Mental disorders, genes

Schaffner, K. F. (2001), Do genes count , in J. Z. Sadler (Ed.), Descriptions and Prescriptions Values, Mental Disorders and the DSMs, Johns Hopkins University Press, Baltimore, MD, in press. 

Mental disorders, also called affective disorders, are multi-level, multi-scale and multiple-system diseases (Fig. 7.1). Mental disturbances generally go along with disturbances of autonomous functions. These essentially are (1) sleep disturbances, both sleep duration and sleep pattern, and (2) disturbances of the hypothalamic-pituitary-adrenal (HPA) axis, the so-called stress axis with elevated cortisol levels. It can be expected that disturbances of autonomous control systems as well as mood are caused by neuronal malfunctioning which may concern practically all neuronal levels systemic interactions, neuronal network connections, single neuron dynamics, synaptic transmitters and/or receptors, ion channels, second messengers, and gene expression (Fig. 7.1a). Nevertheless, despite a manifold of data, there are only vague ideas so far about the differences in neuronal dynamics in the brain of a chronically depressed person compared with a person with a sensitive but balanced mood. 

The autonomous functions exhibit circadian rhythms which are under the control of a neuronal pacemaker, located in the suprachiasmatic nuclei (SCN) of the hypothalamus. The circadian pacemaker arises from complex dynamics of gene expression and is synchronized to the external light. In the case of mental disorders, the regular rhythms of autonomous functions are obviously disturbed which led to the formulation of the desynchronization hypotheses [8, 9], This does not necessarily contradict the transmitter hypothesis . Transmitter imbalance, of course, also interferes with the inherent system dynamics and can change the endogenous rhythmicity, eventually with the result of desynchronization. A first computational approach which simulates the rhythmicity of the HPA axis and its alterations with scaling of transmitter mediated positive and negative feedback loops is briefly summarized in the second Results section. 

Research has produced a group of candidate genes for several mental disorders. For example, for schizophrenia, neuregulin-1, catechol-O-methyltransferase, dysbindin, and G72 are promising leads. The evidence currently available suggests that for most, if not all, psychiatric disorders, not one but many genes will be found to be involved in their heritability risk. 

Cacabelos R (2001) The path to personalized medicine in mental disorders. In Ritsner MS (ed) The handbook of neuropsychiatric biomarkers, endophenotypes and genes, vol 4. Springer, Dordrecht, Netherlands pp 3-63... 

C. R. Cloninger. The discovery of susceptibility genes for mental disorders. Proc Natl Acad Sci,2002. 

The field of psychiatry is predicated on the assumpt-tion that serious mental disorders result from abnormalities in the structure or function of the brain. Although no specific brain anomalies have been identified as the definitive cause of mental illness, the latest neuroscientific studies suggest that imbalances in neurochemicals—also called neurotransmitters— or malfunctions in their transportation from nerve cell to nerve cell might be responsible for the symptoms of mental illness, such as anxiety, depression, hallucinations, and delusions. Neurotransmitters include dopamine, norepinephrine, serotonin, and gamma-amino-butyric acid. Most experts believe that the causes of mental illness stem from a combination of genes (nature) and experiences (nurture). 

Mutations in the gene for adenylosuccinate lyase (ASL), inherited as an autosomal recessive disorder in purine metabolism, are associated with severe mental retardation and autistic behavior, but apparently not self-mutilation [10, 11]. This enzyme catalyzes two distinct reactions in the de novo biosynthesis of purines the cleavages of adenylosuccinate (S-Ado) and succinylaminoimidazole carboxamide ribotide (SAICAR), both of which accumulate in plasma, urine and cerebrospinal fluid of affected individuals [12]. Measurements of these metabolites in urine... 

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