RESUMEN
We report clinical and biochemical finding from three unrelated patients presenting ONCE (Optic Neuropathy, Cardiomyopathy and Encephalopathy with lactic acidosis and combined oxidative phosphorylation deficiency) syndrome. Whole-exome sequencing (WES) of the three patients and the healthy sister of one of them was used to identify the carry gene. Clinical and biochemical findings were used to filter variants, and molecular, in silico and genetic studies were performed to characterize the candidate variants. Mitochondrial DNA (mtDNA) defects involving mutations, deletions or depletion were discarded, whereas WES uncovered a double homozygous mutation in the MTO1 gene (NM_001123226:c.1510C>T, p.R504C, and c.1669G>A, p.V557M) in two of the patients and the homozygous mutation p.R504C in the other. Therefore, our data confirm p.R504C as pathogenic mutation responsible of ONCE syndrome, and p.V557M as a rare polymorphic variant.
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Anomalías Múltiples/genética , Proteínas Portadoras/genética , Predisposición Genética a la Enfermedad/genética , Mutación Missense , Polimorfismo de Nucleótido Simple , Anomalías Múltiples/patología , Acidosis Láctica , Adolescente , Secuencia de Aminoácidos , Encefalopatías , Cardiomiopatías , Exoma/genética , Salud de la Familia , Femenino , Homocigoto , Humanos , Masculino , Enfermedades Mitocondriales , Enfermedades del Nervio Óptico , Linaje , Proteínas de Unión al ARN , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Síndrome , Adulto JovenRESUMEN
BACKGROUND: Conradi-Hünermann-Happle syndrome (CDPX2, OMIM 302960) is an inherited X-linked dominant variant of chondrodysplasia punctata which primarily affects the skin, bones and eyes. CDPX2 results from mutations in EBP (emopamil binding protein), and presents with increased levels of sterol precursors 8(9)-cholesterol and 8-dehydrocholesterol. OBJECTIVES: To expand the understanding of CDPX2, clinically, biochemically and genetically. METHODS: We present one of the largest series reported to date, including 13 female patients belonging to nine Spanish families. Patients were studied biochemically using gas chromatography-mass spectrometry, genetically using polymerase chain reaction and in their methylation status using the HUMARA assay. RESULTS: In our cases, there was a clear relationship between abnormal sterol profile and the EBP gene mutation. We describe three novel mutations in the EBP gene. EBP mutations were inherited in three out of nine families and were sporadic in the remaining cases. CONCLUSIONS: No clear genotype-phenotype correlation was found. Patients' biochemical profiles did not reveal a relationship between sterol profiles and severity of disease. A skewed X-chromosome inactivation may explain the clinical phenotype in CDPX2 in some familial cases.
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Condrodisplasia Punctata/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Mutación/genética , Esteroide Isomerasas/genética , Inactivación del Cromosoma X/genética , Adulto , Colestadienoles/metabolismo , Colesterol/metabolismo , Condrodisplasia Punctata/metabolismo , Análisis Mutacional de ADN/métodos , Femenino , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Genotipo , Humanos , Lactante , Fenotipo , EspañaRESUMEN
Most cases of pyruvate dehydrogenase complex (PDHc) deficiency are attributable to mutations in the PDHA1 gene which encodes the E(1)α subunit, with few cases of mutations in the genes for E(3), E3BP (E(3) binding protein), E(2) and E(1)-phosphatase being reported. Only seven patients with deficiency of the E(1)ß subunit have been described, with mutations in the PDHB gene in six of them. Clinically they presented with a non-specific encephalomyopathy. We report two patients with new mutations in PDHB and Leigh syndrome. Patient 1 was a boy with neonatal onset of hyperlactataemia, corpus callosum hypoplasia and a convulsive encephalopathy. After neurological deterioration, he died at age 5 months. Autopsy revealed the characteristic features of Leigh syndrome. Patient 2, also a boy, presented a milder clinical course. First symptoms were noticed at age 16 months with muscular hypotonia, lactic acidosis and recurrent episodes of somnolence and transient tetraparesis. MRI revealed bilateral signal hyperintensities in the globus pallidus, midbrain and crura cerebri. PDHc and E(1) activities were deficient in fibroblasts in patient 1; in patient 2 PDHc deficiency was found in skeletal muscle. Mutations in PDHA1 were excluded. Sequencing of PDHB revealed a homozygous point mutation (c.302T>C), causing a predicted amino acid change (p.M101T) in patient 1. Patient 2 is compound heterozygote for mutations c.301A>G (p.M101V) and c.313G>A (p.R105Q). All three mutations appear to destabilize the E(1) enzyme with a decrease of both E(1)α and E(1)ß subunits in immunoblot analysis. To our knowledge, these patients with novel PDHB mutations are the first reported with Leigh syndrome.
