Specific mosaic KRAS mutations affecting codon 146 cause oculoectodermal syndrome and encephalocraniocutaneous lipomatosis.

Oculoectodermal syndrome (OES) and encephalocraniocutaneous lipomatosis (ECCL) are rare disorders that share many common features, such as epibulbar dermoids, aplasia cutis congenita, pigmentary changes following Blaschko lines, bony tumor-like lesions, and others. About 20 cases with OES and more than 50 patients with ECCL have been reported. Both diseases were proposed to represent mosaic disorders, but only very recently whole-genome sequencing has led to the identification of somatic KRAS mutations, p.Leu19Phe and p.Gly13Asp, in affected tissue from two individuals with OES. Here we report the results of molecular genetic studies in three patients with OES and one with ECCL. In all four cases, Sanger sequencing of the KRAS gene in DNA from lesional tissue detected mutations affecting codon 146 (p.Ala146Val, p.Ala146Thr) at variable levels of mosaicism. Our findings thus corroborate the evidence of OES being a mosaic RASopathy and confirm the common etiology of OES and ECCL. KRAS codon 146 mutations, as well as the previously reported OES-associated alterations, are known oncogenic KRAS mutations with distinct functional consequences. Considering the phenotype and genotype spectrum of mosaic RASopathies, these findings suggest that the wide phenotypic variability does not only depend on the tissue distribution but also on the specific genotype.

Functional magnetic resonance imaging of the normal and abnormal visual system in early life.

Functional magnetic resonance imaging (fMRI) in young children may provide information about the development of the visual cortex, and may have predictive value for later visual performance. The purpose of this study was to evaluate the usefulness of fMRI for examining cerebral processing of vision in very young infants and in infants with brain damage. We examined 15 preterm infants, 12 children suspected of having a cerebral visual impairment and 10 children with a normal visual system, all of whom were either spontaneously asleep or sedated with chloral hydrate. Cortical response to stroboscopic light stimulation could be demonstrated in all technically acceptable data sets from children with a post-menstrual age (PMA) of > 41 weeks, but not in younger infants. Children < 60 weeks PMA showed either a blood oxygenation level-dependent (BOLD) signal increase or decrease, while all older children showed a signal decrease. The activated cortical volumes showed a linear relation to age for healthy children younger than 90 weeks PMA, but were small in children with visual impairment. In two children with unilateral damage to the optic radiations, activation was strongly asymmetrical with greatest activation on the healthy side. In future prospective studies, results from the period from birth to six months of age should be interpreted with caution, as inter-individual variation of cortical development may be confused with functional deficit.

Prenatal and perinatal striatal injury: a hypothetical cause of attention-deficit-hyperactivity disorder?

Experimental data indicate a particular vulnerability of striatal neurons in the developing brain, and together with the idea that the striatum is important for context recognition and behavior, these data have led the author to search for subtle striatal lesions, in the form of biochemical changes, in children who have suffered perinatal adverse events. Evidence is presented to demonstrate that the composition of metabolites in the striatum is altered, primarily in the form of an elevated level of lactate, in human neonates who have suffered various perinatal disorders, such as germinal matrix hemorrhage, intrauterine growth retardation, and asphyxia. An elevated level of lactate suggests tissue hypoxia, which may interfere with the formation of frontostriatal circuits and may play a role in the pathogenesis of the behavioral disturbances observed in a proportion of children with a history of perinatal adverse events.

Bilateral optic neuritis in acute human immunodeficiency virus infection.

PURPOSE: To report a case of acute viral disease accompanied by bilateral optic neuritis with substantial paraclinical evidence that human immunodeficiency virus was the causative agent. METHODS: Clinical and paraclinical examination. Magnetic resonance imaging. RESULTS: Virus and antibody titers as well as reverse lymphocytosis were consistent with acute infection by the human immunodeficiency virus-1. CONCLUSIONS: Human immunodeficiency virus infection should be considered in the differential diagnosis of acute optic neuritis.

Metabolic changes in the striatum after germinal matrix hemorrhage in the preterm infant.

