Differential corticospinal tract degeneration in homozygous 'D90A' SOD-1 ALS and sporadic ALS.

BACKGROUND: The homogeneous genotype and stereotyped phenotype of a unique familial form of amyotrophic lateral sclerosis (ALS) (patients homozygous for aspartate-to-alanine mutations in codon 90 (homD90A) superoxide dismutase 1) provides an ideal model for studying genotype/phenotype interactions and pathological features compared with heterogeneous apparently sporadic ALS. The authors aimed to use diffusion tensor tractography to quantify and compare changes in the intracerebral corticospinal tracts of patients with both forms of ALS, building on previous work using whole-brain voxelwise group analysis. METHOD: 21 sporadic ALS patients, seven homD90A patients and 20 healthy controls underwent 1.5 T diffusion tensor MRI. Patients were assessed using 'upper motor neuron burden,' El Escorial and ALSFR-R scales. The intracranial corticospinal tract was assessed using diffusion tensor tractography measures of fractional anisotropy (FA), mean diffusivity, and radial and axial diffusivity obtained from its entire length. RESULTS: Corticospinal tract FA was reduced in sporadic ALS patients compared with both homD90A ALS patients and controls. The diffusion measures in sporadic ALS patients were consistent with anterograde (Wallerian) degeneration of the corticospinal tracts. In sporadic ALS, corticospinal tract FA was related to clinical measures. Despite a similar degree of clinical upper motor neuron dysfunction and disability in homD90A ALS patients compared with sporadic ALS, there were no abnormalities in corticospinal tract diffusion measures compared with controls. CONCLUSIONS: Diffusion tensor tractography has shown axonal degeneration within the intracerebral portion of the corticospinal tract in sporadic ALS patients, but not those with a homogeneous form of familial ALS. This suggests significant genotypic influences on the phenotype of ALS and may provide clues to slower progression of disease in homD90A patients.

Sleep and fatigue in multiple sclerosis.

Fatigue is common in multiple sclerosis (MS) and is an important cause of disability. However, the cause of fatigue is poorly understood. This study aimed to describe the frequency and pattern of sleep disturbance in a group of outpatients with MS, and to investigate the relationship between sleep disturbance and fatigue. Sixty outpatients with MS completed the Fatigue Severity Scale (FSS) and the Epworth Sleepiness Scale and kept a sleep diary for seven days. Fatigue and excessive daytime sleepiness were common in this group of patients (64 and 32%). Sleep problems on at least two nights per week occurred frequently, including initial insomnia in 42%, middle insomnia in 53% and terminal insomnia in 58%. The reasons cited for different types of insomnia varied, with anxiety and pain/discomfort being the commonest causes of initial insomnia and nocturia the commonest cause of middle insomnia. Middle insomnia was significantly correlated with daytime fatigue, a relationship that remained after controlling for disability. Sleep disturbance is common in MS and is associated with treatable symptoms, including pain and nocturia. Sleep disturbance may be an important factor contributing to fatigue in patients with MS.

Basal activity of the hypothalamic-pituitary-adrenal axis in patients with depersonalization disorder.

Depersonalisation disorder may occur during severe anxiety or following a traumatic event, suggesting a possible role of stress hormones. This study investigated basal activity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with depersonalisation disorder. Salivary cortisol levels were measured at four time points over 12 h in patients with depersonalisation disorder (N=13), major depressive disorder (MDD, N=14) and healthy controls (N=13). Beck Depression Inventory scores were significantly higher in depersonalised subjects than controls, while MDD subjects demonstrated higher scores than both groups. Basal cortisol levels of depersonalised subjects were significantly lower than those of MDD subjects but not healthy controls. These results point to reduced basal activity of the HPA axis in depersonalisation disorder. This pilot study supports the distinction between depersonalisation disorder and major depressive disorder which should be examined in a larger sample.

Does family functioning affect outcome in children with neurological disorders?

Children with neurological disorders are at increased risk of poor psychological and social adjustment. Medical factors are insufficient to explain the individual variation in outcome, so family variables have been considered. This review evaluates studies which have investigated the effect of family functioning on outcome in children with traumatic brain injuries, epilepsy and other neurological disorders. Methodological problems include the cross-sectional nature of many studies and inadequate control for confounding variables. There is good evidence that family functioning influences behavioural adjustment and adaptive functioning after traumatic brain injury. The role of family functioning in epilepsy and other neurological disorders requires further investigation. The development of effective interventions to improve family functioning may lead to important clinical benefits for children and their families.

Neuropsychological function in euthymic patients with bipolar disorder.

BACKGROUND: The assumption that patients with bipolar disorder make a full inter-episode recovery has been challenged by limited evidence that suggests that neuropsychological dysfunction in bipolar disorder may persist beyond episodes of illness. AIMS: To test the hypothesis that patients with euthymic bipolar disorder show neuropsychological impairment. METHOD: A battery of neuropsychological tests (assessed attention, working memory, learning and executive function) was administered to three matched groups of subjects: good-outcome patients with bipolar disorder (n = 21); poor-outcome patients with bipolar disorder (n = 20); controls (n = 20). All patients were clinically euthymic, although some had low levels of depressive symptoms. RESULTS: Patients performed worse than controls on a number of neuropsychological tests. When age, premorbid IQ and depressive symptoms were controlled for, the results indicated impairment of executive function. CONCLUSIONS: These findings provide good evidence for the existence of neuropsychological impairment in patients with euthymic bipolar disorder, although the possible effect of medication should not be overlooked. This may be of clinical relevance and raises questions about the course and outcome of the illness.

