RESUMEN
We report a 16-month-old asymptomatic male with enzyme confirmed isovaleric acidaemia (IVA; isovaleryl-CoA dehydrogenase deficiency; OMIM 243500) who, upon routine nutritional follow-up, presented evidence of peroxisomal dysfunction. The newborn screen (2 days of life) revealed elevated C(5)-carnitine (2.95 µmol/L; cutoff <0.09 µmol/L) and IVA was subsequently confirmed by metabolic profiling and in vitro enzymology. Plasma essential fatty acid (EFA) analysis, assessed to evaluate nutritional status during protein restriction and L: -carnitine supplementation, revealed elevated C(26:0) (5.0 µmol/L; normal <1.3). Subsequently, metabolic profiling and molecular genetic analysis confirmed X-linked adrenoleukodystrophy (XALD). Identification of co-inherited XALD with IVA in this currently asymptomatic patient holds significant treatment ramifications for the proband prior to the onset of neurological sequelae, and critically important counselling implications for this family.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Ácidos Grasos Esenciales/sangre , Evaluación Nutricional , Trastorno Peroxisomal/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/sangre , Errores Innatos del Metabolismo de los Aminoácidos/complicaciones , Errores Innatos del Metabolismo de los Aminoácidos/genética , Biomarcadores/sangre , Análisis Mutacional de ADN , Humanos , Lactante , Recién Nacido , Isovaleril-CoA Deshidrogenasa/sangre , Isovaleril-CoA Deshidrogenasa/deficiencia , Isovaleril-CoA Deshidrogenasa/genética , Masculino , Tamizaje Neonatal , Trastorno Peroxisomal/sangre , Trastorno Peroxisomal/complicaciones , Trastorno Peroxisomal/genética , Valor Predictivo de las PruebasRESUMEN
The continued expansion of newborn screening programmes to include additional conditions increases the responsibility of newborn screening laboratories to provide testing with the highest sensitivity and specificity to allow for identification of affected patients while minimizing the false-positive rate. Some assays and analytes are particularly problematic. Over recent years, our laboratory tried to improve this situation by developing second-tier tests to reduce false-positive results in the screening for congenital adrenal hyperplasia (CAH), tyrosinaemia type I, methylmalonic acidaemias, homocystinuria, and maple syrup urine disease (MSUD). Beginning in 2004, this approach was applied to Mayo's newborn screening programme and resulted in a false-positive rate of 0.09%, a positive predictive value of 41%, and a positive detection rate of 1 affected case in 1672 babies screened.
Asunto(s)
Hiperplasia Suprarrenal Congénita/diagnóstico , Homocistinuria/diagnóstico , Enfermedad de la Orina de Jarabe de Arce/diagnóstico , Espectrometría de Masas/métodos , Tamizaje Neonatal/métodos , Tirosinemias/diagnóstico , Deficiencia de Vitamina B 12/diagnóstico , Hiperplasia Suprarrenal Congénita/sangre , Reacciones Falso Positivas , Homocistinuria/sangre , Humanos , Recién Nacido , Enfermedad de la Orina de Jarabe de Arce/sangre , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad , Factores de Tiempo , Tirosinemias/sangre , Deficiencia de Vitamina B 12/sangreRESUMEN
Glutaric acidemia type I (GA-1) is a progressive neurodegenerative inborn error of metabolism that typically manifests acutely in infants during an intercurrent illness. The diagnosis is established biochemically by the detection of glutaric acid and 3-hydroxy glutaric acid in urine and glutarylcarnitine in plasma. However, some patients excrete only small amounts of glutaric acid and may be overlooked, especially if the plasma concentration of glutarylcarnitine is not elevated. To test the hypothesis that measuring the excretion of glutarylcarnitine may improve the recognition of GA-1 patients without significant glutaric aciduria, urine glutarylcarnitine was analyzed in 14 cases. Five of them lacked significant glutaric aciduria, 9 (of 10 available) had a normal plasma glutarylcarnitine concentration. As controls, we also evaluated 54 subjects with glutaric aciduria secondary to other causes (16-7509 mmol/mol creatinine; reference range: <15; no significant amounts of 3-hydroxy glutaric acid detectable). The excretion of glutarylcarnitine was significantly elevated in all GA-1 patients (14-522 mmol/mol creatinine; reference range: <5.2) and in none of the controls with glutaric aciduria. These findings suggest that the urinary excretion of glutarylcarnitine is a specific biochemical marker of GA-1 which could be particularly useful in the work up of patients with suggestive clinical manifestations but without glutaric aciduria and with normal plasma acylcarnitine profiles.
Asunto(s)
Carnitina/análogos & derivados , Carnitina/orina , Glutaratos/sangre , Estudios de Casos y Controles , Glutaratos/orina , HumanosRESUMEN
An 18 year old man and his mother both presented with persistent, isolated raised serum creatine kinase (hyperCKaemia) without muscle symptoms. Analysis of caveolin-3 protein expression in muscle biopsy of the propositus showed a reduction in the protein. Genetic analysis revealed a new heterozygous mutation in the caveolin-3 (CAV-3) gene: a C-->T transition at nucleotide position 83 in exon 1 leading to a substitution of a proline for a leucine at amino acid position 28 (P28L). This is the first pathogenic mutation in the CAV-3 gene associated with isolated familial hyperCKaemia. It expands the genetic heterogeneity in patients with caveolin-3 deficiency and confirms that caveolin-3 deficiency should be considered in the differential diagnosis of isolated hyperCKaemia.
