Younger age and early puberty are associated with cognitive function decline in children with Cushing disease.

OBJECTIVE: To investigate the effect of hypercortisolism on the developing brain we performed clinical, cognitive, and psychological evaluation of children with Cushing disease (CD) at diagnosis and 1 year after remission. STUDY DESIGN: Prospective study of 41 children with CD. Children completed diverse sets of cognitive measures before and 1 year after remission. Neuropsychological evaluation included the Wechsler Intelligence Scale, California Verbal Learning Test, Trail Making Test, the combined subset scores of Wide Range Achievement Test and Woodcock-Johnson Psychoeducational Battery Test of Achievement, and the Behavioral Assessment System for Children. RESULTS: Comprehensive cognitive evaluations at baseline and 1 year following cure revealed significant decline mostly in nonverbal skills. Decrements occurred in most of the various indices that measure all aspects of cognitive function and younger age and early pubertal stage largely contributed to most of this decline. Results indicated that age at baseline was associated with positive regression weights for changes in scores for verbal, performance, and full intelligence quotient (IQ) scores and for subtests arithmetic, picture completion, coding, block design, scores; indicating that older age at baseline was associated with less of a deterioration in cognitive scores from pre- to posttreatment. CONCLUSION: Our findings suggest that chronic glucocorticoid excess and accompanying secondary hormonal imbalances followed by eucortisolemia have detrimental effects on cognitive function in the developing brain; younger age and pubertal stage are risk factors for increased vulnerability, while older adolescents have cognitive vulnerabilities like that of adult patients affected with CD.

The neuropsychological phenotype of Chediak-Higashi disease.

BACKGROUND/OBJECTIVES: Chediak-Higashi Disease (CHD) is a rare autosomal disorder, purported to have cognitive and neurological impairments. Prior descriptions of cognitive impairment, however, are solely based on subjective, unstructured observations rather than on formal neuropsychological measures. METHODS: Four pediatric and 14 adult patients with diagnostically confirmed CHD were administered a neuropsychological battery assessing memory, attention, processing speed, psychomotor speed, language fluency, executive function, and general intelligence. Nine of the adult patients received follow-up evaluations to elucidate the longitudinal progression or stability of cognition over time. RESULTS: Pediatric CHD patients performed within the average range. Adult patients, however, performed below average on nearly all measures administered, and endorsed subjective reports of learning difficulties and poor academic performance in childhood. In particular, patients struggled with memory and psychomotor speed tasks, with 75% or more of patients scoring in the bottom 2.3 percentile in these two domains. No significant declines in cognition were observed among the patients who completed follow-up evaluations (M = 39.90, SD = 8.03 months between visits). Exploratory analyses suggested that adult patients who had classic CHD and previously received bone marrow transplants (BMTs; n = 3) exhibited moderately greater cognitive impairment than adult patients who had atypical CHD and had not received BMTs (n = 10). CONCLUSIONS: Adult patients with CHD uniformly exhibit deficits in multiple domains, but in psychomotor speed and memory, in particular. Based on their neuropsychological profile, their ability to hold jobs and succeed in school may require support and special accommodations. The source of cognitive deficits is probably multifactorial including central nervous system involvement in CHD, and, for those transplanted, BMT-related side effects and complications. Absence of cognitive decline at three-year follow-up is encouraging but does not exclude progression at a slower time-scale. Future work should elucidate the possible effects and timing of BMT on cognition, as well as the mechanisms driving neuropsychological impairment in CHD.

Disease progression in C9orf72 mutation carriers.

OBJECTIVE: To assess changes in 3 clinical measures, the Revised ALS Functional Rating Scale (ALSFRS-R), letter fluency, and Frontal Behavioral Inventory (FBI), over time in C9orf72 mutation carriers (C9+) with varied clinical phenotypes. METHODS: Thirty-four unrelated participants with mutations in C9orf72 were enrolled in a prospective natural history study. Participants were classified as asymptomatic, amyotrophic lateral sclerosis (ALS), ALS-familial frontotemporal dementia (FTD), or behavioral-variant FTD by clinical diagnostic criteria. Diagnostic cognitive and motor tests were repeated at 6 and 18 months. The ALSFRS-R, letter fluency, and FBI were administered at baseline and follow-up visits at 6, 12, and 18 months. RESULTS: The clinical diagnosis of most patients did not change over the follow-up. ALSFRS-R scores correlated with measures of motor function. Letter fluency correlated with FBI and cognitive tests. ALSFRS-R, letter fluency, and FBI differed among the C9+ diagnostic subgroups at enrollment and worsened over follow-up in symptomatic patients, with different slopes among the subgroups. Most patients survived to the 6-month time point after enrollment. Survival of C9+ patients with ALS and C9+ patients with ALS-FTD declined over the 12- and 18-month follow-up. CONCLUSIONS: The pattern of scores of the ALSFRS-R, letter fluency, and FBI distinguished between ALS, ALS-FTD, and FTD presentations of C9orf72 mutation carriers and asymptomatic carriers. Longitudinal changes in these measures occurred with disease progression in a manner consistent with presenting phenotype.

