The neuropsychiatry of inborn errors of metabolism

Abstract

A number of metabolic disorders that affect the central nervous system can present in childhood, adolescence or adulthood as a phenocopy of a major psychiatric syndrome such as psychosis, depression, anxiety or mania. An understanding and awareness of secondary syndromes in metabolic disorders is of great importance as it can lead to the early diagnosis of such disorders. Many of these metabolic disorders are progressive and may have illness-modifying treatments available. Earlier diagnosis may prevent or delay damage to the central nervous system and allow for the institution of appropriate treatment and family and genetic counselling. Metabolic disorders appear to result in neuropsychiatric illness either through disruption of late neurodevelopmental processes (metachromatic leukodystrophy, adrenoleukodystrophy, GM2 gangliosidosis, Niemann-Pick type C, cerebrotendinous xanthomatosis, neuronal ceroid lipofuscinosis, and alpha mannosidosis) or via chronic or acute disruption of excitatory/inhibitory or monoaminergic neurotransmitter systems (acute intermittent porphyria, maple syrup urine disease, urea cycle disorders, phenylketonuria and disorders of homocysteine metabolism). In this manuscript we review the evidence for neuropsychiatric illness in major metabolic disorders and discuss the possible models for how these disorders result in psychiatric symptoms. Treatment considerations are discussed, including treatment resistance, the increased propensity for side-effects and the possibility of some treatments worsening the underlying disorder.

Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

“…A number of metabolic disorders that affect the central nervous system can present in childhood, adolescence, or adulthood as a phenocopy of a major psychiatric syndrome, such as psychosis, depression, anxiety, or mania (Walterfang et al 2013). In this study, we observed that rats submitted to chronic administration of H-BCAA have a decreased sweet food intake and increased adrenal gland weight, without any alteration of body weight compared with the control group.…”

“…Evidence from the literature shows that the causality of psychiatric illness is the result of two processes: the interruption of childhood/early adulthood neurodevelopmental trajectories in progressive illness, and the acute alteration of monoaminergic or excitatory/inhibitory neurotransmitter systems in acute or episodic illness (Walterfang et al 2013). Moreover, neurotransmitter deficiency can be a primary cause of psychiatric disorders or entrain compensatory changes in receptor expression and synaptic structure that affect brain function.…”

“…Anecdotal reports suggest that aging MSUD patients are at high risk for chronic neuropsychiatric problems, such as attention deficit disorder, depression, and anxiety (Strauss et al 2006;Walterfang et al 2013). Muelly and colleagues (2013) showed that the neurochemical deficiencies previously demonstrated in MSUD patients and experimental animals may persist in the chronic state, although to a lesser degree, and cumulatively contribute to neuropsychiatric morbidity.…”

Living with Intoxication-Type Inborn Errors of Metabolism: A Qualitative Analysis of Interviews with Paediatric Patients and Their Parents

“…the PKU-QOL (Regnault et al 2015)) address the characteristics of a particular disease or disease group. The latter are therefore the method of choice in clinical trials (Walterfang et al 2013). Since the concept of HrQoL is based on subjective experience, self-assessment using ageappropriate instruments is the gold standard (Matza et al 2013).…”

Neuropsychological Development in Patients with Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency

“…Current research is looking at gene-environment interaction models to explain the etiology and also the variations in phenotypic expression (Chaste and Leboyer 2012). Inborn errors of metabolism are recognized as the underlying cause of several neuropsychiatric conditions (Kayser 2008;Manzi et al 2008;Walterfang et al 2013). LCHADD and other FAODs seem to elicit an increased incidence of autistic behavior (Brown et al 2014).…”