Four Years' Experience in the Diagnosis of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency in Infants Detected in Three Spanish Newborn Screening Centers.

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.

Unidad de Enfermedades Mitocondriales y Enfermedades Metabólicas Hereditarias. Servicio de Pediatría. Hospital Universitario 12 de Octubre / Mitochondrial Disease and Hereditaru Metabolic Disease Unit. Pediatric Department. University Hospital 12 de Octubre

La Unidad Pediátrica de Enfermedades Mitocondriales y Enfermedades Metabólicas Hereditarias (EM-EMH) presta atención a pacientes afectos de errores congénitos del metabolismo (ECM). Asimismo, realiza consejo genético, diagnóstico prenatal y el diagnóstico en sus familiares. Nuestro Hospital dispone de todas las especialidades médicas, pediátricas y de adultos, así como infraestructuras necesarias para proporcionar una atención de calidad. Por el trabajo realizado hemos recibido algunos premios y reconocimientos, otorgados por asociaciones de pacientes (Federación Española de Enfermedades Raras -FEDER-, Asociación Española de Enfermedades Raras -ACME-IM-). Hemos sido denominados Centro Experto de Referencia para centro del diagnóstico y seguimiento clínico de los casos sospechosos de enfermedades metabólicas congénitas detectados en el programa de cribado neonatal universal que se realiza en la Comunidad de Madrid y Centro de Referencia para enfermedades metabólicas congénitas para niños y adultos (CSUR) por el Ministerio de Sanidad, Servicios Sociales e. Igualdad. Recientemente hemos sido nominados dentro de la Red Europea de Referencia de enfermedades metabólicas hereditarias (metabERN) (AU)

The Pediatric Mitochondrial and Hereditary Mctabolic Diseases Unit (MD-IMD) provides care for patients affected by Inborn Errors of Metabolism (IMD). It also provides genetic advice, prenatal diagnosis and diagnosis in their family members. Our hospital has all the medical, pediatric and adult specialities, as well as the necessary infrastructure to provide quality care. We have received some awards and acknowledgments for our work, granted by the associations of patients (Spanish Federation of Rare Diseases-FEDER-, Spanish Association of Rare Diseases -ACMEIM-). We have been named as an Expert Center of Reference for HMD detected in extended neonatal screening of the community of Madrid and a Reference Center for lnborn Err0rs of Metabolism for children and adults (CSUR -Centers, Services and Units of Reference) by the National Health Service. Actually we are working in the European Reference Network for Rare Hereditary Metabolic Disorders (metabERN) (AU)

The homozygous R504C mutation in MTO1 gene is responsible for ONCE syndrome.

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.

Assessment of resting energy expenditure in pediatric mitochondrial diseases with indirect calorimetry.

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.

Nutritional and Pharmacological Management during Chemotherapy in a Patient with Propionic Acidaemia and Rhabdomyosarcoma Botryoides.

We present the nutritional and pharmacological management of a 2-year-old girl with a severe form of propionic acidaemia and a genitourinary embryonal rhabdomyosarcoma. This association has not been described before, nor the utilization of chemotherapy in patients with propionic acidaemia.The patient is a girl with neonatal onset of propionic acidaemia, homozygous for the c.2041-2924del3889 mutation in PCCA gene. At 23 months of age she was diagnosed with genitourinary embryonal rhabdomyosarcoma. Conservative surgery, brachytherapy and nine cycles of chemotherapy with iphosphamide, vincristine and actinomycin were recommended by oncologists. Due to the possibility that the child could present decompensations, we elaborated three different courses of treatment: when the patient was stable (treatment 1), intermittent bolus feeding through gastrostomy, containing 70 kcal/kg/day and 1.4 g/kg/day of total protein (0.6 g/kg/day of natural protein and 0.8 g/kg/day of amino acid-based formula) was prescribed; on the chemotherapy-days (treatment 2), diet consisted on continuous feeding, with the same energy and amino acid-based formula but half of natural protein intake; in case of decompensation (treatment 3), we increased by 10% the energy intake, and completely stopped natural protein in the diet but maintaining the amino acid-based formula. On chemotherapy- days carnitine was increased from 100 mg/kg/day to 150 mg/kg/day, and N-carbamylglutamate was added.Through the 7 months with chemotherapy the patient did not suffer decompensations, while she maintained good nutritional status.Enteral continuous feeding by gastrostomy, amino acid-based formula, and preventive use of N-carbamylglutamate during chemotherapy-days are the principal measures we propose in these situations.