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Enfermedad de Leigh/enzimología , Mutación Puntual , Piruvato Deshidrogenasa (Lipoamida)/deficiencia , Piruvato Deshidrogenasa (Lipoamida)/genética , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Preescolar , Tamización de Portadores Genéticos , Homocigoto , Humanos , Lactante , Recién Nacido , Enfermedad de Leigh/diagnóstico , Enfermedad de Leigh/genética , Masculino , Datos de Secuencia MolecularRESUMEN
Identification of very long-chain acyl-CoA dehydrogenase deficiency is possible in the expanded newborn screening (NBS) due to the increase in tetradecenoylcarnitine (C14:1) and in the C14:1/C2, C14:1/C16, C14:1/C12:1 ratios detected in dried blood spots. Nevertheless, different confirmatory tests must be performed to confirm the final diagnosis. We have revised the NBS results and the results of the confirmatory tests (plasma acylcarnitine profiles, molecular findings, and lymphocytes VLCAD activity) for 36 cases detected in three Spanish NBS centers during 4 years, correlating these with the clinical outcome and treatment. Our aim was to distinguish unambiguously true cases from disease carriers in order to obtain useful diagnostic information for clinicians that can be applied in the follow-up of neonates identified by NBS.Increases in C14:1 and of the different ratios, the presence of two pathogenic mutations, and deficient enzyme activity in lymphocytes (<12% of the intra-assay control) identified 12 true-positive cases. These cases were given nutritional therapy and all of them are asymptomatic, except one. Seventeen individuals were considered disease carriers based on the mild increase in plasma C14:1, in conjunction with the presence of only one mutation and/or intermediate residual activity (18-57%). In addition, seven cases were classified as false positives, with normal biochemical parameters and no mutations in the exonic region of ACADVL. All these carriers and the false positive cases remained asymptomatic. The combined evaluation of the acylcarnitine profiles, genetic results, and residual enzyme activities have proven useful to definitively classify individuals with suspected VLCAD deficiency into true-positive cases and carriers, and to decide which cases need treatment.
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BACKGROUND & AIMS: Mitochondrial diseases (MD) are the most frequent inborn errors of metabolism. In affected tissues, MD can alter cellular oxygen consumption rate leading to potential decreases in whole-body resting energy expenditure (REE), but data on pediatric children are absent. We determined, using indirect calorimetry (IC), whole-body oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory quotient (RQ) and REE in pediatric patients with MD and healthy controls. Another goal was to assess the accuracy of available predictive equations for REE estimation in this patient population. METHODS: IC data were obtained under fasting and resting conditions in 20 MD patients and 27 age and gender-matched healthy peers. We determined the agreement between REE measured with IC and REE estimated with Schofield weight and FAO/WHO/UNU equations. RESULTS: Mean values of VO2, VCO2 (mL·min-1·kg-1) or RQ did not differ significantly between patients and controls (P = 0.085, P = 0.055 and P = 0.626 respectively). Accordingly, no significant differences (P = 0.086) were found for REE (kcal·day-1 kg-1) either. On the other hand, although we found no significant differences between IC-measured REE and Schofield or FAO/WHO/UNU-estimated REE, Bland-Altman analysis revealed wide limits of agreement and there were some important individual differences between IC and equation-derived REE. CONCLUSIONS: VO2, VCO2, RQ and REE are not significantly altered in pediatric patients with MD compared with healthy controls. The energy demands of pediatric patients with MD should be determined based on IC data in order to provide the best possible personalized nutritional management for these children.
