Treatment of methylmalonic acidemia by liver or combined liver-kidney transplantation.

OBJECTIVE: To assess biochemical, surgical, and long-term outcomes of liver (LT) or liver-kidney transplantation (LKT) for severe, early-onset methylmalonic acidemia/acid (MMA). STUDY DESIGN: A retrospective chart review (December 1997 to May 2012) of patients with MMA who underwent LT or LKT at Lucile Packard Children's Hospital at Stanford. RESULTS: Fourteen patients underwent LT (n = 6) or LKT (n = 8) at mean age 8.2 years (range 0.8-20.7). Eleven (79%) were diagnosed during the neonatal period, including 6 by newborn screening. All underwent deceased donor transplantation; 12 (86%) received a whole liver graft. Postoperative survival was 100%. At a mean follow-up of 3.25 ± 4.2 years, patient survival was 100%, liver allograft survival 93%, and kidney allograft survival 100%. One patient underwent liver re-transplantation because of hepatic artery thrombosis. After transplantation, there were no episodes of hyperammonemia, acidosis, or metabolic decompensation. The mean serum MMA at the time of transplantation was 1648 ± 1492 µmol/L (normal <0.3, range 99-4420). By 3 days, post-transplantation levels fell on average by 87% (mean 210 ± 154 µmol/L), and at 4 months, they were 83% below pre-transplantation levels (mean 305 ± 108 µmol/L). Developmental delay was present in 12 patients (86%) before transplantation. All patients maintained neurodevelopmental abilities or exhibited improvements in motor skills, learning abilities, and social functioning. CONCLUSIONS: LT or LKT for MMA eradicates episodes of hyperammonemia, results in excellent long-term survival, and suggests stabilization of neurocognitive development. Long-term follow-up is underway to evaluate whether patients who undergo early LT need kidney transplantation later in life.

Liver transplantation for urea cycle disorders in pediatric patients: a single-center experience.

LT has emerged as a surgical treatment for UCDs. We hypothesize that LT can be safely and broadly utilized in the pediatric population to effectively prevent hyperammonemic crises and potentially improve neurocognitive outcomes. To determine the long-term outcomes of LT for UCDs, charts of children with UCD who underwent LT were retrospectively reviewed at an academic institution between July 2001 and May 2012. A total of 23 patients with UCD underwent LT at a mean age of 3.4 yr. Fifteen (65%) patients received a whole-liver graft, seven patients (30%) received a reduced-size graft, and one patient received a living donor graft. Mean five-yr patient survival was 100%, and allograft survival was 96%. Mean peak blood ammonia (NH(3) ) at presentation was 772 µmol/L (median 500, range 178-2969, normal <30-50). After transplantation, there were no episodes of hyperammonemia. Eleven patients were diagnosed with some degree of developmental delay before transplantation, which remained stable or improved after transplantation. Patients without developmental delay before transplantation maintained their cognitive abilities at long-term follow-up. LT was associated with the eradication of hyperammonemia, removal of dietary restrictions, and potentially improved neurocognitive development. Long-term follow-up is underway to evaluate whether LT at an early age (<1 yr) will attain improved neurodevelopmental outcomes.

Longitudinal rates of lobar atrophy in frontotemporal dementia, semantic dementia, and Alzheimer's disease.

This study compared rates of regional atrophy in Alzheimer disease (AD), frontotemporal dementia (FTD), and semantic dementia (SD). Cross-sectional studies have shown that different dementia syndromes are associated with different patterns of regional brain tissue loss. Rates of atrophy over time may be useful for differential diagnosis, and could be used to monitor disease progression, serving as an outcome measure for clinical trials. We studied patients with AD (n=12), FTD (n=13), SD (n=20), and normal controls (n=23) longitudinally with structural magnetic resonance imaging, using BRAINS2 software to measure frontal, temporal, and parietal lobe volumes. In FTD the rate of frontal lobe atrophy over 1 year was greater than in any other group, whereas SD showed the highest rate in the temporal lobes. Atrophy in these regions progressed twice as quickly in FTD and SD compared with AD. Atrophy was not significantly faster for AD in any brain region compared with the other groups. Regional atrophy over time was significantly faster in FTD and SD compared with AD, and the regions of greatest atrophy were specific for each syndrome. Measuring specific regions of cerebral volume changes by serial neuroimaging may serve as a useful biomarker outcome measure for clinical trials in neurodegenerative diseases.

Relationships between maternal emotion regulation, parenting, and children's executive functioning in families exposed to intimate partner violence.

