ECHS1 mutations in Leigh disease: a new inborn error of metabolism affecting valine metabolism.

Two siblings with fatal Leigh disease had increased excretion of S-(2-carboxypropyl)cysteine and several other metabolites that are features of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a rare defect in the valine catabolic pathway associated with Leigh-like disease. However, this diagnosis was excluded by HIBCH sequencing and normal enzyme activity. In contrast to HIBCH deficiency, the excretion of 3-hydroxyisobutyryl-carnitine was normal in the children, suggesting deficiency of short-chain enoyl-CoA hydratase (ECHS1 gene). This mitochondrial enzyme is active in several metabolic pathways involving fatty acids and amino acids, including valine, and is immediately upstream of HIBCH in the valine pathway. Both children were compound heterozygous for a c.473C > A (p.A158D) missense mutation and a c.414+3G>C splicing mutation in ECHS1. ECHS1 activity was markedly decreased in cultured fibroblasts from both siblings, ECHS1 protein was undetectable by immunoblot analysis and transfection of patient cells with wild-type ECHS1 rescued ECHS1 activity. The highly reactive metabolites methacrylyl-CoA and acryloyl-CoA accumulate in deficiencies of both ECHS1 and HIBCH and are probably responsible for the brain pathology in both disorders. Deficiency of ECHS1 or HIBCH should be considered in children with Leigh disease. Urine metabolite testing can detect and distinguish between these two disorders.

Unravelling offending in schizophrenia: factors characterising subgroups of offenders.

BACKGROUND: Previous studies have led to suggestions that there are at least three sub-types of offenders with schizophrenia, but these have not previously been examined simultaneously in one sample. AIMS: The aims of this study were to investigate categorisation of offenders with psychosis as early or late starters or late first offenders, and test the hypotheses that, compared with non-offenders with psychosis, early starters would be characterised by low educational or occupational achievement, negative childhood experiences and early substance use, whereas positive psychotic symptoms would characterise late starters or late first offenders. METHODS: A retrospective file study was conducted, yielding 97 early starters, 100 late starters and 26 late first offenders identified from a specialist inpatient forensic mental health assessment service and 129 non-offenders identified from general psychiatric services in the same geographic region, all with schizophreniform psychoses. RESULTS: We found little difference between early and later starters in terms of measured antecedents, but substance misuse was up to 20 times less likely among late first offenders. Persecutory and/or grandiose delusions were more strongly associated with each offender group compared with non-offenders, most so with late first offenders. CONCLUSIONS: Our findings underscore the importance of treating delusions--for safety as well as health. Childhood antecedents may be less important indicators of offender sub-types among people with psychosis than previously thought. When patients present with grandiose or persecutory delusions over the age of 35 years without co-morbid substance misuse disorders, but with a history of childhood neglect and low educational achievement, particular care should be taken to assess risk of violence.

Anti-social personality characteristics and psychotic symptoms: Two pathways associated with offending in schizophrenia.

BACKGROUND: Several research groups have shown that people with schizophrenia who offend do not form a homogenous group. A three-group model claimed by Hodgins proposes distinguishing between people who start offending before the onset of psychosis (early starters), after psychosis onset but at age 34 years or under (late starters) and after psychosis onset but at age 35 years or older (late first offenders). AIMS: This study aimed to test the hypotheses (1) that the personality of early starters and non-psychotic offenders would be similar, but different from either late-starter group; (2) that the late-starter groups would be more likely to have positive psychotic symptoms than non-criminal patients with schizophrenia; and (3) that symptom types would differentiate the psychotic groups. METHODS: A retrospective file study was conducted on cases of 97 early starters, 100 late starters and 26 late first offenders all drawn from the Netherlands Institute of Forensic Psychiatry and Psychology (NIFP) archives 1993-2008, 115 non-psychotic offenders from 2005-2008 NIFP archives and 129 patients with schizophrenia and no criminal history from one general service in Rotterdam. RESULTS: Early starters closely resembled the non-psychotic offenders in their premorbid anti-social personality characteristics. The two late-onset offending psychosis groups were more likely to have persecutory and/or grandiose delusions than non-offenders with psychosis, but so were the early starters. IMPLICATIONS: In a first study to compare subgroups of offenders with psychosis directly with non-psychotic offenders and non-offenders with psychosis, we found such additional support for a distinction between early and late starters with psychosis that different treatment strategies would seem indicated, focusing on personality and substance misuse for the former but psychotic symptoms for all. It remains to be seen whether the higher rate of alcohol misuse amongst late first offenders is a fundamental distinction or a function of age difference.

