The relationship between brain structure and complex behavior is governed by large-scale neurocognitive networks. The availability of a noninvasive technique that can visualize the neuronal projections connecting the functional centers should therefore provide new keys to the understanding of brain function. By using high-resolution three-dimensional diffusion magnetic resonance imaging and a newly designed tracking approach, we show that neuronal pathways in the rat brain can be probed in situ. The results are validated through comparison with known anatomical locations of such fibers.

Three-dimensional tracking of axonal projections in the brain by magnetic resonance imaging.

Vulnerable periods during the development of the nervous system are sensitive to environmental insults because they are dependent on the temporal and regional emergence of critical developmental processes (i.e., proliferation, migration, differentiation, synaptogenesis, myelination, and apoptosis). Evidence from numerous sources demonstrates that neural development extends from the embryonic period through adolescence. In general, the sequence of events is comparable among species, although the time scales are considerably different. Developmental exposure of animals or humans to numerous agents (e.g., X-ray irradiation, methylazoxymethanol, ethanol, lead, methyl mercury, or chlorpyrifos) demonstrates that interference with one or more of these developmental processes can lead to developmental neurotoxicity. Different behavioral domains (e.g., sensory, motor, and various cognitive functions) are subserved by different brain areas. Although there are important differences between the rodent and human brain, analogous structures can be identified. Moreover, the ontogeny of specific behaviors can be used to draw inferences regarding the maturation of specific brain structures or neural circuits in rodents and primates, including humans. Furthermore, various clinical disorders in humans (e.g., schizophrenia, dyslexia, epilepsy, and autism) may also be the result of interference with normal ontogeny of developmental processes in the nervous system. Of critical concern is the possibility that developmental exposure to neurotoxicants may result in an acceleration of age-related decline in function. This concern is compounded by the fact that developmental neurotoxicity that results in small effects can have a profound societal impact when amortized across the entire population and across the life span of humans.

Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models.

The goal of this review is to present a comprehensive survey of the many intriguing facets of creatine (Cr) and creatinine metabolism, encompassing the pathways and regulation of Cr biosynthesis an...

http://www.afboard.com/library/creatinemetabolism.pdf

Creatine and Creatinine Metabolism

Aneuploidy (trisomy or monosomy) is the most commonly identified chromosome abnormality in humans, occurring in at least 5% of all clinically recognized pregnancies. Most aneuploid conceptuses perish in utero, which makes this the leading genetic cause of pregnancy loss. However, some aneuploid fetuses survive to term and, as a class, aneuploidy is the most common known cause of mental retardation. Despite the devastating clinical consequences of aneuploidy, relatively little is known of how trisomy and monosomy originate in humans. However, recent molecular and cytogenetic approaches are now beginning to shed light on the non-disjunctional processes that lead to aneuploidy.

To err (meiotically) is human: the genesis of human aneuploidy

The alterations in myocardial energy substrate metabolism that occur in heart failure, and the causes and consequences of these abnormalities, are poorly understood. There is evidence to suggest th...

/pdf/myocardial-substrate-metabolism-in-the-normal-and-failing-1cql6lgwxf.pdf

Myocardial Substrate Metabolism in the Normal and Failing Heart

Summary Recently, we showed that homozygosity for the common 677(C→T) mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, causing thermolability of the enzyme, is a risk factor for neural-tube defects (NTDs). We now report on another mutation in the same gene, the 1298(A→C) mutation, which changes a glutamate into an alanine residue. This mutation destroys an Mbo II recognition site and has an allele frequency of .33. This 1298(A→C) mutation results in decreased MTHFR activity (one-way analysis of variance [ANOVA] P P P n = 86) of the NTD patients compared with 20% ( n = 403) among controls, resulting in an odds ratio of 2.04 (95% confidence interval: .9–4.7). These data suggest that the combined heterozygosity for the two MTHFR common mutations accounts for a proportion of folate-related NTDs, which is not explained by homozygosity for the 677(C→T) mutation, and can be an additional genetic risk factor for NTDs.

A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?