Recently researchers have begun to explore the extent to which children's cognitive development is influenced by experiences in the family environment. Assessing mother-child dyads exposed to intimate partner violence (IPV), a population at risk for emotional and neurocognitive problems, we examined relationships between maternal emotional regulation, parenting, and children's executive functioning (including working memory, inhibitory control, cognitve flexibility and set shifting, and planning). Positive parenting practices, as reported by the children, were correlated with children's planning and problem solving performance. Controlling for children's own emotion regulation and gender, mothers' self-reported emotion regulation abilities predicted children's performance on a task of cognitive flexibility. Girls exhibited superior emotion regulation and executive functioning performance compared to boys, and mothers of girls reported better emotion regulation abilities compared to mothers of boys. These findings add to a nascent literature suggesting that parenting and parental emotional functioning may play important roles in children's neurocognitive functioning. In addition, they help to explain the mechanisms by which children exposed to IPV experience executive functioning deficits.

Know thyself: real-world behavioral correlates of self-appraisal accuracy.

Accurate appraisal of one's own abilities is one metacognitive skill considered to be an important factor affecting learning and behavior in childhood. The present study measured self-appraisal accuracy in children using tasks of executive function, and investigated relations between self-appraisal and informant ratings of real-world behaviors measured by the BRIEF. We examined self-appraisal accuracy on fluency tasks in 91 children ages 10-17. More accurate self-appraisal was correlated with fewer informant ratings of real-world behavior problems in inhibition and shifting, independent of actual performance. Findings suggest that self-appraisal represents cognitive processes that are at least partially independent of other functions putatively dependent on the frontal lobes, and these self-appraisal-specific processes have unique implications for optimal daily function.

Double dissociation in the anatomy of socioemotional disinhibition and executive functioning in dementia.

OBJECTIVE: To determine whether socioemotional disinhibition and executive dysfunction are related to dissociable patterns of brain atrophy in neurodegenerative disease. Previous studies have indicated that behavioral and cognitive dysfunction in neurodegenerative disease are linked to atrophy in different parts of the frontal lobes, but these prior studies did not establish that these relationships were specific, which would best be demonstrated by a double dissociation. METHOD: Subjects included 157 patients with neurodegenerative disease. A semiautomated parcellation program (Freesurfer) was used to generate regional cortical volumes from structural MRI scans. Regions of interest (ROIs) included anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), middle frontal gyrus (MFG), and inferior frontal gyrus (IFG). Socioemotional disinhibition was measured using the Neuropsychiatric Inventory. Principal component analysis including 3 tasks of executive function (EF; verbal fluency, Stroop Interference, modified Trails) was used to generate a single-factor score to represent EF. RESULTS: Partial correlations between ROIs, disinhibition, and EF were computed after controlling for total intracranial volume, Mini-Mental State Examination, diagnosis, age, and education. Brain regions significantly correlated with disinhibition (ACC, OFC, IFG, and temporal lobes) and EF (MFG) were entered into separate hierarchical regressions to determine which brain regions predicted disinhibition and EF. OFC was the only brain region to significantly predict disinhibition, and MFG significantly predicted EF performance. A multivariate general linear model demonstrated a significant interaction between ROIs and cognitive-behavioral functions. CONCLUSIONS: These results support a specific association between orbitofrontal areas and behavioral management as compared with dorsolateral areas and EF.

Neurocognitive assessment.

Neurocognitive symptoms are a prominent feature of nearly all neurodegenerative dementias. Specialized assessment of memory, executive functions, language, and visuospatial skills may aid in the differential diagnosis. This chapter describes the neuropsychological assessment of these domains and provides typical neurocognitive profiles of various dementia types.

Neuropsychological functioning in children with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) has been associated with deficits in the areas of verbal memory and learning, executive functioning, working memory, and attention in adults. Findings have been less consistent in the few studies examining neuropsychological functioning in childhood PTSD, which are often limited by comparing children with PTSD to children without trauma histories, making it unclear whether observed neuropsychological deficits are related to trauma exposure or to PTSD symptomatology. In an ethnically diverse sample of 62 children who witnessed intimate partner violence (n = 27 PTSD+ and 35 PTSD-), children with PTSD exhibited slower and less effective learning, heightened sensitivity to interference, and impaired effect of rehearsal on memory acquisition on the California Verbal Learning Test - Children's Version, a word list learning task. Both groups performed in the below average range on measures of executive functioning, attention, and intellectual ability.