Interpreting Child Sexual Abuse: Empathy and Offense-Supportive Cognitions among Child Sex Offenders.

Researchers have suggested that child sex offenders hold distorted views on social interactions with children. Misinterpreting children's behavior and intentions could lead to sexually abusive behavior toward children. It is further suggested that the interpretation process is influenced by offenders' offense-supportive cognitions and levels of empathy. To examine the relationships between these three concepts, 47 contact offenders completed self-reports on offense-supportive cognitions and empathy. Vignettes were developed to assess the extent to which offenders attributed responsibility, benefit, and complicity to children in hypothetical child molestation incidents. This study showed that cognitions that justify sexual offending against children seem to diminish the threshold for sexual assault by assigning more cooperation and willingness of the victim in a child molestation incident.

Interpreting child sexual abuse: the impact of victim response.

There is little empirical knowledge about whether the interpretation process of child sex offenders is offense-supportive in nature and contributes to the offending process. Vignettes were developed to compare child sex offenders' and nonoffenders' interpretations of child molestation incidents after ambiguous and nonambiguous victim responses. Results showed that child sex offenders' (N = 60) interpretations did not differ from nonoffenders' (N = 40) interpretations. Overall, the more ambiguous the child responses, the more child complicity and child benefit was seen. Our results indicate that offense-supportive interpretations are not unique to child sex offenders. The mechanisms that are responsible for whether or not to commit a sexual offense should be unraveled and treated, to prevent deviant processes to be activated.

Treatment of a methylmalonyl-CoA mutase stopcodon mutation.

There are limited treatment options for the metabolic disorder methylmalonic aciduria. The disorder can be caused by nonsense mutations within the methylmalonyl-CoA mutase gene, resulting in the production of a truncated protein with little or no catalytic activity. We used a genomic reporter assay and mouse primary cell lines which carry a stop-codon mutation in the human methylmalonyl-CoA mutase gene to test the effects of gentamicin and PTC124 for stop-codon read-through potential. Fibroblast cell lines were established from methylmalonic aciduria knockout-stop codon mice. Addition of gentamicin to the culture medium caused a 1.5- to 2-fold increase in mRNA expression of the human methylmalonyl-CoA mutase gene. Without treatment the cells contained 19% of the normal levels of methylmalonyl-CoA mutase enzyme activity which increased to 32% with treatment, suggesting a functional improvement. Treatment with PTC124 increased the amount of human methylmalonyl-CoA mutase gene mRNA by 1.6±0.3-fold and a trend suggesting increased enzyme activity. The genomic reporter assay, BAC_MMA(∗)EGFP, expresses enhanced green fluorescent protein when read-through of the stop codon occurs. Using flow cytometry, RT-real-time PCR and enzyme assay, read-through was measured. Treatment with PTC124 at 20µmol/L resulted in a significant increase in enhanced green fluorescent protein, a 2-fold increase in mRNA expression and a trend to a slight increase in enzyme activity. The clinical relevance of these effects may be tested in mouse models of MMA carrying nonsense mutations in the methylmalonyl-CoA mutase gene. Pharmacological approaches have the advantage of providing a broader effect on multiple tissues, which will benefit many different disorders with similar nonsense mutations.

Fetal progenitor cell transplantation treats methylmalonic aciduria in a mouse model.

Methylmalonic aciduria is a rare disorder caused by an inborn error of organic acid metabolism. Current treatment options are limited and generally focus on disease management. We aimed to investigate the use of fetal progenitor cells to treat this disorder using a mouse model with an intermediate form of methylmalonic aciduria. Fetal liver cells were isolated from healthy fetuses at embryonic day 15-17 and intravenously transplanted into sub-lethally irradiated mice. Liver donor cell engraftment was determined by PCR. Disease correction was monitored by urine and blood methylmalonic acid concentration and weight change. Initial studies indicated that pre-transplantation sub-lethal irradiation followed by transplantation with 5 million cells were suitable. We found that a double dose of 5 million cells (1 week apart) provided a more effective treatment. Donor cell liver engraftment of up to 5% was measured. Disease correction, as defined by a decrease in blood methylmalonic acid concentration, was effected in methylmalonic acid mice transplanted with a double dose of cells and who showed donor cell liver engraftment. Mean plasma methylmalonic acid concentration decreased from 810 ± 156 (sham transplanted) to 338 ± 157 µmol/L (double dose of 5 million cells) while mean blood C3 carnitine concentration decreased from 20.5 ± 4 (sham transplanted) to 5.3 ± 1.9 µmol/L (double dose of 5 million cells). In conclusion, higher levels of engraftment may be required for greater disease correction; however these studies show promising results for cell transplantation biochemical correction of a metabolic disorder.