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Metabolismo Basal , Calorimetría Indirecta , Enfermedades Mitocondriales/fisiopatología , Antropometría , Dióxido de Carbono/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Modelos Logísticos , Masculino , Consumo de OxígenoRESUMEN
Generalized peroxisomal disorders are severe congenital diseases that involve the central nervous system, leading to severe psychomotor retardation, retinopathy, liver disease, and early death. In these disorders, peroxisomes are not normally formed and their enzymes are deficient. Characteristically, plasmalogen synthesis and beta-oxidation of very-long-chain fatty acids (VLCFAs) are affected. We found that patients with generalized peroxisomal disorders have a profound brain deficiency of docosahexaenoic acid (DHA; 22:6n-3) and low DHA concentrations in all tissues and the blood. Given the fundamental role of DHA in neuronal and retinal membranes, a DHA deficiency of this magnitude might be pathogenic. Thus, we studied the possible therapeutic effect of normalizing DHA concentrations in patients with peroxisomal disorders. We chose the DHA ethyl ester (DHA-EE) because of its high degree of purity at daily oral doses of 100-500 mg. This article summarizes the results of treatment of 13 patients with DHA-EE, with some follow-up evidence of clinical improvement. Supplementation with DHA-EE normalized blood DHA values within a few weeks. Plasmalogen concentrations increased in erythrocytes in most patients and after DHA concentrations were normalized, amounts of VLCFAs decreased in plasma. Liver enzymes returned almost to normal in most cases. From a clinical viewpoint, most patients showed improvement in vision, liver function, muscle tone, and social contact. In 3 patients, normalization of brain myelin was detected by magnetic resonance imaging. In 3 others, myelination improved. In a seventh patient, myelination is progressing at a normal rate. These results suggest a fundamental role of DHA in the pathogenesis of Zellweger syndrome. DHA therapy is thus strongly recommended, not only to alleviate symptoms in patients with life-threatening diseases, but also to clarify remaining questions regarding the role of DHA in health and disease.
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Suplementos Dietéticos , Ácidos Docosahexaenoicos/uso terapéutico , Síndrome de Zellweger/dietoterapia , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiología , Niño , Preescolar , Cromatografía de Gases , Ácidos Grasos/sangre , Femenino , Humanos , Lactante , Hígado/efectos de los fármacos , Hígado/metabolismo , Imagen por Resonancia Magnética , Masculino , Vaina de Mielina/patología , Fibras Nerviosas Mielínicas/efectos de los fármacos , Fibras Nerviosas Mielínicas/patología , Plasmalógenos/sangre , Visión OcularRESUMEN
Congenital disorders of glycosylation (CDG) and mitochondrial diseases are multisystem disorders with clinical characteristics that may overlap. We present four patients with CDG whose phenotypes suggested the diagnosis of a mitochondrial disease. Patients 1 and 2 are siblings with hemiplegic headache, stroke-like episodes, lactic acidaemia and history of maternal migraine; their initial clinical diagnosis was MELAS syndrome (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes). Patient 3 suffers from ataxia, neuropathy, ophtalmoplegia and retinitis pigmentosa suggestive of NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome. Patient 4 presented with neurological regression mimicking Leigh disease, with ptosis, myoclonus, ataxia and brainstem and cerebellar atrophy. Screening for mitochondrial disease including enzyme and mtDNA investigations on muscle biopsy were performed on Patients 1, 2 and 4 with normal results. However, evidence for a glycosylation disorder was substantiated by an increased carbohydrate deficient transferrin (CDT). The isoelectric focussing pattern of serum sialotransferrin was typical of CDG type I in Patients 1, 2 and 3 and was shifted towards the less sialylated bands in case 4. A deficiency of phosphomanomutase (PMM) confirmed the diagnosis of CDG-Ia in Patients 1, 2 and 3, who are compound heterozygous for mutations R141H/T237M (Patients 1 and 2) and R141H/P113L (Patient 3). In Patient 4, PMM activity was normal, and further enzymatic and molecular studies are underway. As the search for the primary defect in mitochondrial diseases is often unsuccessful, the pool of mitochondrial patients that remain without definite diagnosis might include CDG cases. Routine screening for CDG may avoid precocious invasive investigations.
