The psychopharmacology of Wilson disease and other metabolic disorders.

Wilson disease (WD) is a hereditary metabolic disorder (HMD) caused by a mutation in the copper-transporting gene ATP7B affecting the liver and central nervous system. About 30% of patients with WD may initially present with psychiatric symptoms, and management can be difficult. More generally, HMDs are a rare but important cause of psychiatric disorders in adolescents and adults. Main signs of HMDs may remain isolated for years before the appearance of hepatic or neurologic signs. The incidence of HMDs has been estimated at approximately 40 cases per 100,000 live births. Some of them are treatable and new diagnostic methods and therapies have become available. HMDs that present purely with psychiatric symptoms are very difficult to diagnose due to low awareness of these rare diseases among psychiatrists and neurologists. However, it is important to identify HMDs in order to provide disease-specific treatment and possible prevention of irreversible physical and neurologic complications. Genetic counseling can also be provided. Psychotropic medications should be prescribed carefully in that indication. This chapter focuses on three HMD categories: chronic, treatable HMDs (e.g., WD); acute, treatable HMDs; and chronic HMDs that are difficult to treat. In this review we focus on the psychopharmacology of WD and other chronic and difficult-to-treat HMDs. We provide some keys to take into account the main side effects associated with common psychotropic medications.

Corpus callosum metrics predict severity of visuospatial and neuromotor dysfunctions in ARID1B mutations with Coffin-Siris syndrome.

ARID1B mutations in Coffin-Siris syndrome are a cause of intellectual disability (0.5-1%), with various degrees of autism and agenesis of the corpus callosum (10%). Little is known regarding the cognitive and motor consequences of ARID1B mutations in humans and no link has been made between corpus callosum anomalies and visuospatial and neuromotor dysfunctions. We have investigated the visuospatial and neuromotor phenotype in eight patients with ARID1B mutations. A paramedian sagittal section of the brain MRI was selected, and corpus callosum was measured in anteroposterior length, genu and trunk width. Spearman's rank order coefficients were used to explore correlations between visuospatial and social cognitive variables and dimensions of the corpus callosum. A significant correlation between genu width size and visual cognition was observed. Retrocerebellar cysts were associated with corpus callosum anomalies. Here, we show that corpus callosum anomalies caused in ARID1B mutations may be predictive of the visuospatial and motor phenotype in Coffin-Siris syndrome.

Additive Effect of Variably Penetrant 22q11.2 Duplication and Pathogenic Mutations in Autism Spectrum Disorder: To Which Extent Does the Tree Hide the Forest?

The 22q11.2 duplication is a variably penetrant copy number variant (CNV) associated with a broad spectrum of clinical manifestations including autism spectrum disorders (ASD), and epilepsy. Here, we report on pathogenic HUWE1 and KIF1A mutations in two severely affected ASD/ID participants carrying a 22q11.2 duplication. Based on previous studies, this CNV was originally considered as disease-causing. Yet, owing to their clinical severity, the participants were further investigated by next generation sequencing and eventually found to carry pathogenic mutations in HUWE1 and KIF1A respectively. We suggest giving consideration to additive effect of 22q11.2 duplication and pathogenic mutations when clinical presentation is either unusually severe or associated with atypical features. Caution should be exercised when delivering genetic counseling for variably penetrant CNVs, as uncertain penetrance of this CNV may lead to ignore additive pathogenic mutations. Systematic panel or exome sequencing of known ASD genes should be recommended when counseling families of patients carrying variably penetrant CNV.

Does COMT val158met polymorphism influence P50 sensory gating, eye tracking or saccadic inhibition dysfunctions in schizophrenia?

Three electrophysiological endophenotypes are routinely studied in schizophrenia (SCZ): smooth pursuit eye movement (SPEM) dysfunction, deficits in P50 auditory-evoked potential inhibition, and saccadic inhibition deficits. The current study aimed to investigate the relationship between the COMT val158met polymorphism and these three endophenotypes. One hundred four SCZ patients (DSM-IV-R criteria) and 89 healthy controls were included in this study. P50 auditory-evoked potential inhibition, antisaccade paradigm and SPEM were analyzed. All individuals were genotyped for the COMT val158met. SCZ patients showed a higher rate of deficits measured by the SPEM, antisaccade and P50 inhibition paradigms without association with COMT val158met. However, in our control group, we have found an association between the Val polymorphism and the smoking status. More importantly, we have found a higher accuracy of saccades during the predictive pursuit task associated to the Met polymorphism in controls but not in SCZ patients who were receiving antidopaminergic medications. This result is in line with the hypothesis of the relationship between the Met polymorphism of the COMT gene, a higher level of dopamine in the prefrontal cortex and the role of the fronto-cerebellar loop in smooth predictive pursuit.

Psychiatric manifestations of treatable hereditary metabolic disorders in adults.

Detecting psychiatric disorders of secondary origin is a crucial concern for the psychiatrist. But how can this reliably be done among a large number of conditions, most of which have a very low prevalence? Metabolic screening undertaken in a population of subjects with psychosis demonstrated the presence of treatable metabolic disorders in a significant number of cases. The nature of the symptoms that should alert the clinician is also a fundamental issue and is not limited to psychosis. Hereditary metabolic disorders (HMD) are a rare but important cause of psychiatric disorders in adolescents and adults, the signs of which may remain isolated for years before other more specific organic signs appear. HMDs that present purely with psychiatric symptoms are very difficult to diagnose due to low awareness of these rare diseases among psychiatrists. However, it is important to identify HMDs in order to refer patients to specialist centres for appropriate management, disease-specific treatment and possible prevention of irreversible physical and neurological complications. Genetic counselling can also be provided. This review focuses on three HMD categories: acute, treatable HMDs (urea cycle abnormalities, remethylation disorders, acute intermittent porphyria); chronic, treatable HMDs (Wilson's disease, Niemann-Pick disease type C, homocystinuria due to cystathionine beta-synthase deficiency, cerebrotendinous xanthomatosis); and chronic HMDs that are difficult to treat (lysosomal storage diseases, X-linked adrenoleukodystrophy, creatine deficiency syndrome). We also propose an algorithm for the diagnosis of HMDs in patients with psychiatric symptoms.