The role of ideational distress in the relation between persecutory ideations and reactive aggression.

BACKGROUND: People with schizophrenia are more likely to be violent than the people without it. Feeling driven to act on persecutory delusions may be one explanation for this, but it remains unclear why some should act on such delusions but some not. Acquisition of data from people who are very ill is problematic. Our study explores testing of hypotheses on similar ideational and behavioural associations among healthy recruits from the general population. AIMS: This study aims to test the effect of distress induced by persecutory ideas on any relationships between those ideas and aggressive behaviour, and the effect of gender. METHODS: Twenty-four men and 53 women from the general population participated in this study. The measures of aggressive behaviour were experimentally induced aggressive responding, self-reported aggressive behaviour in general, and self-reported reactive and proactive aggressive behaviours. RESULTS: Among men, persecutory ideation predicted reactive aggressive responding and aggressive style of behaviour only in those who experienced higher levels of persecutory ideational distress. Among women, with generally lower levels of aggression, the role of ideational distress was more complicated; Women in the low distress group responded with higher aggression on the task. Women in the higher distress group responded with higher aggressive style. For neither men nor women were there links between persecutory ideation and proactive aggression, regardless of distress. CONCLUSIONS: Ideational distress moderates the relation between persecutory ideation and aggression in different measures of aggression in men and women. IMPLICATIONS FOR PRACTICE AND/OR RESEARCH: Recognition of a relation between persecutory ideations and aggression is also important in the general population. Insight in the theory of acting upon delusions may lead to more accurate violence risk assessment. Facilitation of early detection of experienced delusional distress may lead to development of more specific psychotherapeutic interventions to manage violence risk.

Young serious and vulnerable offenders in the Netherlands: a cohort follow-up study after completion of a PIJ (detention) order.

BACKGROUND: About 150-200 'Placement in an Institution for Juveniles Orders' (PIJ orders) are imposed each year in the Netherlands. Many of the young people under these orders have mental disorders or 'threatened psychological development' and are thought to be at high risk of recidivism. There are no previous studies of the range of judicial, correctional or psychiatric contacts after the PIJ order, but this could extend understanding of any links between post-treatment psychological development of these young offenders and their reoffending or desistence from it. AIMS: To examine reoffending and judicial, correctional or psychiatric contacts of juveniles after a PIJ order, any relationship between seriousness of the index offence and first reoffence, and to test the hypothesis that 'threatened psychological development' is associated with higher recidivism rates. METHODS: A records-based follow-up study of a 9-year (1995-2003) national release cohort of 781 Dutch juvenile offenders finishing a PIJ order under the Juvenile Entrustment Act. Descriptive statistics were used to show patterns of reoffending and the reoffending and non-reoffending groups compared. RESULTS: The mean length of the PIJ order was 2.5 years, and mean time subsequently at risk for offending was 83.5 months (range 51-135 months). After treatment under a PIJ order, serious criminal offending was reduced by 50%, and there was a trend towards less serious property offences. Contrary to prediction, 'threatened psychological development' was not associated with worse outcomes. CONCLUSIONS: The data offer support for the value of the PIJ order. The recidivism rate remains high, and although the trend to less serious offending is encouraging, the findings raise questions about whether criminogenic needs are sufficiently met. By contrast, the apparently low rates of adult mental disorder, even among those regarded as having had 'threatened psychological development', suggest that PIJ institutions are doing a good job with respect to mental health.

Gene induction for the treatment of methylmalonic aciduria.

