Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency.

We screened for PDHA1 mutations in 40 patients with biochemically demonstrated PDHc deficiency or strong clinical suspicion, and found changes with probable pathological significance in 20. Five patients presented new mutations: p.A169V, c.932_938del, c.1143_1144 ins24, c.1146_1159dup and c.510-30G> A, this latter is a new undescribed cause of exon 6 skipping. Another four mutations have been found, and previously reported, in our patients: p.H113D, p.P172L, p.Y243del and p.Y369Q. Eleven patients presented seven known mutations: p.R127Q, p.I166I, p.A198T, p.R263G, p.R302C, p.R378C and c.1142_1145dup. The latter three were found in more than one unrelated patient: p.R302C was detected in a heterozygous girl and a mosaic male, p.R378C in two males and finally, c.1142_1145dup in three females; only one in 20 mothers was found to be a carrier (p.R263G). Apart from those 20 patients, the only alteration detected in one girl with clear PDHc and PDH-E1 deficiency was the silent change c.396A> C (p.R132R), and other eight PDHc deficient patients carry combinations of known infrequent polymorphisms that are overrepresented among our 20 unsolved patients. The importance of these changes on PDH activity is unclear. Investigations in the other PDHc genes are in course in order to elucidate the genetic defect in the unresolved patients.

Cervical length and gestational age at admission as predictors of intra-amniotic inflammation in preterm labor with intact membranes.

OBJECTIVES: To evaluate cervical length and gestational age as predictors of intra-amniotic inflammation in patients admitted because of preterm labor and intact membranes. METHODS: Ninety-three pregnant women with preterm labor and intact membranes were included in our study. Cervical length was measured on admission by transvaginal sonography and transabdominal amniocentesis was performed within the first 48 h following admission. Positive amniotic fluid cultures defined intra-amniotic infection. Levels of intra-amniotic interleukin-6 (IL-6) were measured, and a receiver-operating characteristics (ROC) curve was constructed to determine the best cut-off point of IL-6 for predicting intra-amniotic infection. This value was then used as a basis for determining a cut-off of IL-6 for defining intra-amniotic inflammation. Considering inflammatory status, perinatal outcomes were evaluated and compared. Logistic regression was used to investigate associations of different explanatory variables with inflammatory status. A non-invasive approach for detection of intra-amniotic inflammation in women admitted because of preterm labor with intact membranes was evaluated. RESULTS: Intra-amniotic infection and inflammation rates were 14% and 28%, respectively. ROC curve analysis showed that the best cut-off value for IL-6 was 13.4 ng/mL for predicting intra-amniotic infection, which was comparable to the cut-off of 11.3 ng/mL reported previously by other authors (which we used to define inflammation). Regardless of the intra-amniotic microbial status, perinatal outcomes in women who developed intra-amniotic inflammation were worse than in those who did not. Cervical length < 15 mm and gestational age at admission < 28 weeks were independently associated with intra-amniotic inflammation. A strategy considering these two non-invasive parameters (either women admitted < 28 weeks or women admitted between >or= 28 and < 32 weeks with a cervical length < 15 mm) could detect 84.0% of women with intra-amniotic inflammation with a positive predictive value of 48.8%, providing improved diagnostic indices compared to either variable considered alone. CONCLUSIONS: Cervical length and gestational age at admission can be used as a non-invasive method to assess the risk of intra-amniotic inflammation in preterm labor and intact membranes.

[Glutaric aciduria type I. Clinical, biochemical and molecular findings in six patients in Venezuela]. / Aciduria glutárica tipo I. Hallazgos clínicos, bioquímicos y moleculares en seis pacientes venezolanos.