Asunto(s)
Caveolinas/deficiencia , Caveolinas/genética , Creatina Quinasa/sangre , Proteínas Musculares/deficiencia , Proteínas Musculares/genética , Mutación , Adulto , Biopsia , Caveolina 3 , Creatina Quinasa/genética , Femenino , Heterocigoto , Humanos , Inmunohistoquímica , Leucina/metabolismo , Masculino , Persona de Mediana Edad , Músculo Esquelético/química , Prolina/metabolismoRESUMEN
Nine children (five males, four females; age range 6 years 1 month to 11 years 1 month) affected by benign epilepsy of childhood with centrotemporal or Rolandic spikes (BECRS) with EEG evidence of marked activation of interictal epileptic discharges (IEDs) during sleep, and nine unaffected control children matched for age, sex, and socioeconomic status, were enrolled in a prospective study. At the time of detection of IED activation during sleep, patients showed a mean Full-Scale IQ score within the normal range, but significantly below that of control participants; neuropsychological assessment revealed disorders in visuospatial short-term memory (Corsi's Block Tapping Test), attention, and cognitive flexibility (Trail Making Test and Stroop Color-Word Test), picture naming, and fluency (Benton's Naming Test and Word Fluency), visuoperceptual skill (Ghent-Poppelreuter and Street Gestalt Completion Tests) and visuomotor coordination (Bender Test). After detection of IED activation during sleep, children were followed up for 2 years. At the time of IED remission (T1), neuropsychological re-evaluation showed a notable increase in IQ score and a significant improvement (t-test: p<0.007) in visuomotor coordination, non-verbal short-term memory, sustained attention and mental flexibility, picture naming, and visual-perceptual performance. At T1, patients' performance did not differ from the controls (Mann-Whitney U test).
Asunto(s)
Atención , Trastornos del Conocimiento/etiología , Epilepsia Rolándica/complicaciones , Trastornos de la Memoria/etiología , Desempeño Psicomotor , Fases del Sueño , Anticonvulsivantes/uso terapéutico , Estudios de Casos y Controles , Niño , Trastornos del Conocimiento/diagnóstico , Diazepam/uso terapéutico , Electroencefalografía , Epilepsia Rolándica/diagnóstico , Epilepsia Rolándica/fisiopatología , Epilepsia Rolándica/psicología , Femenino , Humanos , Inteligencia , Masculino , Trastornos de la Memoria/diagnóstico , Pruebas Neuropsicológicas , Polisomnografía , Estudios Prospectivos , Inducción de RemisiónRESUMEN
PURPOSE: Landau-Kleffner syndrome (LKS) is characterized by a marked increase of interictal epileptiform discharges (IEDs) during sleep. During nonrapid eye movement (NREM) sleep, neuronal membrane potential oscillations lead to the appearance of spindles and delta waves in the surface EEG and might develop into paroxysmal synchronization. Spectral analysis allows the quantitative description of the dynamics of delta (slow-wave activity, SWA, 0.5-4.5 Hz) and sigma activity (SA, 12.0-16.0 Hz) and can be used to assess the relation between SA, SWA, and IEDs during sleep. METHODS: We performed six overnight continuous EEG-polysomnographic studies in three patients with LKS. The temporal series of SWA and SA were obtained from a spike-free derivation lead. The IEDs count was performed on the most active lead. Relations between sigma and SWA and time series of IEDs were tested by means of correlation techniques after data normalization. RESULTS: Our results revealed a significantly higher correlation between IEDs and SA with respect to SWA in all the subjects, in total sleep time. The same analysis limited to NREM sleep highlights the better correlation between SA and IEDs. CONCLUSIONS: Our data suggest that neural mechanisms involved in the generation of sleep spindles facilitate IEDs production in LKS.
Asunto(s)
Electroencefalografía/estadística & datos numéricos , Síndrome de Landau-Kleffner/diagnóstico , Polisomnografía/estadística & datos numéricos , Sueño/fisiología , Factores de Edad , Análisis de Varianza , Corteza Cerebral/fisiopatología , Preescolar , Ritmo Delta , Humanos , Síndrome de Landau-Kleffner/fisiopatología , Potenciales de la Membrana/fisiologíaRESUMEN
The carbohydrate-deficient glycoprotein (CDG) syndromes are multisystemic disorders involving the glycosylation pathway. The most common subtype is CDG syndrome type I (CDG I). In most CDG I patients a phosphomannomutase (PMM) deficiency has been recognized as the basic defect. We made a neurophysiological evaluation in an 8-year-old boy affected by CDG I with PMM deficiency. The evaluation included central and peripheral nervous system assessment [electroencephalogram (EEG), multimodal evoked potentials (MEP), somatosensory evoked potentials (SEP), visual evoked potentials (VEP), auditory brainstem response (ABR), electroretinogram (ERG) and motor and sensory nervous conduction velocity (NCV)]. We found a peculiar electrophysiological pattern characterized by slowly and mildly progressive motor NCV reduction; progressive impairment of ERG and VEP; slowing of background activity and sharp waves at the EEGs; late sensorineural abnormality of ABR; decreased amplitude and increased latency of SEP. To our knowledge this is the first report involving the neurophysiological aspects both at onset and during follow-up of a case of CDG I with proven PMM deficiency.