralytic ileus. However, even extensive examinations failed to reveal the cause in other patients. Because severe hyponatremia can cause serious complications, clinicians should pay attention to serum sodium levels and maintain them properly in patients with MELAS.
Asunto(s)
Hiponatremia/etiología , Síndrome MELAS/sangre , Síndrome MELAS/complicaciones , Sodio/sangre , Adolescente , Nitrógeno de la Urea Sanguínea , Niño , Preescolar , Creatinina/sangre , Técnicas de Diagnóstico Endocrino , Femenino , Glucosuria/complicaciones , Humanos , Hiponatremia/sangre , Hiponatremia/orina , Cuerpos Cetónicos/orina , Pruebas de Función Renal , Síndrome MELAS/orina , Masculino , Estudios Retrospectivos , Factores de Riesgo , Sodio/orina , Ácido Úrico/sangreRESUMEN
We found that patients with mitochondrial encephalomyopathies excreted urinary phosphatidylethanolamine, cardiolipin, and phosphatidylserine most likely derived from mitochondria and sulfatide which is specific to myelin or the kidney. It is of interest that four patients with myoclonus epilepsy with ragged-red fibers and one patient with chronic progressive external ophthalmoplegia all showed qualitatively similar abnormal excretion of such urinary lipids. It is conceivable that the urinary acidic phospholipids reflect abnormalities in the mitochondrial phospholipids, which are very important for mitochondrial enzymatic activities.