Defects in heart and lung development in compound heterozygotes for two different targeted mutations at the N-myc locus.

Two types of mutant allele, one leaky and one null, have been generated by gene targeting at the N-myc locus in embryonic stem cells and the phenotypes of mice homozygous for these mutations have been described. These mutations have shown that N-myc has a number of functions during development, including a role in branching morphogenesis in the lung, which manifests itself at birth in mice homozygous for the leaky allele, and roles in the development of the mesonephric tubules, the neuroepithelium, the sensory ganglia, the gut and the heart, which become evident at midgestation in embryos homozygous for the null allele. In an attempt to define roles for N-myc at other stages of development, we have combined the two types of N-myc mutant allele in a compound heterozygote that as a result contains approximately 15% of normal levels of N-Myc protein. Compound heterozygotes died during gestation at a time intermediate to the times of death of embryos homozygous for either mutation individually, and their death appeared to result from cardiac failure stemming from hypoplasia of the compact subepicardial layer of the myocardium. Investigation of the expression pattern of N-myc and various markers of differentiation in wild-type and compound heterozygote mutant hearts has suggested that N-myc may function in maintaining the proliferation and/or preventing the differentiation of compact layer myocytes. This study illustrates the importance of generating different mutations at a given locus to elucidate fully the function of a particular gene during development.

Loss of N-myc function results in embryonic lethality and failure of the epithelial component of the embryo to develop.

myc genes are thought to function in the processes of cellular proliferation and differentiation. To gain insight into the role of the N-myc gene during embryogenesis, we examined its expression in embryos during postimplantation development using RNA in situ hybridization. Tissue- and cell-specific patterns of expression unique to N-myc as compared with the related c-myc gene were observed. N-myc transcripts become progressively restricted to specific cell types, primarily to epithelial tissues including those of the developing nervous system and those in developing organs characterized by epithelio-mesenchymal interaction. In contrast, c-myc transcripts were confined to the mesenchymal compartments. These data suggest that c-myc and N-myc proteins may interact with different substrates in performing their function during embryogenesis and suggest further that there are linked regulatory mechanisms for normal expression in the embryo. We have mutated the N-myc locus via homologous recombination in embryonic stem (ES) cells and introduced the mutated allele into the mouse germ line. Live-born heterozygotes are under-represented but appear normal. Homozygous mutant embryos die prenatally at approximately 11.5 days of gestation. Histologic examination of homozygous mutant embryos indicates that several developing organs are affected. These include the central and peripheral nervous systems, mesonephros, lung, and gut. Thus, N-myc function is required during embryogenesis, and the pathology observed is consistent with the normal pattern of N-myc expression. Examination of c-myc expression in mutant embryos indicates the existence of coordinate regulation of myc genes during mouse embryogenesis.

The N-myc proto-oncogene: developmental expression and in vivo site-directed mutagenesis.

The N-myc proto-oncogene is a member of the superfamily of transcription factors. In mammals, expression of this gene is predominantly restricted to the developing embryo. Specifically, the level of expression is highest in differentiating epithelial components of the embryo including those of the developing brain, kidney and lung. The observation that N-myc is expressed in differentiating but not terminally differentiated structures suggests that these genes may function in the maintenance of cells in a determined or proliferative state. Available evidence suggests that when N-myc expression is down-regulated, cells progress through differentiation and acquire their terminal phenotype. N-myc expression is also correlated with poor prognosis in a number of tumor systems. Since malignant tumors are usually poorly differentiated, this may reflect the role that N-myc plays in preventing differentiation of otherwise determined cells. In vivo site-directed mutagenesis by homologous recombination has made it possible to introduce a variety of mutations into mice. This review summarizes this technology and describes our initial results in the characterization of mice that lack a functional N-myc gene. Specifically, we have observed that in the absence of a functional N-myc gene, embryos arrest in midgestation. This body of work demonstrates that this gene is not required for normal development until the onset of organogenesis.

The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor.

Neurotrophic factors are essential for neuronal survival and function. Recent data have demonstrated that the product of the tyrosine kinase trk proto-oncogene binds NGF and is a component of the high affinity NGF receptor. Analysis of the trkB gene product, gp145trkB, in NIH 3T3 cells indicates that this tyrosine kinase receptor is rapidly phosphorylated on tyrosine residues upon exposure to the NGF-related neurotrophic factors BDNF and NT-3. Furthermore, gp145trkB specifically binds BDNF and NT-3 in NIH 3T3 cells and in hippocampal cells, but does not bind NGF. Thus, the trk family of receptors are likely to be important signal transducers of NGF-related trophic signals in the formation and maintenance of neuronal circuits.

Germ line transmission of an inactive N-myc allele generated by homologous recombination in mouse embryonic stem cells.

We have disrupted one allele of the N-myc locus in mouse embryonic stem (ES) cells by using homologous recombination techniques and have obtained germ line transmission of null N-myc ES cell lines with transmission of the null N-myc allele to the offspring. The creation of mice with a deficient N-myc allele will allow the generation of offspring bearing null N-myc alleles in both chromosomes and permit study of the role that this proto-oncogene plays in embryonic development.