Complex Set Of Disorders Research Articles

Pathways to neurodegeneration: lessons learnt from unbiased genetic screens in Drosophila

Neurodegenerative diseases are a complex set of disorders that are known to be caused by environmental as well as genetic factors. In the recent past, mutations in a large number of genes have been identified that are linked to several neurodegenerative diseases. The pathogenic mechanisms in most of these disorders are unknown. Recently, studies of genes that are linked to neurodegeneration in Drosophila, the fruit flies, have contributed significantly to our understanding of mechanisms of neuroprotection and degeneration. In this review, we focus on forward genetic screens in Drosophila that helped in identification of novel genes and pathogenic mechanisms linked to neurodegeneration. We also discuss identification of four novel pathways that contribute to neurodegeneration upon mitochondrial dysfunction.

Frequency of CNKSR2 mutation in the X‐linked epilepsy‐aphasia spectrum

Synaptic proteins are critical to neuronal function in the brain, and their deficiency can lead to seizures and cognitive impairments. CNKSR2 (connector enhancer of KSR2) is a synaptic protein involved in Ras signaling-mediated neuronal proliferation, migration and differentiation. Mutations in the X-linked gene CNKSR2 have been described in patients with seizures and neurodevelopmental deficits, especially those affecting language. In this study, we sequenced 112 patients with phenotypes within the epilepsy-aphasia spectrum (EAS) to determine the frequency of CNKSR2 mutation within this complex set of disorders. We detected a novel nonsense mutation (c.2314 C>T; p.Arg712*) in one Ashkenazi Jewish family, the male proband of which had a severe epileptic encephalopathy with continuous spike-waves in sleep (ECSWS). His affected brother also had ECSWS with better outcome, whereas the sister had childhood epilepsy with centrotemporal spikes. This mutation segregated in the three affected siblings in an X-linked manner, inherited from their mother who had febrile seizures. Although the frequency of point mutation is low, CNKSR2 sequencing should be considered in families with suspected X-linked EAS because of the specific genetic counseling implications.

A learning theory account of depression.

Learning theory provides a foundation for understanding and deriving treatment principles for impacting a spectrum of functional processes relevant to the construct of depression. While behavioral interventions have been commonplace in the cognitive behavioral tradition, most often conceptualized within a cognitive theoretical framework, recent years have seen renewed interest in more purely behavioral models. These modern learning theory accounts of depression focus on the interchange between behavior and the environment, mainly in terms of lack of reinforcement, extinction of instrumental behavior, and excesses of aversive control, and include a conceptualization of relevant cognitive and emotional variables. These positions, drawn from extensive basic and applied research, cohere with biological theories on reduced reward learning and reward responsiveness and views of depression as a heterogeneous, complex set of disorders. Treatment techniques based on learning theory, often labeled Behavioral Activation (BA) focus on activating the individual in directions that increase contact with potential reinforcers, as defined ideographically with the client. BA is considered an empirically well-established treatment that generalizes well across diverse contexts and populations. The learning theory account is discussed in terms of being a parsimonious model and ground for treatments highly suitable for large scale dissemination.

Lysosomal Storage Disease: Revealing Lysosomal Function and Physiology

The discovery over five decades ago of the lysosome, as a degradative organelle and its dysfunction in lysosomal storage disorder patients, was both insightful and simple in concept. Here, we review some of the history and pathophysiology of lysosomal storage disorders to show how they have impacted on our knowledge of lysosomal biology. Although a significant amount of information has been accrued on the molecular genetics and biochemistry of lysosomal storage disorders, we still do not fully understand the mechanistic link between the storage material and disease pathogenesis. However, the accumulation of undegraded substrate(s) can disrupt other lysosomal degradation processes, vesicular traffic, and lysosomal biogenesis to evoke the diverse pathophysiology that is evident in this complex set of disorders.

Computer modelling of epilepsy.

Epilepsy is a complex set of disorders that can involve many areas of the cortex, as well as underlying deep-brain systems. The myriad manifestations of seizures, which can be as varied as déjà vu and olfactory hallucination, can therefore give researchers insights into regional functions and relations. Epilepsy is also complex genetically and pathophysiologically: it involves microscopic (on the scale of ion channels and synaptic proteins), macroscopic (on the scale of brain trauma and rewiring) and intermediate changes in a complex interplay of causality. It has long been recognized that computer modelling will be required to disentangle causality, to better understand seizure spread and to understand and eventually predict treatment efficacy. Over the past few years, substantial progress has been made in modelling epilepsy at levels ranging from the molecular to the socioeconomic. We review these efforts and connect them to the medical goals of understanding and treating the disorder.