To investigate the metabolic consequences of germinal matrix hemorrhage (GMH) we used volume-selective 1H magnetic resonance spectroscopy in the striatal region in 12 preterm infants with predominantly small GMH. Both sides of the brain were investigated twice. Metabolite indices were calculated as the metabolite signal, recorded with TR = 1.6 s and TE = 272 ms, divided by the fully relaxed water signal corrected for transverse relaxation time constant (T2) decay. At the first investigation, when the infants were 32.5 +/- 2.0 (mean +/- SD) wk postmenstrual age, the hemorrhage was unilateral or markedly asymmetrical in size in 10 of 12 infants. The lactate index was higher (p < 0.01) and the phosphocreatine + creatine (Cr) (p < 0.05) and N-acetyl-L-aspartate (NAA) (p < 0.05) indices lower in the side with the larger hemorrhage. At the second investigation, 54.1 +/- 2.7 wk postmenstrual age, no sign of a previous GMH could be seen on magnetic resonance imaging in three of 10 infants. Lactate could be detected in two of 10 infants only, and the Cr and NAA indices did not differ between sides. However, the choline index was significantly higher in the side with the larger hemorrhage (p < 0.01). We conclude that GMH is initially followed by lactate accumulation and possibly a delay in maturation as indicated by the transiently low Cr and NAA indices. Moreover, an increased choline index at the corrected age of 3 mo indicates a more persistent metabolic change after small GMH.

Neonatal seizures associated with cerebral lesions shown by magnetic resonance imaging.

AIM: To determine the diagnostic potential of magnetic resonance imaging (MRI) in neonatal seizures; to elucidate the aetiology, timing, and prognosis of the cerebral lesions detected. METHODS: Thirty one term neonates with clinical seizures underwent ultrasonography between days 1-7 (mean 2.5 days) and a high field spin-echo MRI scan on days 1-30 (mean 8.1 days), both of which were repeated at 3 months of age. Routine investigation excluded, as far as possible, infection, haematological, and metabolic-toxic causes as causes of the neonatal seizures. RESULTS: Brain abnormality was demonstrated by MRI in 68% of infants and ultrasonographically in 10%. Diffuse brain lesions (present in 29%) were associated with high mortality (58%) and morbidity (42%), whatever the aetiology. In contrast to a better short term prognosis for neonates with focal lesions where no infants died, 33% had a handicap, and the rest were normal at a mean follow up age of 2 1/2 years. Cerebral lesions were presumed to have antepartum origin in 43% of cases. Seizure aetiology was considered to be hypoxic-ischaemic in 35%, haemorrhagic in 26%, metabolic disturbances and cerebral dysgenesis in 16% and unknown in 23%. CONCLUSIONS: MRI detected a remarkably high incidence of brain lesions in neonatal seizures. Almost half of these were of prenatal origin and pathogenesis may essentially be attributed to hypoxic and/or haemodynamic causes.

The apparent diffusion coefficient of water in gray and white matter of the infant brain.

PURPOSE: The purpose was to obtain normal values of the apparent diffusion coefficient (ADC) in the infant brain and to compare ADC maps with T1- and T2-weighted images. METHOD: Diffusion was measured in nine infants with an ECG-gated SE sequence compensated for first-order motion. One axial slice at the basal ganglia level was investigated with the diffusion-encoding gradients in the slice-selection direction. RESULTS: On ADC maps, the corpus callosum and the optic radiations appeared dark before the onset of myelination, and the crus posterior of the internal capsule could be visualized before it appeared on T1- or T2-weighted images. In gray and white matter, the mean ADC ranged from 0.95 x 10(-9) to 1.76 x 10(-9) m2/s. In the frontal and occipital white matter, in the genu corporis callosi, and in the lentiform nucleus, the ADC decreased with increasing age. The cortex/white matter ratio of the ADC increased with age and approached 1 at the age of 30 weeks. CONCLUSION: ADC maps add information to the T1 and T2 images about the size and course of unmyelinated as well as myelinated tracts in the immature brain.

Susceptibility contrast imaging of CO2-induced changes in the blood volume of the human brain.