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Glicosilación , Encefalomiopatías Mitocondriales/diagnóstico , Transferrina/análogos & derivados , Acidosis Láctica/diagnóstico , Acidosis Láctica/genética , Adolescente , Adulto , Preescolar , Consanguinidad , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Tamización de Portadores Genéticos , Humanos , Enfermedad de Leigh/diagnóstico , Enfermedad de Leigh/genética , Masculino , Encefalomiopatías Mitocondriales/genética , Fosfotransferasas (Fosfomutasas)/deficiencia , Fosfotransferasas (Fosfomutasas)/genética , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/genética , Degeneraciones Espinocerebelosas/diagnóstico , Degeneraciones Espinocerebelosas/genética , Transferrina/genéticaRESUMEN
We report a boy 20 months of age with encephalopathy, petechiae, and ethylmalonic aciduria (EPEMA). Other clinical features were severe hypotonia, orthostatic acrocyanosis, and chronic diarrhea. Magnetic resonance imaging (MRI) of the brain demonstrated bilateral lesions in the lenticular and caudate nuclei, periaqueductal region, subcortical areas, white matter, and brainstem. Short and medium chain Acyl-CoA dehydrogenase and cytochrome c oxidase (COX) activities in fibroblasts were normal. Muscle histochemistry disclosed diffuse COX deficiency, and respiratory chain activities in muscle disclosed severe COX deficiency. Twelve other patients with similar clinical features have been reported. Muscle COX activity, studied only in four, demonstrated a clear-cut defect.
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Deficiencia de Citocromo-c Oxidasa , Enfermedad de Leigh/genética , Malonatos/orina , Púrpura/genética , Encéfalo/patología , ADN Mitocondrial/genética , Humanos , Lactante , Enfermedad de Leigh/diagnóstico , Enfermedad de Leigh/enzimología , Masculino , Músculo Esquelético/patología , Púrpura/diagnóstico , Púrpura/enzimologíaRESUMEN
INTRODUCTION AND DEVELOPMENT: In the last years we have assisted to a great knowledge of inborn errors of metabolism (IEM). As consequence, the clinical suspicion of IEM in neuropediatrics is more frequent. The IEM must be investigated in the newborn with neurologic symptoms without any evident etiology, when anamnesis of gestation and delivery is not informative. The IEM play an important role in infants with severe hypotonia, seizures, some dysmorphic children and when there is a multisystem disorder. They must be investigated too when the fetus shows hydrops fetalis, seizures, cardiomyopathy, and pericardial effusion; also when there is a family history of IEM or sudden infant death in a brother or HELLP syndrome in the pregnant mother. Some times routine laboratory investigations may be useful for diagnosis, although in other occasions more specific and sophisticated laboratory studies are necessary. CONCLUSIONS: This is a review of different neurological presentation of IEM in the newborn and the importance of different investigations in the diagnosis. We comment the diagnosis problems in some diseases, and new neurometabolic diseases with presentation in the first months of life and how to diagnose them.
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Encefalopatías Metabólicas Innatas/complicaciones , Encefalopatías Metabólicas Innatas/diagnóstico , Diagnóstico Diferencial , Humanos , Recién NacidoRESUMEN
Three groups of disorders are reviewed: the syndromes with carbohydrate deficient glycoproteins, congenital errors of metabolism involving purines and pyrimidines, and finally those of the neurotransmitters. Individually these disorders are rare, but as a group include many different pathological conditions. We list the clinical symptoms and laboratory data in patients with different enzyme deficiencies. Although some disorders have specific clinical characteristics, most have nonspecific clinical features which makes diagnosis difficult.