Clinical, molecular and biochemical characterization of nine Spanish families with Conradi-Hünermann-Happle syndrome: new insights into X-linked dominant chondrodysplasia punctata with a comprehensive review of the literature.

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.

Enfermedad de Niemann-Pick tipo C: desde una colestasis neonatal hacia un deterioro neurológico. Variabilidad fenotípica / Niemann-Pick type C disease: From neonatal cholestasis to neurological degeneration. Different phenotypes

Introducción: La enfermedad de Niemann-Pick tipo C está causada por un defecto en el transporte intracelular de colesterol que produce un acúmulo de lípidos en los lisosomas de diferentes tejidos. Es una enfermedad rara, debida generalmente a mutaciones en el gen NPC1 y solo unos pocos casos se asocian a mutaciones en el gen NPC2. Frecuentemente se manifiesta en la edad pediátrica, presentando gran variabilidad en las manifestaciones clínicas. La enfermedad conduce a un deterioro neurológico con diferentes síntomas que están relacionados con la edad. Una colestasis neonatal transitoria, la aparición de esplenomegalia y/o hepatomegalia pueden preceder en años a los síntomas neurológicos. Pacientes y métodos: Presentamos los 6 casos diagnosticados en nuestra unidad en los últimos 20 años. Se han revisado las manifestaciones clínicas, los hallazgos neurorradiológicos (RM) y el análisis molecular de todos ellos. Resultados: Todos se presentaron antes de los 6 años y 5 casos tuvieron afectación hepática y/o colestasis en el periodo neonatal. En 2 casos se detectó ascitis en el periodo prenatal. La presencia de esplenomegalia se objetivó en 5 casos. En todos los casos se detectaron mutaciones en el gen NPC1. Conclusión: Es importante el conocimiento de esta enfermedad y la identificación de los síntomas clínicos precoces para poder diagnosticarla precozmente, lo que conllevaría a un tratamiento adecuado, pudiendo evitar procedimientos innecesarios. Por otra parte es importante asesorar adecuadamente a las familias y proporcionar un consejo genético (AU)

Introduction: Niemann-Pick type C is a lysosomal storage disorder caused by a defect in intracellular trafficking of cholesterol. It is a rare disease, usually caused by mutations in NPC1 gene, but in some cases by mutations in NPC2 gene. Usually it is present in the paediatric age with a great variability of clinical manifestations. This disease leads to neurological degeneration with various age-related symptoms. Transient neonatal cholestasis, the appearance of splenomegaly and/or hepatomegaly may occur years before the neurological symptoms. Patients and methods: We report 6 cases diagnosed in our unit in the last 20 years. We reviewed the clinical manifestations, neuroradiological findings (MRI) and molecular analysis of all of them. Results: The disease began before 6 years of age and 5 cases had liver dysfunction and cholestasis in the neonatal period. Ascites was detected in 2 cases in prenatal period. Five cases have or had splenomegaly. Mutations in NPC1 gene were detected in all of them. Conclusions: It is important to understand this disease and the identification of early clinical symptoms to make an early diagnosis, leading to appropriate treatment and avoiding unnecessary tests. Moreover, it is important to suitably advise families and provide them with genetic counseling (AU)

Síndromes de Pearson y de Kearns-Sayre: dos enfermedades mitocondriales multisistémicas, debidas a deleciones en el ADN mitocondrial / Pearson and Kearns-Sayre syndromes: two multisystem mitochondrial diseases caused by mitochondrial DNA deletions