PURPOSE: To investigate changes in the regional cerebral blood volume (rCBV) in human subjects during rest and hypercapnia by MR imaging, and to compare the results from contrast-enhanced and noncontrast-enhanced susceptibility-weighted imaging. MATERIAL AND METHODS: Five healthy volunteers (aged 24-29 years) were studied during inhalation of atmospheric air and 7% CO2. A bolus injection of Gd-DTPA was given during the acquisition of a series of susceptibility-weighted, fast gradient echo images (TR/TE = 27/22 ms). The images were converted to delta R2* maps, and CBV was calculated pixelwise by fitting a gamma-variate function to the data. The tissue concentration vs time curves were deconvoluted using an input function obtained by arterial sampling. RESULTS: The ratio of gray to white matter CBV (1.9-2.5) as well as the fractional increase in rCBV during hypercapnia (about 30%) was found to be in accordance with results obtained by other methods. Noncontrast functional MR (fMR) imaging showed signal increases in gray matter, but also inconsistent changes in some white matter regions. CONCLUSION: In this experiment, contrast-enhanced imaging seemed to show a somewhat higher sensitivity towards changes in cerebral hemodynamics than noncontrast-enhanced imaging. The results of the deconvolution analysis suggested that perfusion calculation by conventional tracer kinetic methods may be impracticable because of nonlinear effects in contrast-enhanced MR imaging.

Cerebral glucose metabolism is decreased in white matter changes in patients with phenylketonuria.

Cerebral magnetic resonance imaging (MRI) has revealed white matter changes in patients with phenylketonuria (PKU), an inborn error of metabolism with increased plasma phenylalanine level. Because the significance of these lesions is unknown, this study was undertaken to determine whether glucose metabolism was depressed in cerebral white matter MRI changes in patients with PKU. Four patients with PKU and nine healthy volunteers with an average age of 23 y (range 19-26 y) and 23 y (range 20-27 y), respectively, were studied. The IQ of patients with PKU was between 58 and 97. Cerebral MRI and positron emission tomography images with 18F-deoxyglucose were obtained, and arteriovenous differences for oxygen and glucose as well as cerebral blood flow was measured simultaneously to determine global cerebral oxygen and glucose metabolism. Cerebral MRI revealed that all patients with PKU had white matter changes with characteristic localization. In patients with PKU, regional glucose metabolism was 36% lower in the anterior periventricular areas, 0.14 +/- 0.06 compared with 0.22 +/- 0.04 mumol.g-1.min-1 in controls (mean +/- SD, p < 0.05, Mann-Whitney). Further, the ratio between glucose metabolism in the affected white matter and the cortex was 14% lower in the patients, decreasing from 0.57 +/- 0.05 to 0.48 +/- 0.06 (p < 0.05). Global cerebral blood flow, oxygen and glucose consumption were similar in the two groups. In conclusion, regional glucose metabolism is lower in MRI-demonstrated white matter changes. In mildly intellectually impaired patients with PKU, global cerebral glucose and oxygen metabolism remain intact.

Use of brain lactate levels to predict outcome after perinatal asphyxia.

Perinatal asphyxia is an important cause of neurological disability, but early prediction of outcome can be difficult. We performed proton magnetic resonance spectroscopy (MRS) and global cerebral blood flow measurements by xenon-133 clearance in 16 infants with evidence of perinatal asphyxia. Cerebral blood flow was determined daily in the first 3 days after birth in seven cases. Proton MRS was performed in 11 infants within the first week (mean 3.7 days), the rest within the first month (mean 22.2 days), and all had a scan around 3 months of age. Four infants died neonatally, three showed neurological deficits and the rest seemed to be progressing normally at neurodevelopmental follow-up at 1 year of age. A significant correlation was found between initial brain lactate levels and severe outcome (p = 0.0003) just as between cerebral hyperperfusion (mean cerebral blood flow (CBF) 86 ml(100 g)-1 min-1), (p = 0.02) and outcome. The diagnostic and prognostic implications of early MRS and CBF are predictive of poor outcome in severely asphyxiated infants.

Volumetric analysis of the normal infant brain and in intrauterine growth retardation.

Twenty-eight infants with postmenstrual ages (PMA) in the range of 32-80 weeks were investigated. Twenty were newborn; among these the observed birth weight divided by the expected weight ranged from 0.31 to 1.1. Axial magnetic resonance images were recorded with a triple spin-echo sequence and the volumes were determined by encircling each structure of interest on every slice. Segmentation into grey matter, white matter and CSF was done by semi-automatic discriminant analysis. Growth charts for the cerebrum, cerebellum, corpora striata, thalami, ventricles, and grey and white matter are provided for infants with appropriate birth weight. The striatal (P = 0.02) and thalamic (P < 0.001) percentage of the hemispheric volume decreased with age, whereas the ratio of grey matter to white matter (G/W-ratio) increased (P = 0.01). In the neonatal patients, brain volumes were independently associated with both PMA and the degree of growth retardation. It was calculated that the hemispheric volume was reduced by from 16% to 23% if the total bodyweight was reduced by 40%. The G/W-ratio was found to be independently associated with the PMA (P < 0.05) and the degree of IUGR (P < 0.1) suggesting that fetal growth retardation reduces grey matter volume more than white matter.

