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The brain begins its development as the neural tube, proliferating cells along this tube migrate to take up their proper locations within the developing brain. This results in an 'inside-out' process of development in which new brain cells are formed in the middle of the brain, and migrate out through the brain tissues before they reach their correct location. This process does not always work properly, and several distinct brain abnormalities appear to result from disordered neuronal migration. These disorders can be collectively called neuronal migration disorders( NMDs). One NMD is lissencephaly, in which the brain is smooth, failing to develop the normal pattern of convolutions or gyri. Such patients are profoundly retarded and usually die before two years of age. Another NMD, one with a more mild outcome, is the so-called 'double cortex' syndrome. In this condition, some of the migrating brain cells fail to reach their proper destination on the surface of the brain. These brain cells do not die, but try to fulfill their destiny in the wrong location, beneath the mantle of properly located cortex. In the brains of such patients a cell-rich layer of tissue, or grey matter, can be seen beneath the cerebral cortex, an area in which only myelinated nerve fibers, or white matter, is normally located. It is this second anomalous layer of grey matter that is responsible for the term 'double cortex'. Patients with double cortex are usually retarded, though the syndrome is compatible with a normal lifespan. Patients with double cortex syndrome are commonly affected by epilepsy as well. In the past, double cortex syndrome was observed only at autopsy. The advent of modern imaging techniques has made it possible to identify cases of double cortex syndrome among living patients. Since the presence of double cortex syndrome would affect decisions on the most appropriate treatment for epilepsy in some patients, the indications of double cortex syndrome on magnetic resonance imaging (MRI) or computed tomography (CT) should be recognized. (Consumer Summary produced by Reliance Medical Information, Inc.)

A glycolipid is a fatty molecule which contains at least one sugar molecule as well; gangliosides are glycolipids which also contain a molecule called sialic acid. These molecules are important part of many cell membranes. In some genetic diseases, the enzymes needed to break down the gangliosides are deficient, and the gangliosides build up within cells. Such disorders are generally called gangliosidoses. They are genetically recessive, since just one normal enzyme gene inherited from just one parent is sufficient to prevent the metabolic disorder. One of the most common gangliosidoses is Tay-Sachs disease, in which a deficiency of an enzyme called hexosaminidase A results in the pathological accumulation of a specific ganglioside, GM2. Tay-Sachs disease is not the only disorder involving hexosaminidase A, however. While Tay-Sachs normally affects infants who then die early in life, there are more chronic forms of the enzyme deficiency. Seven cases from three different families illustrate the different manifestations of hexosaminidase A deficiency disorders. Two patients, a brother and sister, developed a ''juvenile'' type of the disorder, in which symptoms in early childhood progress, becoming fatal within a few years. The remaining patients developed the ''adult'' form of the disorder, which may be something of a misnomer; the ''adult'' form may also develop early in childhood, but it progresses more slowly and might therefore better be called the chronic form. Biochemical tests revealed that all patients had some measurable deficiency of hexosaminidase A. Two families had a peculiar deficiency in which the enzyme could digest an artificial compound used for the laboratory test but not the natural GM2 it is supposed to digest. Testing limited to the artificial compound would have missed the abnormality in these cases. The two patients from the remaining family had a measured enzymatic defect that was indistinguishable from that of Tay-Sachs disease. However, while Tay-Sachs patients die in infancy, these two brothers remain alive as teenagers, albeit with serious neurological deficits. Why the biochemical deficit should appear to be the same in these vastly different disorders is not understood, and illustrates the poorly understood relationship of disorders of hexosaminidase A and the clinical features of the disease which results. (Consumer Summary produced by Reliance Medical Information, Inc.)

We report a case of iatrogenic Creutzfeldt-Jakob disease(iCJD) in a child with a neonatal growth hormone (GH) deficiency that was treated with native human growth hormone (hGH) between the ages of 9 months and 7 years. Three years after the end of treatment a progressive neurological syndrome consistent with Creutzfeldt-Jakob disease (CJD) developed, leading to death within a year, at age 11. Neuropathological examination showed an unusual widespread form of CJD, notably characterized by (i) involvement of the cerebellar white matter, (ii) cortico-spinal degeneration and (iii) ballooned neurons. A transitional form of the disease between common iatrogenic and panencephalopathic CJD is suggested.

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12-p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD = 3.54, alpha = 0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum non-parametric linkage score was 2.87 (P < 0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP-based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear pedigrees. Evidence for transmission disequilibrium (P < or = 0.01) was found for SNPs within a approximately 35 kb region of high LD encompassing the 5'UTR, exon 1 and part of intron 1 of CACNG3. Re-sequencing of this interval was undertaken in 24 affected individuals. Seventy-two variants were identified: 45 upstream; two 5'UTR; and 25 intronic SNPs. No coding sequence variants were identified, although four variants are predicted to affect exonic splicing. This evidence supports CACNG3 as a susceptibility locus in a subset of CAE patients.

