Fatal neonatal lactic acidosis caused by a novel de novo mitochondrial G7453A tRNA-Serine ((UCN)) mutation.

INTRODUCTION: Heteroplasmic mitochondrial DNA (mtDNA) mutations are an important cause of childhood disorders, but the role of homoplasmic mtDNA mutations in severe neonatal manifestations is not well understood. METHODS: The following were performed: full mtDNA sequencing for mutation detection, blue-native protein analysis of autopsy-derived tissues to detect respiratory chain (RC) deficiency, light and electron microscopy for morphologic analysis, and northern blot and computational modeling to study the effect of mtDNA mutations on transfer RNA (tRNA) stability. RESULTS: We describe data from a patient with fatal neonatal lactic acidosis caused by a novel homoplasmic mutation at a highly conserved nucleotide G7453A within the tRNA(Ser (UCN)) in mtDNA. The patient's heart, skeletal muscle, brain, and liver showed severe combined complex I and IV (CI and CIV) deficiencies, accompanied by severe depletion of mature tRNA(Ser (UCN)). The mutation was absent in the patient's mother and in a placental sample from a subsequent pregnancy of the mother, suggesting a de novo mutation. DISCUSSION: We conclude that the G7453A mutation of mtDNA manifests with exceptional severity as compared with other tRNA(Ser (UCN)) mutations, typically associated with sensorineural deafness. De novo homoplasmic mtDNA tRNA-mutations should be considered as a cause of fatal neonatal lactic acidosis.

School performance of adolescents born preterm: neuropsychological and background correlates.

In this longitudinal study the development of preterm and control children was followed from infancy until adolescence. School performance at the age of 16 in subjects born very preterm with a gestational age (GA) of

Spatial span in very prematurely born adolescents.

The working memory functions and processing speed of 35 adolescents born preterm (< or = 32 weeks of gestation) and those of 31 control adolescents were assessed at the age of 16 years. All study participants were free from major disabilities. There were no statistically significant differences in verbal IQ between the study groups. Adolescents born preterm performed less well in complex spatial span compared to their peers born full term, even when verbal IQ and processing speed were allowed to covary. Both groups performed equally well in other working memory tasks and processing speed. Gestational age was the primary contributor to spatial span performance. These results indicate a minor spatial working memory deficit in preterm born adolescents without major disability and with normal cognitive capacity. Our results are encouraging and indicate only minor neuropsychological consequences due to very preterm birth.

Primary human herpesvirus-6 infection in the central nervous system can cause severe disease.

Human herpesvirus-6 (HHV-6) infection is common in infancy, and symptoms are usually mild. However, encephalitis and other neurologic complications have been reported. Primary HHV-6 infection has been rarely confirmed in the central nervous system. We studied 21 children with suspected HHV-6 infection, drawn from a prospective, large-scale study of neurologic infections in Finland. Human herpesvirus-6 polymerase chain reaction was performed on cerebrospinal fluid samples, and antibody tests were performed on serum and cerebrospinal fluid. We identified nine children, aged 3 to 24 months, who had HHV-6-specific nucleic acid in cerebrospinal fluid. Primary infection was confirmed by seroconversion of specific antibodies in six, whereas one had a fourfold increase, and one had a fourfold decrease, in the antibody titer supporting recent infection. Generalized and prolonged seizures appeared in six children, four had a rash, four had ataxia, and four had gastroenteritis. All but two had a high fever. At follow-up, four children had evident neurologic sequelae, ataxia, and developmental disability, and needed special education. Primary HHV-6 infection may invade the central nervous system, and can cause neurologic symptoms and potentially permanent disability in children aged

More severe epilepsy and cognitive impairment in the offspring of a mother with mosaicism for the ring 20 chromosome.

