Acidemia metilmalónica / Methylmalonic acidemia

Presentamos el caso de una mujer de 20 años que acude a nuestra consulta por tics motores y fónicos que empeoran con el nerviosismo y desaparecen con el sueño y maniobras de distracción. Se deriva al hospital y se decide su ingreso. Al revisar sus antecedentes observamos que había sido ingresada en varias ocasiones durante su infancia antes de ser diagnosticada a los cuatro años de edad de acidemia metilmalónica. La sintomatología de esa patología comenzó durante su primera semana de vida, manifestando vómitos, hipotonía y fallo de medro. La acidemia metilmalónica es una enfermedad congénita que provoca un defecto a nivel de la enzima metilmalonil CoA-mutasa, ocasionando como consecuencia un acúmulo del ácido metilmalónico. Se diagnostica por aumento de ácido metilmalónico en orina y se confirma mediante análisis molecular genético. Durante este último ingreso la paciente fue diagnosticada de un tourettismo, sin determinar si fue secundario al tratamiento o si se trata de una manifestación crónica de su patología. La acidemia metilmalónica es una enfermedad rara de difícil diagnóstico tanto por su clínica inespecífica como por el escaso conocimiento sobre la misma por parte del personal sanitario (AU)

The following is the case of a 20-year-old woman in seek of professional help because of chronic motor and phonic tics which worsened when nervous and disappeared when sleeping or when distraction manoeuvres were employed. She was referred to a hospital where she was hospitalized. In examining her medical history, we found that she required hospitalization on a number of occasions during childhood before being diagnosed with methylmalonic acidemia at the age of four. Her symptoms began within the first week of life, suffering from vomiting, hypotonia, failure to thrive and asthenia. Methylmalonic acidemia is a congenital disease which provokes a defect in the enzyme methylmalonyl-CoA mutase therefore causing a build-up of methylmalonic acid. It is diagnosed by an increase of methylmalonic acid in urine samples and it is confirmed with a molecular genetic analysis. In addition to this rare illness, the patient was also diagnosed with tourettism, without determining if it was due to treatment or a chronic presentation of her pathology. Methylmalonic acidemia is a rare disease, and consequently difficult to diagnose because of its unspecific clinical manifestations and because of healthcare workers' limited awareness of it (AU)

Assessment of response of brain metastases to radiotherapy by PET imaging of apoptosis with ¹8F-ML-10.

PURPOSE: Early assessment of tumor response to therapy is vital for treatment optimization for the individual cancer patient. Induction of apoptosis is an early and nearly universal effect of anticancer therapies. The purpose of this study was to assess the performance of (18)F-ML-10, a novel PET radiotracer for apoptosis, as a tool for the early detection of response of brain metastases to whole-brain radiation therapy (WBRT). MATERIALS AND METHODS: Ten patients with brain metastases treated with WBRT at 30 Gy in ten daily fractions were enrolled in this trial. Each patient underwent two (18)F-ML-10 PET scans, one prior to the radiation therapy (baseline scan), and the second after nine or ten fractions of radiotherapy (follow-up scan). MRI was performed at 6-8 weeks following completion of the radiation therapy. Early treatment-induced changes in tumor (18)F-ML-10 uptake on the PET scan were measured by voxel-based analysis, and were then evaluated by correlation analysis as predictors of the extent of later changes in tumor anatomical dimensions as seen on MRI scans 6-8 weeks after completion of therapy. RESULTS: In all ten patients, all brain lesions were detected by both MRI and the (18)F-ML-10 PET scan. A highly significant correlation was found between early changes on the (18)F-ML-10 scan and later changes in tumor anatomical dimensions (r = 0.9). CONCLUSION: These results support the potential of (18)F-ML-10 PET as a novel tool for the early detection of response of brain metastases to WBRT.

Estudio epidemiológico de las enfermedades metabólicas con homocistinuria en España / Epidemiological study of the metabolic diseases with homocystinuria in Spain

Objetivos: Conocer la prevalencia en España de los diferentes errores congénitos del metabolismo que presentan homocistinuria y establecer las medidas oportunas para garantizar su prevención, diagnóstico y tratamiento, en aquellos casos posibles. Material y métodos: En abril 2009 se realizó una encuesta nacional de carácter transversal mediante cuestionario enviado a 35 centros, en los que se atiende a pacientes infantiles y adultos. La finalidad de la encuesta era establecer la prevalencia en ese momento recogiendo el histórico de pacientes que cada centro tuviera documentados. Resultados: A través de los cuestionarios respondidos por 25 médicos de 16 centros, se han identificado 75 pacientes: 41 defectos de transulfuración (uno fallecido), 27 de remetilación (6 fallecidos) y 7 sin diagnóstico etiológico definitivo. La edad de diagnóstico muestra una amplia variación, en 18 casos había más de un hermano afectado. Las manifestaciones clínicas más graves inciden en el grupo de los pacientes afectados de trastornos de la remetilación. Destaca el alto porcentaje de déficit cognitivo, seguido de la patología de cristalino; casi la mitad de los pacientes presentan trastornos neurológicos, es elevada la afectación vascular en los adultos con deficiencia de CBS; las opciones terapéuticas más utilizadas han sido el ácido fólico, la hidroxicobalamina y la betaína. Conclusiones: A la vista de estos resultados, y en especial del escaso número de deficiencias de CBS detectadas, se concluye la necesidad de implantar el cribado neonatal para la homocistinuria clásica y asegurar la puesta en marcha del proceso diagnóstico oportuno en todos los pacientes de riesgo(AU)