El síndrome de Pearson (SP) y el síndrome de Kearns-Sayre (SKS) son enfermedades mitocondriales multisistémicas con diferente fenotipo, causadas por deleciones en el ADN mitocondrial (ADN mt).Objetivo: Describir las manifestaciones clínicas y los hallazgos neurorradiológicos, bioquímicos y genético-moleculares de ambos síndromes, con objeto de difundir su conocimiento entre los pediatras. Pacientes y métodos: Se han estudiado retrospectivamente 6 pacientes con SKS y 3 con SP inicial, dos de los cuales evolucionaron a SKS. Resultados: La edad de inicio de los síntomas fue inferior en los SP. Los síntomas más precoces fueron los hematológicos (anemia), seguidos de los renales (Fanconi) y digestivos (insuficiencia pancreática), y de forma más tardía se presenta la afectación ocular, endocrinológica, cardiológica y neurológica. Cuatro pacientes precisaron implantación de marcapasos. Seis casos presentaron alteraciones cerebrales y/o del tronco del encéfalo en la resonancia magnética. Se observó hiperlactatorraquia, hiperproteinorraquia y descenso de ácido fólico en el líquido cefalorraquídeo. La mitad de los SKS presentaron fibras musculares rojo-rasgadas y fibras citocromo C oxidasa negativas. En ocho pacientes se detectó una deleción única del ADN mt. Conclusiones: 1) Las diferencias más acusadas entre el SP y el SKS fueron la edad de comienzo y las manifestaciones iniciales. Los síntomas en la evolución, así como los hallazgos bioquímicos, neurorradiológicos y genéticos, fueron similares. 2) Las enfermedades mitocondriales deberían incluirse en el diagnóstico diferencial del síndrome de Fanconi, el déficit de la hormona del crecimiento y los trastornos de la conducción cardiaca, especialmente en los casos con afectación multiorgánica. El diagnóstico se confirma por la presencia de una gran deleción en el ADN mt (AU)

Kearns-Sayre (KSS) and Pearson syndromes are both multisystem mitochondrial diseases whose underlying genetic defect is a single large-scale mitochondrial DNA (mt DNA) deletion. Objectives: To describe the clinical spectrum of KSS and PS, with the object of spreading the knowledge of these disease to the pediatricians. Patients and methods: We reviewed the clinical notes of 6 patients diagnosed with KSS and 3 patients initially diagnosed with PS. Results: The age at the onset was lower in PS patients. First appearing symptoms were hematological (anemia), followed by renal (Fanconi) and digestive involvement (pancreatic insufficiency). Ophthalmological, endocrinological, cardiological and neurological symptoms were manifested at later stages. Four patients required pacemaker implantation. Six showed cerebral and/or brain stem involvement in MRI. CSF analysis showed increased levels of both lactic acid and proteins where as folate levels were diminished. Half of the KSS patients showed ragged-red fibers and COX negative fibers in their skeletal muscle. A large-scale mt DNA deletion was found in eight patients. Conclusions: 1. The most remarkable differences between PS and KSS were the age at presentation and the initial clinical symptoms; symptoms during evolution, and biochemical, neuroradiological and genetic findings were similar in both disorders,2. Mitochondrial diseases should be included in the differential diagnosis of the Fanconi syndrome, growth hormone deficiency and cardiac conduction disorders. A single large scale mt DNA is essential to confirm the diagnosis (AU)

Long-term needs of adult patients with organic acidaemias: outcome and prognostic factors.