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Enfermedad de Canavan/diagnóstico , Trastornos Congénitos de Glicosilación/diagnóstico , Hiperglucemia/diagnóstico , Monoaminooxidasa/deficiencia , Monoaminooxidasa/metabolismo , Errores Innatos del Metabolismo de la Purina-Pirimidina/diagnóstico , Ácido gamma-Aminobutírico/metabolismo , Trastornos Congénitos de Glicosilación/genética , Humanos , Hiperglucemia/genética , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo de la Purina-Pirimidina/genéticaRESUMEN
INTRODUCTION: We found that patients with the Zellweger syndrome and other generalized peroxisomal disorders have a dramatic decrease of docosahexaenoic acid (DHA, 22:6n-3) in the blood, brain, retina and other tissues. DHA is believed to play an important role in the brain and retina. DEVELOPMENT: Patients with the Zellweger syndrome and its variants have severe cerebral and retinal defects that could be related to their DHA deficiency. With this rationale, we have been treating peroxisomal-disorder patients with a DHA derivative of a high degree of purity (DHA ethyl ester, > 90% pure) since 1991. So far, we have treated 13 DHA-deficient peroxisomal patients, one with the classic Zellweger syndrome and 12 with milder variants of the disease. This paper presents the follow-up of these DHA-treated patients. In summary, we have found important improvements in liver function, in the plasmalogen levels and in the two ratios 26:0/22:0 y 26:1/22:0, diagnostic of the disease. We have also found clear clinical improvements in most cases. Most significantly, magnetic resonance imaging has shown advances in brain myelination, so far in 6 of the treated patients. CONCLUSION: We strongly recommend treatment with DHA ethyl ester in all DHA-deficient patients with generalized peroxisomal disorders. Logically, treatment should be started as soon as possible, in the hope of preventing cerebral and visual damage.
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Ácidos Docosahexaenoicos/uso terapéutico , Trastorno Peroxisomal/tratamiento farmacológico , Encéfalo/patología , Niño , Preescolar , Enfermedades Desmielinizantes/patología , Ácidos Docosahexaenoicos/sangre , Éter/uso terapéutico , Humanos , Lactante , Imagen por Resonancia Magnética , Trastorno Peroxisomal/patología , Resultado del TratamientoAsunto(s)
Calorimetría Indirecta , Enfermedades Mitocondriales , Niño , Metabolismo Energético , Humanos , Mitocondrias , DescansoRESUMEN
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.
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Homocistinuria/epidemiología , Adolescente , Niño , Preescolar , Estudios Transversales , Femenino , Homocistinuria/diagnóstico , Homocistinuria/etiología , Homocistinuria/terapia , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Enfermedades Metabólicas/complicaciones , Prevalencia , EspañaRESUMEN
Mitochondrial diseases result from structural, biochemical or genetic defects of mitochondria, which contain the respiratory chain. They usually affect children and young adults. We report the CT and MRI findings in 17 patients under 14 years of age, the youngest reported to date, with various mitochondrial diseases. Although imaging studies may be normal negative in the early stages, follow-up usually shows many abnormalities, which depend on clinical status and the disease. We have recognised a spectrum of findings that can be divided into four patterns: nonspecific myelin lesions (8/17); grey-matter nuclei involvement (6/17); a leukodystrophic pattern; and calcification of the brain (1/17), although mixed forms, particularly myelin and grey-matter lesions are frequent.