Cerebral energy metabolism during hypoxaemia. A 31P and 1H magnetic resonance study.

By means of proton and phosphorous magnetic resonance spectroscopy at 1.5 Tesla the human cerebral metabolism was investigated during mild and moderate hypoxaemia. Seven volunteers participated and spectra were obtained while the subjects were breathing atmospheric air, 16, 12 and 10% oxygen in N2.PaO2, PCO2 and arterial oxygen saturation were determined during the spectroscopic measurements. Haemodynamic and respiratory mechanisms compensated the hypoxic condition and no lactate production was found. There was no change in N-acetyl-aspartate. No change in intracellular pH was found. A slight but non-significant decrease in PCr/P(i)-ratio was found, indicating a decrease in the phosphorylation potential of the brain in response to hypoxaemia. The brain sustains aerobic metabolism during mild to moderate hypoxaemia.

Brain lactate in preterm and growth-retarded neonates.

Glucose is the predominant cerebral energy source under physiological conditions, although other substrates may support cerebral metabolism. The present study was undertaken to determine if lactate is present in the immature human brain, and if so, whether or not concentrations of lactate differ between small-for-gestational-age and appropriate-for-gestational-age infants. Thirty stable, healthy infants with normal brains were investigated. As the only nutrient, all received milk enterally prior to the investigation, which was carried out without sedation. Mean gestational age was 35 completed weeks (range 28-41 weeks) and mean birth weight was 2170 g (range 855-4100 g). Proton nuclear magnetic resonance spectra from the striatal region were obtained while the infants were sleeping quietly. Lactate was present in all 10 preterm small-for-gestational-age and 10 of 13 preterm appropriate-for-gestational-age infants, and the concentration was inversely related to postmenstrual age (p < 0.002). In addition, lactate increased with the degree of growth retardation (p < 0.01). At present the significance of lactate is unclear. Lactate may be produced locally or in peripheral tissues, and may support brain metabolism.

Signal changes in gradient echo images of human brain induced by hypo- and hyperoxia.

The effect of hypoxia (inspired oxygen fraction, FiO2 of 10% and 16%) and hyperoxia (FiO2) of 100%) on gradient echo images of the brain using long echo times was investigated in six healthy volunteers (age 24-28 years). Different flip angles were used with an FiO2 of 10% to assess the importance of saturation effects. The total cerebral blood flow was measured by a phase mapping technique during normoxia as well as hypoxia (FiO2 of 10% and 16%) and hyperoxia (FiO2 of 50% and 100%). High relative signal changes were found, independently of the flip angle, with FiO2 of 10%. With a flip angle of 40 degrees the values of delta R2* for cortical grey matter, central grey matter, white matter and the sagittal sinus were 0.79, 0.41, 0.26 and 3.00/s; with a flip angle of 10 degrees the corresponding values were 0.70, 0.37, 0.24 and 3.15/s. The total cerebral blood flow increased by 41% during inhalation of 10% O2 and decreased by 27% during 100% O2; no flow changes were seen during moderate changes in FiO2. It is concluded that flow effects play a minor role for fMRI signal strength in this application since (i) they did not abolish the signal changes caused by changes in blood oxygenation during hyper- and hypoxia, (ii) the observed signal changes were closely related to the changes in arterial oxygen saturation during hypoxia and (iii) the signal changes were little affected by changing the flip angle from 40 degrees to 10 degrees.

Local vascular CO2 reactivity in the infant brain assessed by functional MRI.

The local cerebral vascular response to hyperventilation was investigated in five distressed, intubated infants by means of a T2 sensitive gradient-echo MRI technique at 1.5 T. In one preterm infant, the MR signal change during hyperventilation was sparse. In four term infants, the mean MR signal of the brain slice investigated decreased by 1.2-2.6% per kPa change in PCO2 as a reflection of decreased cerebral blood flow during hyperventilation. Pixel-wise analysis revealed absence of vascular response in the basal ganglia, the thalamus or in the occipital region. In two adult controls, who hyperventilated voluntarily, the vascular reactivity was homogeneously distributed predominantly over the grey matter. The experiments demonstrate that local impairment of vascular CO2 reactivity in the distressed infant brain can be detected by T2 sensitive gradient-echo MRI, which is also known as functional MRI.

