2.14 Neuropsychiatry of Neurometabolic and Neuroendocrine Disorders 655
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2.14 Neuropsychiatry of Neurometabolic and Neuroendocrine Disorders 655 Ware AL, Glass L, Crocker N, et al. Effects of prenatal alcohol exposure and attention- metabolic disorders have been described, and only a very limited deficit/hyperactivity disorder on adaptive functioning. Alcohol Clin Exp Res. 2014; 38:1439–1447. number of these are screened for in the neonatal period (usually less Ware AL, O’Brien JW, Crocker N, et al. The effects of prenatal alcohol exposure and than ten in most centers). This may provide the clinician with a false attention-deficit/hyperactivity disorder on psychopathology and behavior. Alcohol assurance that any significant and/or serious metabolic disorders will Clin Exp Res. 2013;37:507–516. already have been detected. This situation is further complicated by the fact that the age of onset and presentation, in addition to disease expression, vary greatly across and within these disorders, and dis- orders that present later or in a less severe form are often missed by ▲▲ 2.14 Neuropsychiatry screening processes during the neonatal and childhood periods. Those metabolic disorders that present initially, or predominantly, of Neurometabolic and with neuropsychiatric syndromes generally have their onset in the period of the life cycle associated with the onset of the majority of Neuroendocrine Disorders psychiatric illnesses, that is, adolescence or early adulthood. The dis- orders that present in this stage will commonly be inborn errors of MARK WALTERFANG, PH.D., FRANZCP, RAMON MOCELLIN, metabolism, affecting cellular function in the CNS. A wide range OLIVIER BONNOT, M.D. PH.D., AND DENNIS VELAKOULIS, of phenotype–genotype correlations occur in such disorders, as dif- DMEDSCI, FRANZCP fering mutations in the gene for the protein serving a key function in metabolism will result in different structural or conformational changes to the protein product and differential metabolic effects. For Metabolic and endocrine disturbance can have wide-ranging effects example, some mutations in the gene encoding for the NPC1 protein on the CNS. Neurons, because of their high metabolic level of activity in Niemann–Pick disease type C are associated with an early onset and demand, are often acutely sensitive to derangements in more sys- or illness, severe mental retardation, and death in childhood, whereas temic metabolic processes. As a result, disorders affecting systemic others are associated with a less significant protein defect, a reduced metabolism often have a very high rate of associated CNS distur- effect on NPC1’s role in intracellular cholesterol metabolism (even bance, ranging from the severe—with gross neurodevelopmental dis- falling into the “normal” range), and a presentation in adolescence or ruption, delirium, and/or coma—to the mild, with subtle cognitive and early adulthood. The adult-onset forms of these diseases often form behavioral disturbance. However, a number of these disorders cause a minority of cases of these disorders, although they will generally recognizable and significant psychiatric illness, including psychotic respond as favorably to primary treatments for the disorder. In addi- disorders, affective disturbance, anxiety disorders, attention-deficit tion, some carriers with autosomal recessive disorders who were disturbance, and other behavioral disturbance such as apathy, dysex- previously considered asymptomatic (such as female carriers with ecutive syndromes, and catatonia. For the purposes of this section, adrenomyeloneuropathy) have been shown to have “borderline” syn- those disorders of metabolism and endocrine function associated with dromes often involving subtle psychiatric disturbance. For most of significant CNS disturbance will be referred to as neurometabolic these disorders, gross metabolic disturbance results in severe impair- and neuroendocrine disorders, respectively, and those associated with ment of CNS function (such as delirium or coma), with moderate major neuropsychiatric syndromes will be highlighted. impairments often resulting in dementia (or mental retardation in The relevance of recognition of neuropsychiatric comorbidity children) and movement disorders. More subtle impairments, how- in neurometabolic and neuroendocrine syndromes extends to both ever, are less likely to disrupt these core vegetative and functional diagnostic and treatment issues. A number of these disorders can systems of the brain, but rather disrupt higher-order functions that produce an accurate phenocopy of psychiatric illness, where illness are much more dependent on highly synchronous corticocortical and presentation carries most or all the characteristic features of a psy- subcortical connectivity, with