PURPOSE: Ring chromosome 20 [r(20)] syndrome is a rare chromosomal disorder. Cases tend to be sporadic. We elucidate the characteristics of an inherited r(20) mosaicism by describing the clinical features of three family members: a mother and her two children. RESULTS: The mosaicism rate of the mother was 10% and that of the children 40%. The mother experienced her first epileptic seizures at 24 years of age. Epilepsy was diagnosed two years later. After an unstable period lasting 3 years, she has been seizure-free for 13 years on a combination of valproate and lamotrigine. She has normal intelligence with full working capacity. The daughter exhibited her first epileptic seizures at the age of 7 years and she continues to have seizures weekly. The first epileptic seizures in the son were observed at 5 years of age. The son's epilepsy has been drug resistant from the onset, and a vagal nerve stimulator (VNS) has been ineffective. Psychomotor development was normal in both children up to the onset of epilepsy. Learning difficulties increased throughout school age and both children needed special educational programs. Neuropsychological evaluations have shown deterioration of cognitive levels. Both children had behavioural problems during school age but no longer in adolescence. All three subjects are nondysmophic, normocephalic and of normal growth. CONCLUSION: In this family the phenotype of r(20) mosaicism seems to be more severe in the successive generation along with a greater level of mosaicism. The aggravated clinical picture in inherited r(20) mosaicism concerned the onset of epilepsy, drug responsiveness, the cognitive level and behavioural features.

Increased number of febrile seizures in children born very preterm: relation of neonatal, febrile and epileptic seizures and neurological dysfunction to seizure outcome at 16 years of age.

PURPOSE: In prematurely born population, a cascade of events from initial injury in the developing brain to morbidity may be followed. The aim of our study was to assess seizures in prematurely born children from birth up to 16 years and to evaluate the contribution of different seizures, and of neurological dysfunction to the seizure outcome. METHODS: Pre- and neonatal data and data from neurodevelopmental examination at 5 years of 60 prospectively followed children born at or before 32 weeks of gestation, and of 60 matched term controls from the 2 year birth cohort were available from earlier phases of the study. Later seizure data were obtained from questionnaires at 5, 9, and 16 years, and from hospital records and parent interviews. RESULTS: In the preterm group, 16 children (27%) exhibited neonatal seizures, 10 children (17%) had seizures during febrile illness and 5 children had epilepsy. Eight children had only febrile seizures, and 3 of these had both multiple simple and complex febrile seizures and neurodevelopmental dysfunction. None of the 8 children had experienced neonatal seizures, 6 had a positive family history of seizures, but none developed epilepsy. The children with epilepsy had CP and neurocognitive problems, and all but one had experienced neonatal seizures; two of them had also had fever-induced epileptic seizures. In controls 3 children (5%) had simple febrile seizures. CONCLUSION: Children born very preterm have increased rate of febrile seizures compared to the controls. However, no cascade from initial injury via febrile seizures to epilepsy could be shown during the follow-up of 16 years. Symptomatic epilepsy in prematurely born children is characterised by neonatal seizures, major neurological disabilities and early onset of epilepsy.

Naming skills of children born preterm in comparison with their term peers at the ages of 9 and 16 years.

The linguistic abilities of children born preterm at 32 weeks' gestation or earlier at Kuopio University Hospital during 1984 to 1986 were evaluated during successive phases of a prospective study. The study protocol included the Rapid Automatic Naming test and Wechsler Intelligence Scale for Children - Revised at 9 years of age and a modified Stroop Color-Word test and the Wechsler Intelligence Scale - Revised at the age of 16 years. Fifty-one children born preterm (26 males, 25 females) and 51 age-matched and sex-matched term controls (26 males, 25 females) were studied at the age of 9 years. At the age of 16 years, 40 children born preterm (19 males, 21 females) and 31 term controls (14 males, 17 females) participated in the study. The children born preterm scored significantly lower in two naming tasks than the controls at the age of 9 years. However, there was no difference between the study groups in naming skills at the age of 16 years or in verbal IQ in either study phase. Maternal education level was not associated with naming skills. Thus, the consequences of preterm birth seem to be minor in relation to linguistic skills during school age and diminish by adolescence.