Blood-brain barrier transport of amino acids in healthy controls and in patients with phenylketonuria.

Blood-brain barrier permeability to phenylalanine and leucine in four patients with phenylketonuria and in four volunteers was measured five times by the double-indicator method at increasing plasma concentrations of phenylalanine. Based on the permeability-surface area product (PS) from blood to brain (PS1) and on plasma phenylalanine levels, Vmax and the apparent Km for phenylalanine were determined. Statistically significant relationships between plasma phenylalanine and PS1 were established in three out of four volunteers, the average Vmax value being 46.7 nmol/g per min and the apparent Km 0.328 mmol/L. Owing to saturation of the carrier, such a relationship could not be established in the patients. In phenylketonuria, PS1 for phenylalanine and leucine decreased significantly by 55% and 46%, respectively. Transport from brain back to blood, PS2, decreased significantly and cerebral large neutral amino acid net uptake was generally decreased in patients with phenylketonuria. In conclusion, the transport of L-phenylalanine across the human blood-brain barrier follows Michaelis-Menten kinetics. In phenylketonuria, brain permeability to large neutral amino acids is reduced by about 50% and net uptake appears decreased.

Metabolite concentrations in the developing brain estimated with proton MR spectroscopy.

The purpose of the present study was to estimate absolute concentrations and relaxation time constants of metabolites that were detectable with proton magnetic resonance (MR) spectroscopy in the healthy preterm, term, and infant brain. Five MR spectra were recorded for each infant by using STEAM (stimulated-echo acquisition mode) sequences with different TEs and TRs. Water was used as an internal standard. The T1 of choline-containing compounds (Cho) and the T1 of phosphocreatine plus creatine (PCr+Cr) decreased. The T2 of the N-acetyl-L-aspartate (NAA) resonance increased, probably because of a relatively larger signal overlap with glutamate in the most immature brains. The concentration of NAA almost doubled, whereas the Cho concentration showed only a nonsignificant tendency to decrease; therefore, the well-known increase in the ratio of NAA to Cho appears to be due mostly to an increase in NAA concentration. The concentration of PCr+Cr increased rapidly and reached adolescent values at approximately 4 months of age.

Functional MRI of CO2 induced increase in cerebral perfusion.

The sensitivity of MR gradient echo imaging towards CO2 induced changes in cerebral blood flow was investigated in 10 normal subjects. The subjects were inhaling 5% and 7% CO2 and the experiments were carried out at 1.5 T (n = 6) and 2.0 T (n = 5), allowing a comparison of field strengths. Additional experiments were carried out using a higher spatial resolution. The largest signal increases were noted in areas corresponding to larger vessels, but significant changes were also conspicuous in deeper cortical and central grey matter. The changes appeared linearly related to the arterial CO2 tension, within the range of PaCO2 studied. In white matter, the changes were not statistically significant.

Phosphorous and proton spectroscopy in relation to near incarceration and incarceration of the human brain.

We report 3 cases of 31P and 1H MR spectroscopy (MRS) performed at different stages on patients with clinical signs of near or fulminant incarceration of the brain. The measurements were made on a whole body, 1.5 T scanner. 1H-MRS was obtained with the STEAM sequence and 31P-spectra were obtained using the chemical shift imaging technique. Medical treatment including controlled ventilation and sedation of the patients was carried out during the examination. The first patient was evaluated on days 6 and 10 after evacuation of an acute subdural haematoma. An intracranial pressure of 35 mm Hg was registered during the first examination. The 2nd patient had suffered a spontaneous intracerebral haemorrhage and showed clinical signs of imminent incarceration during the examination. The 3rd patient showed clinical signs of incarceration just prior to the examination. In the 1st patient 1H-MRS showed a 3-fold increase in the concentration of choline-containing compounds and a small decrease in N-acetyl aspartate from the 1st to the 2nd examination, which we interpret as a loss of neurones. In case 2 only small changes in metabolism could be detected, indicating that, despite signs of imminent clinical incarceration, the energy supply to the brain was substantial. 1H-MRS of the 3rd patient showed massive lactate concentration, and 31P-MRS revealed the total absence of high-energy phosphorous compounds leaving only one single peak of inorganic phosphate, indicating irreversible brain death.