Intrachromosomal insertions are uncommon rearrangements, in which a chromosomal segment is intercalated into another part of the same chromosome. The insertion may occur in the same arm (paracentric) or in the other arm (pericentric). The cytogenetic recognition of these structurally rearranged chromosomes can be difficult, and intrachromosomal insertions can be easily mistaken for inversions. We describe a case of a familial pericentric insertion of chromosome 20, initially misdiagnosed as a pericentric inversion in the healthy carrier and then reinterpreted as insertion in an abnormal child with a recombinant chromosome. Fluorescence in situ hybridization (FISH) allowed us to confirm the mechanism of recombinant formation and to locate the three breakpoints precisely. Our cytogenetically unbalanced epileptic patient carried a 20q deletion and 20p duplication, and the genes, CHRNA4 and KCNQ2 that have been implicated in autosomal dominant epilepsy, were deleted. The haplo-insufficiency of these two genes may contribute to the cause of epilepsy in patients with ring chromosome 20.

Through a report of 4 late-onset cases with mitochondrial DNA (mtDNA) depletion, we address the specificity of the clinical entities associated with a very low residual amount of mtDNA. Three of the patients met the diagnostic criteria of Kearns Sayre syndrome, which has never been associated with mtDNA depletion. The fourth patient had an isolated skeletal myopathy. Deleted mtDNA molecules were found by long-range polymerase chain reaction (PCR) only in the Kearns Sayre syndromes, which strengthens the clinical differences between the two types of patients. All patients had extremely low residual amounts of mtDNA as shown by Southern blot analysis. Using an original method based on competitive PCR, we were able to measure the number of mtDNA copies per diploid genome. These results demonstrated the severity of the depletion in the patients by comparison not only to normal controls but also to patients with mtDNA disorders. Despite the severity of the depletion, in situ hybridization using two mtDNA transcripts revealed a normal steady-state level of transcription. Such compensation provides clues to the striking contrast between the severity of mtDNA depletion and the late onset and slowly progressive disease.

Three fetuses with normal chromosomes were found to have uni- or bilateral hydronephrosis during the third trimester of pregnancy. At birth, they presented with coarse face, hypertelorism, and a deep groove under the eyes. Fontanelles and sutures were wide open. Genital abnormalities were present in 2 cases. Skeletal radiographs showed delayed bone maturation, broad and dense ribs, and a wide synchondrosis between the exoccipital and supraoccipital bones. The combination of such findings suggested the diagnosis of Schinzel-Giedion syndrome. Two patients died soon after birth, whereas the third one developed severe mental and motor retardation with seizures and spasticity, and died at 18 months. Schinzel-Giedion syndrome is rare and likely to be inherited as an autosomal recessive trait. So far, 13 well-documented cases have been reported allowing major and minor traits of the syndrome to be distinguished. Since no genetic marker is available, the prenatal diagnosis of Schinzel-Giedion syndrome relies on ultrasound examination, especially detection of renal abnormalities.

We report 2 sisters with a degenerative neurological disorder presenting clinically as a leukodystrophy. CT scan and MRI demonstrated small symmetrical foci of necrosis in the substentia nigra and in the basal ganglia typical of Leigh syndrome and diffuse cerebral white matter abnormalities. In these patients a deficiency in complex II of the respiratory chain was demonstrated in isolated mitochondria from muscle, as well as in fibroblasts and lymphocytes.

The electrophysiological recordings (E.R.G. associated with C.V.E.P.) performed on 101 children suffering from encephalopathy of different origins demonstrate a trend towards retinal integrity for subjects with encephalopathy and no suspicion of acid-base disorders. However a functional macular deficiency is frequently observed in encephalopathy with suspicion of acid-base disorders (encephalopathy due to intracranial hypertension or cardio-vascular disorders or metabolic deficiencies with acid-base disturbance). In these cases, a common pathophysiological substratum with disturbance of the acute or chronic acid-base equilibrium has been assumed. Over a period of time, in fixed encephalopathy, the electrophysiological results reflect a real but slow maturation of the visual pathways.

The authors studied 5 patients with neonatal myoclonic encephalopathy commencing in the hours immediately after birth and consisting of erratic, asynchronous, non-periodic myoclonus associated with generalized jerks in 4. The EEG showed bursts of pseudo-periodic activity on a low voltage background rhythm. Neuropathological study showed poliodystrophy in one case and a disturbance of cortical lamination in another. The relation of these cases with non-ketotic hyperglycinaemia is discussed.

In a series of 1334 consecutive pneumoencephalographies in children 0-15 years, there were 2 deaths, 3 severe apneas and 1 pneumomediastinum. Respiratory insufficiency, due to contention of the patient with resulting impairment of the motion of thoracic muscles was an important mechanism and pneumoencephalography is contra-indicated in children with respiratory difficulties prior to the examination. In 90 consecutive patients submitted to pneymoencephalography CSF changes and fundus oculi abnormalities were studied prospectively. Aseptic meningitis of a mild degree is common following the examination, whereas significant meningeal haemorrhage is rare. Haemorrhages in the fundi were noted in 10% of the patients. The general tolerance of the examination was good.

Four cases of encephalitis occurring in children treated for lymphatic malignancies by immunosuppressive drugs are reported. Measles virus was isolated from the brain in one case and identified immunologically in another. Nucleocapsids identical to those seen in subacute sclerosing panencephalitis were demonstrated in three cases. Severe immunosuppression was evidenced in two patients by failure of rosette formation and low phytohemagglutinin tests. Pathologically, the inflammatory reaction was absent in one brain and moderate in two. Clinically, epilepsia partialis continua was a prominent feature in three patients. A history of measles or of contact was elicited in three cases, five weeks to three months before onset. All cases ran an acute fatal course. Measles virus can behave as an opportunistic invader of the central nervous system in children and the diagnosis of measles encephalitis should be considered in immunosuppressed patients.