INTRODUCTION: Glutaric aciduria type I is an autosomal recessive inborn error of metabolism that is due to a deficiency of the enzyme glutaryl-CoA dehydrogenase, which gives rise to an accumulation of glutaric and 3-hydroxyglutaric acids in biological fluids. Clinical features present as a sudden-onset severe neurological disorder, characterised by extrapyramidal signs (dystonia-dyskinesia), hypotonia, irritability, macrocephaly and degeneration of the basal ganglia; it may also manifest with unspecific symptoms, such as hypotonia and psychomotor retardation. AIMS: To describe the clinical, biochemical, neuroimaging and molecular aspects in six Venezuelan patients and to highlight the importance of an early diagnosis of glutaric aciduria type I so as to be able to establish early treatment and thus prevent the neurological damage produced by this disease. CASE REPORTS: Two patients were referred because of macrocephaly, hypotonia and psychomotor retardation, and four more following an encephalopathic crisis. In all of them, neuroimaging studies showed delays in myelination, bilateral frontotemporal hypoplasia and symmetric widening of the Sylvian fissures with poor opercularisation. Urinary organic acid analyses showed raised levels of glutaric and 3-hydroxyglutaric acids, and a molecular analysis confirmed the diagnosis. CONCLUSIONS: Organic acid analysis should be indicated in all patients who present macrocephaly, hypotonia, psychomotor retardation or an encephalopathic crisis of unknown causation. This study allowed us to determine the behaviour of the disease in Venezuela, since no epidemiological data exist in the country.

Aciduria glutárica tipo I. Hallazgos clínicos, bioquímicos y moleculares en seis pacientes venezolanos / Glutaric aciduria type I. Clinical, biochemical and molecular findings in six patients in Venezuela

Introducción. La aciduria glutárica tipo I es un error congénito del metabolismo, con herencia autosómica recesiva, debido a la deficiencia de la enzima glutaril-CoA deshidrogenasa, que da lugar a la acumulación de ácido glutárico y 3-hidroxiglutárico en fluidos biológicos. El cuadro clínico se presenta como un trastorno neurológico grave, de inicio súbito, caracterizado por signos extrapiramidales (distonía-discinesia), hipotonía, irritabilidad, macrocefalia y degeneración de los ganglios basales; o puede manifestarse con síntomas inespecíficos, como hipotonía y retraso psicomotor. Objetivos. Describir los aspectos clínicos, bioquímicos, de neuroimagen y moleculares en seis pacientes venezolanos y resaltar la importancia del diagnóstico precoz de la aciduria glutárica tipo I para instaurar tratamiento temprano y evitar el daño neurológico que esta enfermedad produce. Casos clínicos. Se remitieron dos pacientes por macrocefalia, hipotonía y retraso psicomotor, y cuatro posteriores a una crisis encefalopática. Los estudios de neuroimagen mostraron en todos ellos retraso en la mielinización, hipoplasia frontotemporal bilateral y ensanchamiento simétrico de las cisuras de Silvio con pobre opercularización. El análisis de ácidos orgánicos en orina mostró niveles incrementados de los ácidos glutárico y 3-hidroxiglutárico, y el análisis molecular permitió la confirmación del diagnóstico. Conclusiones. En todo paciente que se presenta con macrocefalia, hipotonía, retraso psicomotor o una crisis encefalopática sin causa determinada debe indicarse el análisis de ácidos orgánicos. Este estudio permitió conocer el comportamiento de la enfermedad en Venezuela, ya que no existen datos epidemiológicos en el país

Introduction. Glutaric aciduria type I is an autosomal recessive inborn error of metabolism that is due to a deficiency of the enzyme glutaryl-CoA dehydrogenase, which gives rise to an accumulation of glutaric and 3-hydroxyglutaric acids in biological fluids. Clinical features present as a sudden-onset severe neurological disorder, characterised by extrapyramidal signs (dystonia-dyskinesia), hypotonia, irritability, macrocephaly and degeneration of the basal ganglia; it may also manifest with unspecific symptoms, such as hypotonia and psychomotor retardation. Aims. To describe the clinical, biochemical, neuroimaging and molecular aspects in six Venezuelan patients and to highlight the importance of an early diagnosis of glutaric aciduria type I so as to be able to establish early treatment and thus prevent the neurological damage produced by this disease. Case reports. Two patients were referred because of macrocephaly, hypotonia and psychomotor retardation, and four more following an encephalopathic crisis. In all of them, neuroimaging studies showed delays in myelination, bilateral frontotemporal hypoplasia and symmetric widening of the Sylvian fissures with poor opercularisation. Urinary organic acid analyses showed raised levels of glutaric and 3-hydroxyglutaric acids, and a molecular analysis confirmed the diagnosis. Conclusions. Organic acid analysis should be indicated in all patients who present macrocephaly, hypotonia, psychomotor retardation or an encephalopathic crisis of unknown causation. This study allowed us to determine the behaviour of the disease in Venezuela, since no epidemiological data exist in the country