the result being disturbance to higher chiatric diagnosis. For example, a schizophrenia-like psychosis may cognitive functions and a predisposition toward major mood and psy- develop in metachromatic leukodystrophy (MLD) that is otherwise chotic disorders. As these systems tend to mature later in the brain’s indistinguishable from “typical” schizophrenia, at least until other neurodevelopmental trajectory, those disorders that alter or inter- features more typical of the primary neurometabolic illness super- rupt late neurodevelopment are more likely to cause neuropsychi- vene. Awareness of the types of disorders that may present as psy- atric syndromes. For progressive disorders, it is not uncommon for chiatric illness phenocopies, and their associated physical, cognitive, these disorders to present initially with a neuropsychiatric syndrome, or neurological concomitants, allows for the appropriate recognition which may be diagnosed and treated as a primary psychiatric illness. and diagnostic confirmation of an underlying metabolic or endocrine As the pathological effect of the metabolic derangement impinges illness. In some circumstances, this may mean medical treatment of further on the CNS and begins to result in degenerative change, frank an endocrine illness, enzyme replacement, or substrate reduction neurological illness and dementia often supervene. therapy for a metabolic illness. Failure to recognize the underlying In addition to those metabolic disorders that impact on neurode- illness while focusing on psychiatric treatment alone can delay the velopment, some metabolic disorders are associated with episodic institution of appropriate management and result in potentially irre- but reversible metabolic disturbances (such as the acute porphyrias). versible CNS changes. As opposed to impacting late-maturing developmental networks, Most clinicians will undertake a routine set of investigations these disorders impact metabolically on presumably mature or nor- for underlying “organic” causes of psychiatric illness at first pre- mally developed brain systems. Those disorders that show a predi- sentation, including screening for thyroid illness, infective disease, lection for neuropsychiatric disturbance are more likely to affect electrolyte disturbance, and renal and kidney function, in addition brain regions (such as the frontal or temporal cortical regions) or to brain imaging and/or electroencephalography (EEG). Although transmitter systems (particularly dopaminergic and serotonergic sys- these tests are relatively high yield and detect a number of illnesses tems) that are strongly associated with psychiatric illness. Similarly, producing secondary psychiatric syndromes, less common but no the majority of major endocrine disorders that are associated with less significant conditions are often missed. Literally hundreds of psychiatric disturbance do so in the setting of an otherwise intact LWBK1571-CH2.12-CH2.14_p627-685.indd 655 19/09/16 4:23 PM 656 Chapter 2. Neuropsychiatry and Behavioral Neurology CNS. These endocrine systems are crucially involved in energy as seizures, chorea, or dystonia. Dementia is an inexorably progres- metabolism, cell turnover, and downstream metabolic effects. Dis- sive component of the illness, initially presenting as attentional dis- orders associated with elevated rates of psychiatric disturbance act turbance, reduced speed of processing and executive impairment, via a direct effect of the altered hormonal system on particularly vul- and may present as a phenocopy of frontotemporal dementia; if dis- nerable cellular populations or neurotransmitter systems such as the inhibition is a prominent feature, it may present as a phenocopy of effects of elevated cortisol levels on hippocampal neurons, or thyroid hypomania. Diagnosis is made by demonstrating reduced enzyme hormone on serotonin turnover. activity in leukocytes or skin fibroblasts. MRI generally demon- strates typical periventricular white matter changes sparing sub- cortical U-fibers, and often shows pathology with a frontotemporal NEUROMETABOLIC SYNDROMES preponderance (Fig. 2.14–1). Lysosomal Disorders Treatment is generally symptomatic, although bone marrow transplantation has shown benefit in some patients, and enzyme The lysosome is a subcellular organelle that is manufactured by the replacement therapies are currently being investigated. Adolescent/ Golgi apparatus and contains a number of hydrolytic enzymes such adult MLD provides an intriguing model for the understanding of as proteases, lipases, nucleases, and polysaccharidases. They func- the neurobiology of psychosis, as it interrupts myelinative pro- tion as the “garbage disposal” system of the cell, via phagocytosis cesses that occur during this critical period of neurodevelopment, (digestion of extracellular material),