Objectives: To determine the prevalence of homocystinuria in Spain and to establish the measures and mechanisms to ensure its prevention, diagnosis and treatment. Material and methods: A national cross-sectional survey was conducted by means of a questionnaire sent to 35 hospitals in which children and adult patients are treated. Results: Using the questionnaires submitted by 25 physicians from 16 centres, 75 patients were identified: 41 transsulphuration defects (one deceased), 27 remethylation (six deaths) and 7 without a syndromic diagnosis. The age at diagnosis varied widely, and 18 cases had more than one sibling affected. The more severe clinical manifestations involved the patients with remethylation defects. There was a high percentage of cognitive impairment, followed by lens diseases. Almost half of the patients had neurological disorders. There was increased vascular involvement in CBS-deficient adults. The therapeutic options most used were, folic acid, hydroxycobalamin and betaine. Conclusions: In view of these results and especially the small number of CBS deficiencies detected, we conclude that there is a need to introduce newborn screening for classical homocystinuria and ensure implementation of an appropriate diagnostic workup in all patients at risk(AU)

18F-ML-10, a PET tracer for apoptosis: first human study.

UNLABELLED: Clinical PET of apoptosis may have substantial value in advancing patient care. We report here the first-in-humans study with (18)F-labeled 2-(5-fluoropentyl)-2-methyl malonic acid ((18)F-ML-10), a small-molecule PET tracer for apoptosis. Presented are the dosimetry, biodistribution, stability, and safety profiles of this PET tracer in healthy human volunteers. Also reported is tracer binding to targeted apoptotic cells in testicular tissue, where a relative abundance of apoptotic cells is normally observed. METHODS: (18)F-ML-10 (233 ± 90 MBq) was intravenously administered to 8 healthy subjects, followed by whole-body PET/CT for 220 min. Serial blood and urine samples were collected for radioactivity measurement, and plasma tracer stability was assessed by high-performance liquid chromatography. Dosimetry calculations were performed using OLINDA/EXM software. RESULTS: (18)F-ML-10 manifested high stability in vivo and rapid distribution followed by fast clearance, with an elimination half-life of 1.3 ± 0.1 and 1.1 ± 0.2 h from the blood and from all other organs, respectively, and excretion through the urine. Dosimetry showed an average effective whole-body dose of 15.4 ± 3.7 µSv/MBq, with the urinary bladder being the dose-limiting organ. Selective accumulation and retention of the tracer in the testes was observed in all male subjects, a finding also demonstrated in mice using both small-animal PET and histopathology, confirming binding to apoptotic cells. Administration of (18)F-ML-10 was safe, without adverse effects. CONCLUSION: (18)F-ML-10 administered to healthy humans demonstrated a favorable dosimetry, biodistribution, stability, and safety profile. Binding to apoptotic sites was also demonstrated. These data support further development of this small-molecule probe for clinical PET of apoptosis.

Efficacy of living donor liver transplantation for patients with methylmalonic acidemia.

Application of liver transplantation to methylmalonic acidemia (MMAemia) is controversial because MMAemia is caused by a systemic defect of methylmalonyl-CoA mutase. The clinical courses of seven pediatric patients with MMAemia undergoing living donor liver transplantation (LDLT) were reviewed. Serum and urinary methylmalonic acid (MMA) levels were found to be significantly decreased after LDLT, whereas serum and urinary MMA levels did not return to normal in any patient. One patient died of sepsis 44 days after LDLT. The other six patients are currently doing well. All patients had preoperative history of acute metabolic decompensation and/or metabolic stroke. However, no episode of acute metabolic decompensation or metabolic stroke was observed postoperatively in any surviving patients. In the preoperative period, all patients showed lethargy and cognitive deficit, both of which were eradicated after LDLT in all surviving patients. Preoperatively, all patients were subjected to dietary protein intake restriction and tube feeding, and were administered several metabolism-correcting medications. The metabolism-correcting medications being administered remained mostly unchanged after LDLT, whereas protein restriction was liberalized and tube feeding became unnecessary in all surviving patients. In addition, physical and neurodevelopmental growth delay remained in all surviving patients during the observation period, which ranged from 4 to 21 months with a median of 10.5 months.

The role of nitric oxide on the convulsive behavior and oxidative stress induced by methylmalonate: an electroencephalographic and neurochemical study.

Methylmalonic acidemias consist of a group of inherited metabolic disorders caused by deficiency of methylmalonyl-CoA mutase activity and biochemically characterized by methylmalonate (MMA) accumulation, impairment mitochondrial oxidative metabolism and reactive species production. Preliminary studies with nitric oxide synthase (NOS) inhibitors have suggested that nitric oxide (NO) plays a role in the convulsant effect of MMA. However, definitive biochemical and electrophysiological evidence of the involvement of NO in the convulsions induced by MMA are lacking. In this study, we investigated whether the inhibition of NOS by 7-nitroindazole (7-NI, 3-60mg/kg, i.p.) altered the convulsions, protein oxidative damage, NO(x) (NO(2) plus NO(3)) production and Na(+),K(+)-ATPase activity inhibition induced by MMA. 7-NI decreased striatal NO(x) content, but increased seizures and protein carbonylation induced by MMA (6mumol/striatum). The intrastriatal injection of l-arginine (50nmol/0.5mul), but not of d-arginine (50nmol/0.5mul), increased striatal NO(x) content and protected against MMA-induced electroencephalographic seizures, striatal protein carbonylation and Na(+),K(+)-ATPase inhibition. Furthermore, l-arginine (50nmol/0.5mul) and MMA had no additive effect on NO(x) increase. These results are experimental evidence that endogenous NO plays a protective role in the convulsions and acute neurochemical alterations induced by this organic acid.