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Encéfalo/patología , Esclerosis Cerebral Difusa de Schilder/diagnóstico , Síndrome de Kearns-Sayre/diagnóstico , Enfermedad de Leigh/diagnóstico , Encefalomiopatías Mitocondriales/diagnóstico , Niño , Preescolar , Medios de Contraste , Femenino , Gadolinio DTPA , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Tomografía Computarizada por Rayos XRESUMEN
CDG Ie is caused by a deficiency of dolichol-phosphate-mannose synthase 1 (DPM1), an enzyme involved in N-glycan assembly in the endoplasmic reticulum. Three proteins are known to be part of the synthase complex: DPM 1, DPM2 and DPM3. Only mutations in DPM1, the catalytic subunit, have been described in three families. One was homozygous for the c274C>G (R92G) mutation in DPM1 and two others were compound heterozygous for R92G and a c628delC deletion or a c331-343del13, respectively. Clinical features were a severe infantile encephalopathy, early intractable seizures, acquired microcephaly, and some dysmorphic features. We report a patient with milder symptoms: microcephaly, dysmorphic features, developmental delay, optic atrophy, and cerebellar dysfunction without cerebellar atrophy. The patient is homozygous for a new mutation in exon 9 of the DPM1 gene (c742T>C (S248P)). Our findings extend the spectrum of CDG Ie.
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Errores Innatos del Metabolismo de los Carbohidratos/diagnóstico , Manosiltransferasas/deficiencia , Manosiltransferasas/genética , Encéfalo/patología , Errores Innatos del Metabolismo de los Carbohidratos/clasificación , Niño , Discapacidades del Desarrollo/genética , Exones , Facies , Femenino , Fibroblastos/metabolismo , Eliminación de Gen , Heterocigoto , Homocigoto , Humanos , Lipopolisacáridos/análisis , Imagen por Resonancia Magnética , Masculino , Microcefalia/genética , Mutación , Atrofia Óptica/genética , Tomografía Computarizada por Rayos XRESUMEN
A patient with intention and action myoclonus, epilepsy, ataxia, and mental deterioration in association with ragged-red fibers in striated muscle is described. This patient demonstrated a unique form of erratic myoclonus with continuous EEG spike activity during eye closure. Both the myoclonus and the EEG spiking disappeared on opening the eyes. A defect in the activity of complex I in the respiratory chain was demonstrated.
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Epilepsias Mioclónicas/patología , Mitocondrias Musculares/ultraestructura , Adolescente , Ataxia/fisiopatología , Electroencefalografía , Epilepsias Mioclónicas/fisiopatología , Femenino , Humanos , Discapacidad Intelectual/fisiopatología , Enfermedades Musculares/fisiopatología , Sarcolema/ultraestructura , SíndromeRESUMEN
Nineteen children with defects of the mitochondrial respiratory chain are described. First symptoms appeared during the first two years of their lives. Four types of clinical pictures were identified: 1/neonatal hypotonia. 2/cardiomyopathy. 3/progressive neurological deterioration. 4/multisystem disease. A study of pyruvate and fatty acids metabolism and a skeletal muscle biopsy were performed in all cases. Elevation of beta-hydroxybutyrate/acetoacetate and lactate were the most frequent biochemical abnormalities. Muscular biopsy in light microscopy showed in most cases abnormal lipid storage.
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Encefalopatías Metabólicas/etiología , Cardiomiopatías/etiología , Transporte de Electrón , Enfermedad de Leigh/etiología , Mitocondrias/patología , Hipotonía Muscular/etiología , Biopsia , Preescolar , Complejo IV de Transporte de Electrones/análisis , Metabolismo Energético , Femenino , Humanos , Lactante , Masculino , Mitocondrias/metabolismo , Insuficiencia Multiorgánica/etiología , Músculos/patologíaAsunto(s)
Encéfalo/metabolismo , Deficiencia de Ácido Fólico/metabolismo , Enfermedades Mitocondriales/metabolismo , Tetrahidrofolatos/deficiencia , Adolescente , Adulto , Niño , Preescolar , Femenino , Deficiencia de Ácido Fólico/líquido cefalorraquídeo , Deficiencia de Ácido Fólico/diagnóstico , Humanos , Lactante , Masculino , Enfermedades Mitocondriales/líquido cefalorraquídeo , Enfermedades Mitocondriales/diagnóstico , Tetrahidrofolatos/líquido cefalorraquídeoRESUMEN
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)