BACKGROUND: With improvements in the treatment of children with organic acidaemias (OA), the number surviving to adulthood is increasing. To plan appropriate services for their care it is important to know what their needs are. OBJECTIVE: To describe the clinical and social problems affecting adult patients with OA. PATIENTS AND METHODS: We reviewed the medical records of 15 adult patients diagnosed with OA. Social attainment (housing, schooling and occupation) was analysed. Nutritional status was evaluated by body mass index (BMI) and laboratory studies. Neurological and visceral complications were noted. Cognitive outcome was evaluated by psychometric testing and/or educational attainment. RESULTS: Seven had methylmalonic acidaemia (MMA), 4 isovaleric acidaemia (IVA) and 4 propionic acidaemia (PA). Ten were female, and median age was 23.5 years (range 18-48). All but three had late-onset disease. Two patients became pregnant during follow up. Four patients had obtained university degrees and were working. Three-quarters of the patients required some kind of social support. All had a good nutritional status. Height was normal in IVA and 3 PA patients. Osteoporosis was present in 2 out of 8 patients assessed. A variety of neurocognitive or visceral complications were seen in two-thirds of the patients. Metabolic decompensations were unusual. CONCLUSIONS: The approach to adult patients with OA has to be multidisciplinary, with the clinician and dietician as the core of the team, but with the collaboration of clinical nurses specialists, social workers and other specialist services and the support of a biochemical and molecular laboratory.

[Congenital disorder of glycosylation type 1b. Experience with mannose treatment]. / Defecto congénito de glucosilación tipo Ib. Experiencia en el tratamiento con manosa.

Congenital disorders of glycosylation (CDG) are recessively inherited multisystemic disorders resulting from several genetic defects affecting the assembly, transfer or processing of oligosaccharides onto proteins and other glycoconjugates. CDG type Ib is due to a deficiency of phosphomannose isomerase (PMI) encoded by the MPI gene. PMI catalyzes the interconversion of fructose-6-P and mannose-6-P. The clinical phenotype is characterized by gastro-intestinal and hepatic symptoms. In contrast to most CDG patients, there is no neurological affectation. It's a mannose treatable disorder. We report the first recognised case of CDG Ib in Spain. He presented at 6 months with hypoglycaemia, failure to thrive and hypertransaminasaemia. He subsequently developed an enteropathy with subtotal villous atrophy on biopsy. The %CDT was very high and he presented with a type 1 pattern in transferrin isoelectric focusing. PMI activity in fibroblasts was very deficient. Mutations in MPI gene at R219Q and R56fs were found. Clinical and biochemical parameters normalised after treatment with mannose 1 g/kg/day in 5 doses. CDG Ib should be considered in patients with hypoglycaemia, liver disease, enteropathy and hypercoagulability, in the absence of other common causes, and particularly if some of them are combined.

Defecto congénito de glucosilación tipo Ib. Experiencia en el tratamiento con manosa / Congenital disorder of glycosylation type 1b. Experience with mannose treatment

Los defectos congénitos de la glucosilación (CDG, por sus siglas en inglés) son enfermedades genéticas, en general multisistémicas, de herencia autosómica recesiva. Son causadas por defectos que afectan al ensamblaje, la transferencia o el procesamiento de los oligosacáridos de las proteínas u otros glucoconjugados. El CDG tipo Ib está causado por la deficiencia de la enzima citosólica fosfomanosa isomerasa (PMI), codificada por el gen MPI, que cataliza la interconversión de fructosa-6-P y manosa-6-P. Los síntomas son, fundamentalmente, gastrointestinales y hepáticos, y a diferencia de la mayoría de los pacientes con otros tipos de defectos congénitos de la glucosilación, no existe afectación neurológica. El tratamiento con manosa es muy eficaz. Describimos el primer caso de un paciente con CDG-Ib diagnosticado en España. La enfermedad se inició clínicamente a los 6 meses con hipoglucemia, fallo de medro e hipertransaminasemia; posteriormente el paciente desarrolló una enteropatía con atrofia vellositaria subtotal detectada en la biopsia. El paciente presentaba un porcentaje de transferrina deficiente en carbohidratos en el suero del 42 %, un patrón tipo 1 en el isoelectroenfoque de la transferrina sérica, una actividad PMI en fibroblastos del 16 % y las mutaciones R219Q y R56fs en el gen MPI. El tratamiento con manosa a dosis de 1 g/kg/día en 5 dosis resultó muy eficaz, y se normalizaron tanto los parámetros clínicos como los bioquímicos. El defecto congénito de la glucosilación Ib debería incluirse en el diagnóstico diferencial de hipoglucemias, hepatopatías, enteropatías y situaciones de hipercoagulabilidad, en ausencia de otras etiologías más comunes y, sobre todo, si se asocian varios de estos síntomas (AU)

