Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation

Two families, originally diagnosed as having nonsyndromic X-linked mental retardation (NSXLMR), were reviewed when it was shown that they had a 24-bp duplication (428-45 1dup(24bp)) in the ARX gene [Stromme et al., 2002: Nat Genet 30:441-445]. This same duplication had also been found in three other families: one with X-linked infantile spasms and hypsarrhythmia (X-linked West syndrome, MIM 308350) and two with XLMR and dystonic movements of the hands (Partington syndrome, MIM 309510). On review, manifestations of both West and Partington syndromes were found in some individuals from both families. In addition, it was found that one individual had autism and two had autistic behavior, one of whom had epilepsy. The degree of mental retardation ranged from mild to severe. A GCG trinucleotide expansion (GCG)10+7 and a deletion of 1,517 by in the ARX gene have also been found in association with the West syndrome, and a missense mutation (1058C >T) in a family with a newly recognized form of myoclonic epilepsy, severe mental retardation, and spastic paraplegia [Scheffer et al., 2002: Neurology, in press]. Evidently all these disorders are expressions of mutations in the same gene. It remains to be seen what proportions of patients with infantile spasms, focal dystonia, autism, epilepsy, and nonsyndromic mental retardation are accounted for by mutations in the ARX gene. (C) 2002 Wiley-Liss, Inc.

Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation

We have identified truncating mutations in the human DLG3 ( neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation. DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane-associated guanylate kinase protein family. Neuronal SAP102 is expressed during early brain development and is localized to the postsynaptic density of excitatory synapses. It is composed of three amino-terminal PDZ domains, an src homology domain, and a carboxyl-terminal guanylate kinase domain. The PDZ domains interact directly with the NR2 subunits of the NMDA glutamate receptor and with other proteins responsible for NMDA receptor localization, immobilization, and signaling. The mutations identified in this study all introduce premature stop codons within or before the third PDZ domain, and it is likely that this impairs the ability of SAP102 to interact with the NMDA receptor and/or other proteins involved in downstream NMDA receptor signaling pathways. NMDA receptors have been implicated in the induction of certain forms of synaptic plasticity, such as long-term potentiation and long-term depression, and these changes in synaptic efficacy have been proposed as neural mechanisms underlying memory and learning. The disruption of NMDA receptor targeting or signaling, as a result of the loss of SAP102, may lead to altered synaptic plasticity and may explain the intellectual impairment observed in individuals with DLG3 mutations.

Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy

Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation(1). At least eight autosomal genes involved in idiopathic epilepsy have been identified(2), and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome-linked, Aristaless-related, homeobox gene (ARX), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine(3) and polyglutamine(4) disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.

Enhancing employment services for people with severe mental illness: the challenge of the Australian service environment

Objectives: Comparatively few people with severe mental illness are employed despite evidence that many people within this group wish to obtain, can obtain and sustain employment, and that employment can contribute to recovery. This investigation aimed to: (i) describe the current policy and service environment within which people with severe mental illness receive employment services; (ii) identify evidence-based practices that improve employment outcomes for people with severe mental illness; (iii) determine the extent to which the current Australian policy environment is consistent with the implementation of evidence-based employment services for people with severe mental illness; and (iv) identify methods and priorities for enhancing employment services for Australians with severe mental illness through implementation of evidence-based practices. Method: Current Australian practices were identified, having reference to policy and legal documents, funding body requirements and anecdotal reports. Evidence-based employment services for people with severe mental illness were identified through examination of published reviews and the results of recent controlled trials. Results: Current policy settings support the provision of employment services for people with severe mental illness separate from clinical services. Recent studies have identified integration of clinical and employment services as a major factor in the effectiveness of employment services. This is usually achieved through co-location of employment and mental health services. Conclusions: Optimal evidence-based employment services are needed by Australians with severe mental illness. Providing optimal services is a challenge in the current policy environment. Service integration may be achieved through enhanced intersectoral links between employment and mental health service providers as well as by co-locating employment specialists within a mental health care setting.