Mental retardation (AIR) is a serious and lifelong disability that places heavy demands on society and the health system. Since the first publication on this topic',theprevalenceofMR has been thoroughly studied for different purposes. Most prevalence studies are designed for the planning of services and establish an 'ascertained' prevalence rate, which is the number of cases officially recorded by the authorities'.The 'true'prevalence rate is the total number of mentally retarded people in a population, whether or not they require services,and is defined by the prevalence of MR a t birth and the mortality rate.For mild mental retardation (MWR, I& 50-70) ' the true prevalence rate is more difficult to estimate than for severe mental retardation (SMR, IQ <50).Very often ascertained prevalence rates are mistaken for true prevalence rates. Moreover, the estimates of both rates are influenced by the design of the study, the assessment criteria used, and the method applied for the identification of case^^-^. As a result, differences in prevalence rates might partly reflect the true variation over populations and partly reveal discrepancies between studies and in the interpretation of the prevalence measure used. For instance, different frequencies are yielded by uses of the organic, psychological and social WHO criteria, which are reflected in impairment, disability and handicaps. The prevalence rates observed range from two to 85 per 1000. According to the WHO, the true prevalence rate of total MR in industrialised countries comes close to 3%\".O, but in the United States controversy exists over whether the rate is 1% versus 3%5.7.'0.1', whereas the Scandinavian countries claim that the 1 % figure is their true pre~alence~. '~ . '~ . ' The aim ofthis annotation is to establish valid estimates of the true prevalence rates for SMR and AIMR in children of school age and to elucidate the variation in prevalence rates. Therefore the methodology of prevalence studies performed since 1960 was critically evaluated and a distinction was made between ascertained and true prevalence estimates.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-8749.1997.tb07395.x

The prevalence of mental retardation: a critical review of recent literature.

We identified nine children with a leukoencephalopathy of similar type according to clinical and MRI findings. The patients included three affected sibling pairs. The age range was 3 to 19 years. The onset of the disease was in childhood; the course was both chronic-progressive and episodic. There were episodes of deterioration following infections and minor head traumas, and these could result in unexplained coma. In eight patients with advanced disease, MRI revealed a diffuse cerebral hemispheric leukoencephalopathy, in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In one patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter, which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate, compatible with the presence of mainly CSF and little brain tissue. Spectra of the cortex were much better preserved. However, in addition to the normal resonances, there were signals representing lactate and glucose. MRS of the white matter in the patient whose disease was at an early stage was much less abnormal. Autopsy in one patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. Typical involvement of pontine tegmental white matter was suggested by MRI and confirmed by autopsy. The disease probably has an autosomal recessive mode of inheritance, but the basic metabolic defect is not known.

/pdf/a-new-leukoencephalopathy-with-vanishing-white-matter-435t7ppu09.pdf

A new leukoencephalopathy with vanishing white matter.

By direct sequencing, we have discovered a novel heteroplasmic mutation (T-->C) at nucleotide position 8993 in the mitochondrial ATPase 6 gene in a family with Leigh's syndrome. Another mutation in the same codon (T8993G) has been reported before in Leigh's syndrome. As these two mutations led to different amino acid substitutions, it provides strong evidence for the relevance of ATP synthase dysfunction in maternally inherited Leigh's syndrome.

A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP 27), due to mutations in its gene. In this study we report on mutations in 58 patients with CTX out of 32 unrelated families. Eight of these were novel mutations, two of which were found together with two already known pathogenic mutations. Twelve mutations found in this patient group have been described in the literature. In the patients from 31 families, mutations were found in both alleles. In the literature, 28 mutations in 67 patients with CTX out of 44 families have been described. Pooling our patient group and the patients from the literature together, 37 different mutations in 125 patients out of 74 families were obtained. Identical mutations have been found in families from different ethnic backgrounds. In 41% of all the patients, CYP 27 gene mutations are found in the region of exons 6-8. This region encodes for adrenodoxin and haem binding sites of the protein. Of these 125 patients, a genotype-phenotype analysis was done for 79 homozygous patients harbouring 23 different mutations, out of 45 families. The patients with compound heterozygous mutations were left out of the genotype-phenotype analysis. The genotype-phenotype analysis did not reveal any correlation.

Fons J. M. Gabreëls

Papers

A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects?

The prevalence of mental retardation: a critical review of recent literature.

A new leukoencephalopathy with vanishing white matter.

A second missense mutation in the mitochondrial ATPase 6 gene in Leigh's syndrome

Clinical and molecular genetic characteristics of patients with cerebrotendinous xanthomatosis.