Congenital disorders of glycosylation (CDG) are recessively inherited multisystemic disorders resulting from several genetic defects affecting the assembly, transfer or processing of oligosaccharides onto proteins and other glycoconjugates. CDG type Ib is due to a deficiency of phosphomannose isomerase (PMI) encoded by the MPI gene. PMI catalyzes the interconversion of fructose-6-P and mannose-6-P. The clinical phenotype is characterized by gastro-intestinal and hepatic symptoms. In contrast to most CDG patients, there is no neurological affectation. It's a mannose treatable disorder. We report the first recognised case of CDG Ib in Spain. He presented at 6 months with hypoglycaemia, failure to thrive and hypertransaminasaemia. He subsequently developed an enteropathy with subtotal villous atrophy on biopsy. The % CDT was very high and he presented with a type 1 pattern in transferrin isoelectric focusing. PMI activity in fibroblasts was very deficient. Mutations in MPI gene at R219Q and R56fs were found. Clinical and biochemical parameters normalised after treatment with mannose 1 g/kg/day in 5 doses. CDG Ib should be considered in patients with hypoglycaemia, liver disease, enteropathy and hypercoagulability, in the absence of other common causes, and particularly if some of them are combined (AU)

Enfermedades congénitas del metabolismo en el periodo neonatal (II). Manifestaciones clínicas / Inborn errors of metabolism during the neonatal period (II). Clinical manifestations

Analizamos las formas de presentación clínica y el diagnóstico diferencial de los errores congénitos del metabolismo en el periodo neonatal. La identificación precoz de los pacientes con riesgo de padecer una de estas enfermedades nos permitirá poner en marcha los estudios encaminados a establecer el diagnóstico y, al mismo tiempo, iniciar las primeras medidas terapéuticas, consiguiendo así una mejoría en el pronóstico

We analyse the clinical manifestations and the differential diagnosis of inborn errors of metabolism during the neonatal period. The early identification of patients at risk for these diseases enables us to under take studies to achieve the diagnosis and initiate specific therapy, thus improving the prognosis

Enfermedades congénitas del metabolismo en el periodo neonatal (I). Generalidades / Inborn errors of metabolism during the neonatal period (I). General aspects

Las enfermedades congénitas del metabolismo son raras individualmente pero frecuentes en su conjunto, debido al gran número de entidadeds escritas. A menudo se presentan clínicamente en el periodo neonatal. Los avances en su diagnóstico y tratamiento, por un lado, han mejorado enormemente el pronóstico en muchas de ellas y, por otro, nos permiten prevenir nuevos casos mediante el consejo genético y el diagnóstico prenatal. Por todo ello, es de suma importancia que los neonatólogos y pediatras estén familiarizados con estas enfermedades, y a que serán ellos los que habrán de identificar a los pacientes que se pueden beneficiar de un estudio más profundo y de un tratamiento específico

Inborn errors of metabolism are rare at the individual level, but are common at the collective level, due to the great number of entities described in recent years. The first signs are often detected during the neonatal period. The advances in the diagnosis and treatment of these diseases have substantially improved the prognosis of many of them, while they have also enabled us to prevent new cases through genetic counseling and prenatal diagnosis. For these reasons, it is of the utmost importance that general pediatricians and neonatologists familiarize themselves with these disorders, since they need to beable to identify those patients that might benefit from metabolic studies and specific treatment

Persistent increase of plasma butyryl/isobutyrylcarnitine concentrations as marker of SCAD defect and ethylmalonic encephalopathy.

High concentrations of butyryl/isobutyrylcarnitine (C(4)-carnitine) in plasma with increase of ethylmalonic acid (EMA) in urine point to different genetic entities, and further investigations are required to differentiate the possible underlying defect. Here we report three unrelated cases, two neurologically affected and one asymptomatic, with this abnormal metabolite pattern due either to mutations in the ETHE1 gene or to a short-chain acyl-CoA dehydrogenase (SCAD) defect.