Healthy ageing - Adults with intellectual disabilities: Physical health issues

This report has been prepared by the Ageing Special Interest Research Group of the International Association for the Scientific Study of Intellectual Disabilities (IASSID) in collaboration with the Department of Mental Health and Substance Dependence and the Programme on Ageing and Health, World Health Organization (WHO), Geneva, Switzerland, and all rights are reserved by the above mentioned organization. The document may, however, be freely reviewed, abstracted, reproduced or translated in part, but not for sale or use in conjunction with commercial purposes. It may also be reproduced in full by non-commercial entities for information or for educational purposes with prior permission from WHO/IASSID. The document is likely to be available in other languages also.

PRN Sedation-patterns of prescribing and administration in a child and adolescent mental health inpatient service

Objective: To identify utilisation rates of prn (pro re nata) sedation in children and adolescents receiving inpatient psychiatric treatment, and to compare correlates of prn prescribing and administration. Method A retrospective chart review examined 122 medical charts from a child and youth mental health inpatient service. Results 71.3% of patients were prescribed prn sedation and 50.8% were administered prn sedation. Patients received an average of 8.0 doses of prn sedation, with 9.8% receiving 10 or more doses. Chlorpromazine and diazepam were the most commonly utilised agents. Prescribing of prn sedation was only related to use of regular medications (p < 0.01), and non-parent carers (p < 0.01). In contrast, administration of prn sedation was associated with multiple diagnoses (p < 0.01), pervasive development disorder (p < 0.01), mental retardation (p < 0.01) ADHD (p < 0.01), longer hospital admission (p < 0.01), use of atypical antipsychotics (p < 0.01) and polypharmacy (p < 0.01). Conclusions Despite lack of data to inform practice, prn sedation is widely utilised, especially in complex patients. Future research in this area needs to incorporate nurses and examine whether patients benefit from prn sedation, which drugs and dosing patterns optimise safety and efficacy, and what is the role of prn sedation in the context of other medication.

Cannabis use and psychosis

This paper reviews evidence on two hypotheses about the relationship between cannabis use and psychosis. The first hypothesis is that heavy cannabis use may cause a cannabis psychosis-a psychosis that would not occur in the absence of cannabis use, the symptoms of which are preceded by heavy cannabis use and remit after abstinence. The second hypothesis is that cannabis use may precipitate schizophrenia, or exacerbate its symptoms. Evaluation of these hypotheses requires evidence of an association between cannabis use and psychosis, that is unlikely to be due to chance, in which cannabis use precedes psychosis, and in which we can exclude the hypothesis that the relationship is due to other factors, such as other drug use, or a personal vulnerability to psychosis. There is some clinical support for the first hypothesis. If these disorders exist they seem to be rare, because they require very high doses of THC, the prolonged use of highly potent forms of cannabis, or a pre-existing (but as yet unspecified) vulnerability. There is more support for the second hypothesis, in that a large prospective study has shown a linear relationship between the frequency with which cannabis has been used by age 18 and the risks over the subsequent 15 years of a diagnosis of schizophrenia. It is still unclear whether this means that cannabis use precipitates schizophrenia, whether it is a form of self-medication, or whether the association is due to the use of other drugs, such as amphetamines, which heavy cannabis users are more Likely to use. There is stronger evidence that cannabis use can exacerbate the symptoms of schizophrenia. Mental health services should identify patients with schizophrenia who use alcohol, cannabis and other drugs and advise them to abstain or to greatly reduce their drug use.

The currency of case management: benefits and costs

Case management models evolved as the mental health care system shifted hospital to community settings. The research evidence underscores the efficacy of certain case management models under 'ideal' conditions; what is less clear, is how these models perform in day to day clinical practice. Moreover, the economic perspective adopted by most studies is relatively narrow thus limiting a proper understanding of the costs and benefits of such models. This paper reviews recent work in the field and highlights gaps in both method and application as a focus for future work. Curr Opin Psychiatry 12:195-199, (C) 1999 Lippincott Williams & Wilkins.