BACKGROUND: Methylmalonic aciduria is an autosomal recessive inborn error of the propionate metabolic pathway. One form of this disorder is caused by mutations in methylmalonyl-coenzyme A mutase (MCM), resulting in reduced levels of enzyme activity. The pharmacological up-regulation of residual mutase activity is one approach to advance treatment strategies for individuals affected by this disorder. We describe the construction, characterization and use of a cellular genomic reporter assay for MCM expression that will potentially identify therapeutic pharmacological agents for methylmalonic aciduria treatment. METHODS: Homologous recombination was used to insert an enhanced green fluorescent protein (EGFP) cassette inframe before the last codon of exon 13 of the MCM gene (MUT) in a BAC clone. The construct was used to generate stable HeLa cell lines. EGFP expression was measured by flow cytometry and the real-time reverse transcriptase-polymerase chain reaction was used to quantify changes in MUT gene mRNA levels. RESULTS: The genomic reporter assay used to screen a selection of compounds. Cisplatin, zidovudine and adefovir were found to increase the levels of MCM mRNA and EGFP expression, providing support for the possible efficacy of these pharmacological compounds in treating methylmalonic aciduria. CONCLUSIONS: This assay has the potential of being used in high-throughput screening of chemical libraries for the identification of novel compounds that specifically modulate the expression of MCM.

Stop codon read-through of a methylmalonic aciduria mutation.

A stop codon defect in methylmalonyl-CoA mutase (resulting in a truncated unstable protein) accounts for up to 14% of mutations identified as causes of Methylmalonic aciduria. There are currently limited treatment regimes for patients with this inherited condition. We aimed to investigate the use of stop codon read-through drugs in a genomic reporter assay cell line with a defect in the mutase gene. A single C-T base change was introduced into exon 6 of the human MUT sequence in the BAC clone RP11-463L20 resulting in an arginine residue being replaced with a TGA stop codon. An enhanced green fluorescent protein reporter gene was introduced in-frame with exon 13 of the MUT gene. The construct was transfected into HeLa cells to produce the genomic reporter assay cell line. To test the suppression of nonsense mutations, cells were incubated in the presence of different compounds for a period of 72 h then analysed by flow cytometry. Treatment of the cells with gentamicin resulted in a 1.6-fold increase in reporter protein, whilst G418 treatment resulted in no change, however the two drugs together acted synergistically to increase the production of methylmalonyl-CoA mutase 2.0-fold (confirmed by mRNA, flow cytometry and enzyme activity). Zidovudine, adefovir and cisplatin were also found to have some activity in the stop codon read-through genomic reporter assay. These results encourage further testing of compounds as well as follow up animal studies. This is the first study to demonstrate the use of stop codon read-through drugs for the potential treatment of Methylmalonic aciduria.

The effects of conceptual processing versus suppression on analogue PTSD symptoms after a distressing film.

BACKGROUND: Researchers have begun to scrutinize the assumption that active processing in response to a traumatic event is beneficial whereas avoidance of thoughts, emotions and reminders about the traumatic event is detrimental. Indications that avoidance is not always detrimental come from studies on grief and debriefing. AIMS: In an analogue experimental study, the hypothesis was tested that conceptually-driven processing immediately after a distressing film is more successful in reducing analogue PTSD symptoms than suppression of thoughts and images related to the film. METHOD: Ninety students watched a distressing film after which they were instructed to either elaborate on the meaning of the film (conceptual processing) (n = 31), suppress all thoughts and images of the film by performing a task (n = 29), or were given no instruction (n = 30). Four hours later, analogue PTSD symptoms were assessed. RESULTS: The results showed that conceptually-driven processing does not result in fewer analogue PTSD symptoms than suppression. CONCLUSIONS: It is speculated that suppression may only be dysfunctional when individuals interpret their symptoms negatively or when suppression is believed to be dysfunctional.

Psychometric properties of the Trauma Relevant Assumptions Scale.

This article describes the psychometric properties of a novel questionnaire, i.e. the Trauma Relevant Assumptions Scale (TRAS). The added value of the TRAS over previous trauma relevant belief questionnaires is that the TRAS enables measuring valence and rigidity of beliefs simultaneously. Both aspects are thought to be predictive of the development of chronic PTSD symptoms. For the exploratory factor analysis, the TRAS was administered to 309 adult volunteers. Principal components analysis yielded two factors: Assumptions about Self and Assumptions about the World. The two-factor structure was confirmed in a sample of 185 traumatized individuals. The TRAS seems to be a valid and reliable instrument, which is strongly related to post-trauma symptoms and has good discriminative validity. Apart from research settings, the TRAS may also be suitable in therapeutic settings to identify the severity of dysfunctional assumptions, and to assess the progress in change from negative assumptions to more positive assumptions.

Perceptual and conceptual processing as predictors of treatment outcome in PTSD.