What treatment for which patient?

The field of addictions is a lively and exciting one in which controversy thrives. This is a healthy thing. It indicates that we are constantly thinking, growing and learning more about the processes involved in addictions and how best to manage at a biological, psychological and societal level. In this issue, several of the ‘growth’ areas in the addictions field are discussed. Marijuana abuse and dependence is a growing concern throughout the world, particularly in adolescent populations. In spite of this, we know little about efficacious treatment. Copeland (pp. 161–167) provides a thorough and scholarly review of the field, pointing out areas that are ripe for further investigation. In particular, there are currently no pharmacotherapeutic treatments that have demonstrated efficacy in the treatment of marijuana dependence. With the development of the cannabinoid antagonists, this is a new and exciting avenue for exploration. The area of replacement therapies versus abstinencebased therapies or the controlled use of substances is an area that has received much attention. In this issue, there are two articles discussing these issues. Waal and Kornor (pp. 169–174) discuss the use of abstinence-oriented therapies compared with replacement therapies for opiate addicts. In another article, Saladin and Santa Ana (pp. 175–187) discuss the use of controlled drinking strategies in the treatment of alcohol use disorders. Of interest is the fact that these two articles written by different groups of investigators viewing different addictive disorders come to largely the same conclusion. Abstinence-oriented, replacement therapies and controlled drinking strategies all have a place in the treatment of substance use disorders. Substance use disorders are an extraordinarily heterogeneous and complex set of disorders, and there are likely to be a number of efficacious treatments in which the utility of the treatment depends upon administering the treatment to the right patient at the right time in the course of their disorder. In other words, matching patients to treatments. Treatment matching is a construct that has been discussed for a long time. As we grow and develop our knowledge about addictions and new efficacious treatments emerge, this construct will become increasingly important in practice.

PERSONAL CONSTRUCT PSYCHOLOGY AND AUTISM

There has been no significant writing within personal construct psychology about autistic spectrum disorders, despite the fact that this approach provides promising models in a number of other specific areas of human difficulty. This article outlines a PCP model of autism, based on a wide variety of recent research findings and writings, including those of autism sufferers themselves. Autism is considered in the light of Kelly's fundamental postulate and 11 corollaries as well as Procter's (1978) group and family corollaries. It is argued that Kelly's theory provides an integrative framework for considering this complex set of disorders with implications for further research in autism and the early development of social cognition as well as for therapeutic and educational intervention in helping people struggling with autistic spectrum disorders.

The determinants of arithmetic skills in young children: some observations.

The cause or causes of arithmetic difficulties in young children are manifold. The condition has its origins in a set of complex disorders and may be due to genetic factors, developmental delays, experiential limitations, language problems, and perceptual, motor, memory and other cognitive weaknesses. Other factors which may cause the disorder are inappropriate and ineffectual instructional practices. Anxiety and unfavourable attitudes towards the subject may influence mastery of arithmetic attainment in young children.

A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy.

The human diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy are caused by mutations in a set of interacting gene products, which carry out the process of nucleotide excision repair. The majority of the genes have now been cloned and many mutations in the genes identified. The relationships between the distribution of mutations in the genes and the clinical presentations can be used for diagnosis and for understanding the functions and the modes of interaction among the gene products. The summary presented here represents currently known mutations that can be used as the basis for future studies of the structure, function, and biochemical properties of the proteins involved in this set of complex disorders, and may allow determination of the critical sites for mutations leading to different clinical manifestations. The summary indicates where more data are needed for some complementation groups that have few reported mutations, and for the groups for which the gene(s) are not yet cloned. These include the Xeroderma pigmentosum (XP) variant, the trichothiodystrophy group A (TTDA), and ultraviolet sensitive syndrome (UVs) groups. We also recommend that the XP-group E should be defined explicitly through molecular terms, because assignment by complementation in culture has been difficult. XP-E by this definition contains only those cell lines and patients that have mutations in the small subunit, DDB2, of a damage-specific DNA binding protein.