Cannabis use and psychosis: a review of clinical and epidemiological evidence

Objective: This paper evaluates evidence for two hypotheses about the relationship between cannabis use and psychosis: (i) that heavy cannabis use causes a 'cannabis psychosis', i.e, a psychotic disorder that would not have occurred in the absence of cannabis use and which can be recognised by its pattern of symptoms and their relationship to cannabis use; and (ii) that cannabis use may precipitate schizophrenia, or exacerbate its symptoms. Method: Literature relevant to drug use and schizophrenia is reviewed. Results: There is limited clinical evidence for the first hypothesis. If 'cannabis psychoses' exist, they seem to be rare, because they require very high doses of tetrahydrocannabinol, the prolonged use of highly potent forms of cannabis, or a preexisting (but as yet unspecified) vulnerability, or both. There is more support for the second hypothesis in that a large prospective study has shown a linear relationship between the frequency with which cannabis had been used by age 18 and the risk over the subsequent 15 years of receiving a diagnosis of schizophrenia. Conclusions: It is still unclear whether this means that cannabis use precipitates schizophrenia, whether cannabis use is a form of 'self-medication', or whether the association is due to the use of other drugs, such as amphetamines, which heavy cannabis users are more likely to use. There is better clinical and epidemiological evidence that cannabis use can exacerbate the symptoms of schizophrenia.

X-linked myoclonic epilepsy with spasticity and intellectual disability - Mutation in the homeobox gene ARX

Objective: To describe a new syndrome of X-linked myoclonic epilepsy with generalized spasticity and intellectual disability (XMESID) and identify the gene defect underlying this disorder. Methods: The authors studied a family in which six boys over two generations had intractable seizures using a validated seizure questionnaire, clinical examination, and EEG studies. Previous records and investigations were obtained. Information on seizure disorders was obtained on 271 members of the extended family. Molecular genetic analysis included linkage studies and mutational analysis using a positional candidate gene approach. Results: All six affected boys had myoclonic seizures and TCS; two had infantile spasms, but only one had hypsarrhythmia. EEG studies show diffuse background slowing with slow generalized spike wave activity. All affected boys had moderate to profound intellectual disability. Hyperreflexia was observed in obligate carrier women. A late-onset progressive spastic ataxia in the matriarch raises the possibility of late clinical manifestations in obligate carriers. The disorder was mapped to Xp11.2-22.2 with a maximum lod score of 1.8. As recently reported, a missense mutation (1058C>T/P353L) was identified within the homeodomain of the novel human Aristaless related homeobox gene (ARX). Conclusions: XMESID is a rare X-linked recessive myoclonic epilepsy with spasticity and intellectual disability in boys. Hyperreflexia is found in carrier women. XMESID is associated with a missense mutation in ARX. This disorder is allelic with X-linked infantile spasms (ISSX; MIM 308350) where polyalanine tract expansions are the commonly observed molecular defect. Mutations of ARX are associated with a wide range of phenotypes; functional studies in the future may lend insights to the neurobiology of myoclonic seizures and infantile spasms.

Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX

Clinical data from 50 mentally retarded (MR) males in nine X-linked MR families, syndromic and non-specific, with mutations (duplication, expansion, missense, and deletion mutations) in the Aristaless related homeobox gene, ARX, were analysed. Seizures were observed with all mutations and occurred in 29 patients, including one family with a novel myoclonic epilepsy syndrome associated with the missense mutation. Seventeen patients had infantile spasms. Other phenotypes included mild to moderate MR alone, or with combinations of dystonia, ataxia or autism. These data suggest that mutations in the ARX gene are important causes of MR, often associated with diverse neurological manifestations. (C) 2002 Elsevier Science B.V. All rights reserved.