Cognitive behavioural treatment (CBT) is highly effective in treating post-traumatic stress disorder (PTSD). However, the mechanisms of change are still poorly understood. The aim of the present study was to investigate trauma processing during and after CBT for PTSD. Treatment consisted of imaginal exposure combined with rescripting. The rationale of this treatment is that dysfunctional interpretations may best be corrected by inducing new perspectives on what happened during trauma by experiencing new views and new emotions. In twenty-five chronic patients with PTSD, we tested whether an initial increase of perceptual processing and a subsequent increase of conceptual processing predicted treatment outcome. Possible changes in perceptual/conceptual processing during and after treatment were inferred from changes in trauma memories from pre- to post-treatment and from post- to 1-month follow-up. These memory parameters were assessed by analysing trauma narratives that were produced before the first treatment session, after the last treatment session and at follow-up. Consistent with predictions, a relative increase of conceptual processing after treatment predicted treatment outcome levels for both PTSD symptoms and general psychopathology at 1-month follow-up. Although a relative increase of perceptual processing during treatment also predicted treatment outcome, this effect was explained by the beneficial effect of a subsequent increase of conceptual processing. But an increase of perceptual processing during treatment was strongly related to an increase of conceptual processing after treatment. The results suggest that imaginal reliving during CBT is not crucial for symptom reduction, but it may promote conceptual processing, which in itself predicts a better treatment outcome.

Positive symptoms, substance use, and psychopathic traits as predictors of aggression in persons with a schizophrenia disorder.

It is still not clear what the unique contribution of particular psychopathological factors is in explaining aggression in schizophrenia. The current study examined whether persecutory ideations, psychopathy and substance use are associated with different measures of aggressive behavior. We expected that persecutory ideations are associated with reactive aggression, and psychopathic traits are more associated with proactive aggression of inpatients. 59 inpatients with schizophrenia were included. Persecutory ideations we assessed using the Persecutory Ideation Questionnaire (PIQ), psychopathic traits with the revised version of Psychopathic Personality Inventory (PPI-R) and substance use was assessed using the Comprehensive Assessment of Symptoms and History (CASH). In addition, aggression was measured with the Reactive and Proactive Aggression Questionnaire (RPQ), in an experimental task using the Point Subtraction Aggression Paradigm (PSAP) and on the ward using the Social Dysfunction and Aggression Scale (SDAS). Results showed that psychopathy explains most of the variance in self-reported proactive and reactive aggression. In contrast, persecutory ideations explain most of the variance in observed aggression on the ward. Results implicate that it is important to acknowledge comorbid factors in patients with schizophrenia for more precise risk assessment and appropriate treatment for aggressive patients with schizophrenia.

Dissociation related to subjective memory fragmentation and intrusions but not to objective memory disturbances.

The present study was a replication of Kindt and Van den Hout (Behaviour Research and Therapy 41 (2003) 167) with several methodological adaptations. Two experiments were designed to test whether state dissociation is related to objective memory disturbances, or whether dissociation is confined to the realm of subjective experience. High trait dissociative participants (N(exp.1)=25; N(exp.2)=25) and low trait dissociative participants (N(exp.1)=25; N(exp.2)=25) were selected from normal samples (N(exp.1)=372; N(exp.2)=341) on basis of scores on the Dissociative Experience Scale (DES). Participants watched an extremely aversive film, after which state dissociation was measured by the Peri-traumatic Dissociative Experience Questionnaire (PDEQ). Memory disturbances were assessed 4h later (Exp. 1) or 1 week later (Exp. 2). Objective memory disturbances were assessed by a sequential memory task, items tapping perceptual representations (Exp. 1), or an open question with respect to the remembrance of the film (Exp. 2). Subjective memory disturbances were measured by means of visual analogue scales assessing fragmentation and intrusions. The two experiments provided a fairly exact replication of an earlier experiment (Behaviour Research and Therapy 41 (2003) 167-178), indicating a relation between dissociation and memory disturbances that appeared to be confined to the subjective experience of memory.

The potential of bone marrow stem cells to correct liver dysfunction in a mouse model of Wilson's disease.