Congenital disorder of glycosylation (CDG) type Ie. A new patient.

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.

[Vesical uric acid lithiasis in a child with renal hypouricemia]. / Litiasis vesical por ácido úrico en un niño con hipouricemia renal.

We report a 12-month-old boy with renal hypouricemia who presented with crying due to obstructing vesicourethral uric acid stones. Metabolic study revealed persistent acidic urine with normal blood pH, and hypouricemia (1.4-1.7 mg/dl) with an increased ratio of uric acid clearance to creatinine clearance (24-32 %). Pyrazinamide produced no response but the patient showed a positive response to benzbromarone. These findings were consistent with a presecretory defect. No other tubular dysfunctions, such as renal glycosuria, aminoaciduria or phosphaturia were found. The patient underwent surgical treatment and was subsequently treated with potassium citrate. After a 2-year follow-up, he remains asymptomatic, despite persistent hyperuricosuria. To our knowledge, this is the youngest reported case of renal hypouricemia and lithiasis.

Litiasis vesical por ácido úrico en un niño con hipouricemia renal / Vesical uric acid lithiasis in a child with renal hypouricemia

Se presenta el caso de un niño de 12 meses con hipouricemia renal cuya primera manifestación fue crisis de llanto y globo vesical, secundarios a litiasis úrica vesicouretral. El estudio metabólico reveló una orina persistentemente ácida con gasometrías sanguíneas normales y un aumento de la excreción fraccional de ácido úrico (24-32 por ciento) con hipouricemia (1,4-1,7 mg/dl), que no respondió a la piracinamida, pero sí al benzbromarone, consistente todo ello con un defecto presecretor. No se encontraron otras alteraciones en la función tubular, como aminoaciduria, glucosuria o fosfaturia, así como tampoco otras enfermedades de base causantes de hipouricemia. El paciente fue intervenido quirúrgicamente y después se trató con citrato potásico, permaneciendo asintomático tras 2 años de seguimiento, a pesar de persistir la hiperuricosuria. En nuestro conocimiento es el paciente más joven descrito en la bibliografía con hipouricemia renal y litiasis (AU)

[Urethrocystography in children. Practical considerations of irradiation doses]. / Uretrocistografía en niños. Consideraciones prácticas en relación con las dosis de irradiación.

OBJECTIVE: Rational use of voiding cystourethrography (VCUG) is imperative, as it is an invasive procedure exposing the child to ionizing radiation and other well documented risks. The objective of this study was to contribute to the achievement of a reduction in the irradiation dose in VCUG. PATIENTS AND METHODS: We reviewed the medical records of a consecutive sample of 125 children that underwent VCUG in our hospital between January 1995 and June 1996. RESULTS: Of the 125 VCUGs, 100 were normal, 13 showed vesicoureteric reflux grade II or higher, and 12 of them presented with other anomalies. The indication for VCUG was febrile UTI in 54 children, hydronephrosis detected prenatally in 12 and other causes in 60 children. It is important to note that children with vesicoureteric reflux presented as febrile UTI or fetal hydronephrosis. The age was significantly lower in the reflux group (p < 0.01). Eleven of the 13 children with vesicoureteric reflux were less than one year of age. Ultrasound anomalies and renal scarring in Tc99 DMSA were seen in a larger proportion in the reflux group. Preliminary X-rays showed anomalies in only 3 of 125 cases. CONCLUSIONS: 1) Vesicoureteric reflux is related to febrile UTI and fetal hydronephrosis. The other indications are questionable. 2) VCGU is not recommended following the first UTI in the evaluation of children 6 years of age or older who have a normal ultrasound and Tc99 DMSA. 3) VCUG could be substituted by a nuclear cystogram in girls who do not have a history of voiding dysfunction. 4) A preliminary X-ray is not justified.