P3 amplitude and time-on-task effects in distractible adolescents.

OBJECTIVE: The aim of our study was to examine the role of brain activity related to stimulus evaluation processes in distractibility by analyzing the P3 event-related potential. METHODS: We studied the P3 response to target stimuli at the beginning, in the middle, and at the end of a two-tone auditory oddball task in easily distractible (n = 16) and non-distractible (n = 16) adolescents. RESULTS: Easily distractible adolescents showed enhanced frontal and reduced parietal P3 amplitude across the blocks relative to non-distractible adolescents. Also, the usual decline in P3 amplitude at the end of the task was significantly larger in distractible than in non-distractible adolescents. CONCLUSIONS: These results suggests that the P3 effects are not limited to the neuropsychiatric disorders, and that increased distractibility may be characterized by reduced amount of resources allocated to the task with continued testing. SIGNIFICANCE: The results of this study contribute to elucidation of the functional basis of distractibility.

Ophthalmologic and neurologic findings in two children exposed to vigabatrin in utero.

Vigabatrin (VGB) is an important treatment option for infantile spasms. Vigabatrin-induced visual field defects are at present the most important safety issue in the use of the drug. The knowledge concerning VGB-associated visual dysfunction in pediatric patients, particularly in those who have been exposed to VGB in utero is limited. We explored ophthalmic and neurologic findings in two children who have been exposed prenatally to VGB.

Event-related potentials to elementary auditory input in distractible adolescents.

OBJECTIVE: The aim of our study was to examine the role of brain activity related to orienting in distractibility. METHODS: Event-related potentials (ERPs) were recorded in response to intermittently presented, non-attended trains of identical auditory stimuli in otherwise healthy but easily distractible (n=16) and non-distractible (n=16) 15-to-16 year old adolescents. RESULTS: In easily distractible adolescents, the first tone in each train elicited a significantly larger N1 response than in non-distractible adolescents. A later positivity in the P3 latency range, which may be correlated with the posterior part of the orienting-related P3, was also significantly larger in distractible than in non-distractible adolescents. CONCLUSIONS: The findings of this study suggests that the susceptibility to distraction in adolescence is characterized by abnormally strong orienting response as indexed by enhanced N1 component, and that distractible adolescents allocate proportionately more attentional resources to the irrelevant stimuli as indexed by larger parietal P3 amplitude to the first stimulus of each train. SIGNIFICANCE: The results of this study contribute to elucidation of the functional basis of distractibility.

Ambulatory blood pressure in 12-year-old children born small for gestational age.

An association between low birth weight and subsequent elevated blood pressure has been demonstrated in a large number of studies, but the number of subjects born small for gestational age in these studies has been negligible. The inverse relationship between birth weight and blood pressure in children has been evaluated previously with an ambulatory blood pressure device, but only in children with normal birth weights. In this prospective case-control study from birth to the age of 12, we evaluated the ambulatory blood pressures in 50 children born at term but small for gestational age and in 50 full-term children born appropriate for gestational age. Children born small for gestational age had similar mean+/-SD systolic (117.5+/-8.5 mm Hg versus 115.3+/-7.4 mm Hg, P=0.221), and diastolic (69.2+/-5.3 mm Hg versus 67.3+/-4.4 mm Hg, P=0.075) 24-hour ambulatory blood pressure compared with the values of the children born appropriate for gestational age. However, 24-hour systolic blood pressure in the small-for-gestational-age children was higher (3.90 mm Hg; 95% confidence interval, 0.65 to 7.15) after adjusting for current body mass index. The difference in current body mass index was the only determinant for the difference in systolic blood pressure between the groups. Birth weight had no direct association with the blood pressure values. Impaired fetal growth may have a relationship with higher later blood pressure, but in 12-year-old children, blood pressure differences between small for gestational age and appropriate for gestational age children are much more dependent on current body size.