Metabolic liver diseases are excellent targets for correction using novel stem cell, hepatocyte, and gene therapies. In this study, the use of bone marrow stem cell transplantation to correct liver disease in the toxic milk (tx) mouse, a murine model for Wilson's disease, was evaluated. Preconditioning with sublethal irradiation, dietary copper loading, and the influence of cell transplantation sites were assessed. Recipient tx mice were sublethally irradiated (4 Gy) prior to transplantation with bone marrow stem cells harvested from normal congenic (DL) littermates. Of 46 transplanted tx mice, 11 demonstrated genotypic repopulation in the liver. Sublethal irradiation was found to be essential for donor cell engraftment and liver repopulation. Dietary copper loading did not improve cell engraftment and repopulation results. Both intravenously and intrasplenically transplanted cells produced similar repopulation successes. Direct evidence of functionality and disease correction following liver repopulation was observed in the 11 mice where liver copper levels were significantly reduced when compared with mice with no liver repopulation. The reversal of copper loading with bone marrow cells is similar to the level of correction seen when normal congenic liver cells are used. Transplantation of bone marrow cells partially corrects the metabolic phenotype in a mouse model for Wilson's disease.

Review of risk assessment instruments for juvenile sex offenders: what is next?

Risk assessment is considered to be a key element in the prevention of recidivism among juvenile sex offenders (JSOs), often by imposing long-term consequences based on that assessment. The authors reviewed the literature on the predictive accuracy of six well-known risk assessment instruments used to appraise risk among JSOs: the Juvenile Sex Offender Assessment Protocol-II (J-SOAP-II), Juvenile Sexual Offence Recidivism Risk Assessment Tool-II (J-SORRAT-II), Estimate of Risk of Adolescent Sexual Offence Recidivism (ERASOR), Juvenile Risk Assessment Scale (JRAS), Structured Assessment of Violent Risk in Youth (SAVRY), and Hare Psychopathy Checklist:Youth Version (PCL:YV). Through a systematic search, 19 studies were reviewed. Studies showed differences in the predictive accuracies for general, violent, and sexual recidivism, and none of the instruments showed unequivocal positive results in predicting future offending. Not unexpectedly, the accuracy of the SAVRY and PCL:YV appeared to be weaker for sexual recidivism compared with specialized tools such as the J-SOAP-II or the ERASOR. Because of the rapid development of juveniles, it is questionable to impose long-term restrictions based on a risk assessment only. New challenges in improving risk assessment are discussed.

Delusional distress partly explains the relation between persecutory ideations and inpatient aggression on the ward.

Previous research showed that there is an association between persecutory delusions and inpatient aggression. However, it is not clear why some persons act upon their delusions with aggression. Research showed that persons with persecutory delusions have higher levels of delusional distress resulting from these delusions. This may explain why some persons act upon their delusions. Persecutory ideations lead to ideational distress which in turn can lead to aggression. The main aim of the present study was to test whether persecutory ideations have an indirect effect on inpatient aggression through delusional distress. The sample of the study consisted of 44 male inpatients from different general psychiatric inpatient wards. Results showed that the effect of persecutory ideations on inpatient aggression was partly explained by the level of delusional distress. Insight in the theory of acting upon delusions can be obtained by acknowledging this role of delusional distress in the relation between persecutory ideation and inpatient aggression. Early diagnosis of persecutory ideations and experienced delusional distress can be used in risk assessment of inpatients. Early interventions to reduce delusional distress, such as cognitive behavioral therapy, may prevent inpatient aggression.

Development of transgenic mice containing an introduced stop codon on the human methylmalonyl-CoA mutase locus.

The mutation R403stop was found in an individual with mut(0) methylmalonic aciduria (MMA) which resulted from a single base change of C→T in exon 6 of the methylmalonyl-CoA mutase gene (producing a TGA stop codon). In order to accurately model the human MMA disorder we introduced this mutation onto the human methylmalonyl-CoA mutase locus of a bacterial artificial chromosome. A mouse model was developed using this construct.The transgene was found to be intact in the mouse model, with 7 copies integrated at a single site in chromosome 3. The phenotype of the hemizygous mouse was unchanged until crossed against a methylmalonyl-CoA mutase knockout mouse. Pups with no endogenous mouse methylmalonyl-CoA mutase and one copy of the transgene became ill and died within 24 hours. This severe phenotype could be partially rescued by the addition of a transgene carrying two copies of the normal human methylmalonyl-CoA mutase locus. The "humanized" mice were smaller than control litter mates and had high levels of methylmalonic acid in their blood and tissues. This new transgenic MMA stop codon model mimics (at both the phenotypic and genotypic levels) the key features of the human MMA disorder. It will allow the trialing of pharmacological and, cell and gene therapies for the treatment of MMA and other human metabolic disorders caused by stop codon mutations.