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.

Native iron in the continental lower crust: petrological and geophysical implications.

Lower crustal granulite xenoliths recovered from a kimberlite pipe in western Africa contain native iron (Fe(0)) as a decomposition product of garnet and ilmenite. Magnetic measurements show that less than 0.1 percent (by volume) of iron metal is present. Data from geothermometry and oxygen geobarometry indicate that the oxide and metal phases equilibrated between iron-wüstite and magnetite-wüstite buffers, which may represent the oxidation state of the continental lower crust, and the depleted lithospheric upper mantle. Ferromagnetic native iron could be stable to a depth of approximately 95 kilometers and should be considered in the interpretation of long-wavelength static magnetic anomalies.

Topography of unmyelinated axons in regenerated soleus nerves of the rat.

The topography of unmyelinated axons on cross sections of normal and regenerated soleus nerves of rat was studied by electron microscopy. The experimental nerves were crushed and assessed after 1-19 weeks. Unmyelinated axons in normal nerves were arranged in few groups. Nerve crush did not alter the arrangement of unmyelinated axons in the proximal nerve. Distal to the crush lesion, however, the unmyelinated axons became scattered throughout the entire cross section. The grouping of unmyelinated axons within the cross section was quantitated by means of a "clustering factor", defined as the percentage of unmyelinated axons in those 10% of the cross-sectional area which had the highest density of unmyelinated axons. The results indicate that unmyelinated axons during regeneration do not follow their original pathways.

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.

MR-visible water content in human brain: a proton MRS study.

In vivo measurement of metabolite concentrations in the human brain by means of proton-MRS contributes significantly to the clinical evaluation of patients with diseases of the brain. The fully relaxed water signal has been proposed as an internal standard for calibration of the MRS measurements. The major drawbacks are the necessity to make the assumptions that the water concentrations in the brain and that all tissue water is MR-visible. A number of in vivo measurements were carried out to estimate the concentration of MR-visible water in the brain of healthy volunteers divided into four age groups: newborn (0-23 days), adolescents (10-15 yr), adults (22-28 yr), and elderly people (60-74 yr). The examinations were carried out using a Siemens Helicon SP 63/84 MR-scanner operating at 1.5 T. Except for the newborn, four regions were studied in each subject using stimulated echo (STEAM) sequences without water suppression. In vitro measurements on a standard phantom were used for calibration. The calculated water concentrations ranged between 35.8 and 39.6 (mean 36.9) mol.[kg wet weight]-1 in the three groups, whereas it was 51.5 mol.[kg wet weight]-1 in the newborn, p < .01. The observed water concentration of neither the four regions nor of the three oldest age groups were significantly different. Comparisons between the water concentrations measured and those expected based on estimation of the content of grey and white matter in the region of interest from T1-weighted images and biochemical data published, suggest that only a small fraction (< 5%) of the tissue water may be MR-invisible.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral magnetic resonance spectroscopy in Rett syndrome. Failure to detect mitochondrial disorder.

A total of eight girls with Rett syndrome were examined, by 31phosphorous magnetic resonance spectroscopy (31P MRS) (4 girls), proton MRS (1H MRS) (4 girls), muscle biopsying (2 girls), and determination of pyruvate and lactate in plasma (5 girls), to investigate the hypothesis of a mitochondrial malfunction as the etiology for this neurologic disorder. Almost all examinations, including electron microscopy in search of structural mitochondrial abnormalities, gave normal results, the only exception being the not unexpected finding of slight neurogenic atrophy in the muscle biopsy specimen from a 15-year-old girl.

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.

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.

Axonal branching following crush lesions of peripheral nerves of rat.

Branching of myelinated and unmyelinated nerve fibers in normal and regenerating personal and soleus nerves was studied by light and electron microscopy. There were at most 2% more myelinated and 13% more unmyelinated axons in the distal as compared with the proximal nerve segments. Two to four weeks after a crush lesion the distal axons became 2-3 times more numerous; thereafter their number decreased. The number of axons in the proximal nerve segment did not change. The number of myelinated sprouts in most regenerated nerves equalled the number of myelinated fibers in the proximal nerve, while the number of unmyelinated axons after 12-19 weeks was 18-60% higher than normal. Branching was not restricted to the crush region. The results indicate that following a crush lesion all axons branch but only branches of unmyelinated fibers persist for a prolonged period of time. It is tentatively suggested that regenerating axons branch when searching for a target and that when contact is made with the target this prevents additional branching and eliminates redundant branches. Myelinated axons are guided by existing Schwann cells, whereas unmyelinated axons do not follow predetermined pathways; this may explain their greater tendency to form permanent branches.

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.