Cystic cerebellar dysplasia and biallelic LAMA1 mutations: a lamininopathy associated with tics, obsessive compulsive traits and myopia due to cell adhesion and migration defects.

BACKGROUND: Laminins are heterotrimeric complexes, consisting of α, ß and γ subunits that form a major component of basement membranes and extracellular matrix. Laminin complexes have different, but often overlapping, distributions and functions. METHODS: Under our clinical protocol, NCT00068224, we have performed extensive clinical and neuropsychiatric phenotyping, neuroimaging and molecular analysis in patients with laminin α1 (LAMA1)-associated lamininopathy. We investigated the consequence of mutations in LAMA1 using patient-derived fibroblasts and neuronal cells derived from neuronal stem cells. RESULTS: In this paper we describe individuals with biallelic mutations in LAMA1, all of whom had the cerebellar dysplasia, myopia and retinal dystrophy, in addition to obsessive compulsive traits, tics and anxiety. Patient-derived fibroblasts have impaired adhesion, reduced migration, abnormal morphology and increased apoptosis due to impaired activation of Cdc42, a member of the Rho family of GTPases that is involved in cytoskeletal dynamics. LAMA1 knockdown in human neuronal cells also showed abnormal morphology and filopodia formation, supporting the importance of LAMA1 in neuronal migration, and marking these cells potentially useful tools for disease modelling and therapeutic target discovery. CONCLUSION: This paper broadens the phenotypes associated with LAMA1 mutations. We demonstrate that LAMA1 deficiency can lead to alteration in cytoskeletal dynamics, which may invariably lead to alteration in dendrite growth and axonal formation. Estimation of disease prevalence based on population studies in LAMA1 reveals a prevalence of 1-20 in 1 000 000. TRIAL REGISTRATION NUMBER: NCT00068224.

Executive Function and Adaptive Behavior in Muenke Syndrome.

OBJECTIVE: To investigate executive function and adaptive behavior in individuals with Muenke syndrome using validated instruments with a normative population and unaffected siblings as controls. STUDY DESIGN: Participants in this cross-sectional study included individuals with Muenke syndrome (P250R mutation in FGFR3) and their mutation-negative siblings. Participants completed validated assessments of executive functioning (Behavior Rating Inventory of Executive Function [BRIEF]) and adaptive behavior skills (Adaptive Behavior Assessment System, Second Edition [ABAS-II]). RESULTS: Forty-four with a positive FGFR3 mutation, median age 9 years, range 7 months to 52 years were enrolled. In addition, 10 unaffected siblings served as controls (5 males, 5 females; median age, 13 years; range, 3-18 years). For the General Executive Composite scale of the BRIEF, 32.1% of the cohort had scores greater than +1.5 SD, signifying potential clinical significance. For the General Adaptive Composite of the ABAS-II, 28.2% of affected individuals scored in the 3rd-8th percentile of the normative population, and 56.4% were below the average category (<25th percentile). Multiple regression analysis did not identify craniosynostosis as a predictor of BRIEF (P = .70) or ABAS-II scores (P = .70). In the sibling pair analysis, affected siblings performed significantly poorer on the BRIEF General Executive Composite and the ABAS-II General Adaptive Composite. CONCLUSION: Individuals with Muenke syndrome are at an increased risk for developing adaptive and executive function behavioral changes compared with a normative population and unaffected siblings.

Cognitive, sensory, and psychosocial characteristics in patients with Bardet-Biedl syndrome.

Forty-two patients with a clinical diagnosis of Bardet-Biedl syndrome ages 2-61 years were given a neuropsychological test battery to evaluate cognitive, sensory, and behavioral functioning. These tests included the Wechsler scales of intelligence, Rey Auditory Verbal Learning Test, Boston Naming Test, D-KEFS Verbal Fluency Test, D-KEFS Color-Word Interference Test, D-KEFS Sorting Test, Wide Range Achievement Test: Math and Reading Subtests, Purdue Pegboard, The University of Pennsylvania Smell Identification Test, Social Communication Questionnaire, Social Responsiveness Scale, and Behavior Assessment System for Children, Second Edition, Parent Rating Scale. On the age appropriate Wechsler scale, the mean Verbal Comprehension was 81 (n = 36), Working Memory was 81 (n = 36), Perceptual Reasoning was 78 (n = 24) and Full Scale IQ was 75 (n = 26). Memory for a word list (Rey Auditory Verbal Learning Test) was in the average range with a mean of 89 (n = 19). Fine motor speed was slow on the Purdue with mean scores 3-4 standard deviations below norms. All subjects were microsmic on the University of Pennsylvania Smell Identification Test. Of these 42 patients, only 6 were able to complete all auditory and visual tests; 52% were unable to complete the visual tests due to impaired vision. A wide range of behavioral issues were endorsed on questionnaires given to parents. Most had social skill deficits but no pattern of either externalizing or internalizing problems. We identify a characteristic neuro-behavioral profile in our cohort comprised of reduced IQ, impaired fine-motor function, and decreased olfaction.

Neurocognitive phenotype of isolated methylmalonic acidemia.

OBJECTIVE: Methylmalonic acidemia (MMA) is a metabolic disorder with a poorly defined long-term neurocognitive phenotype. We studied the neuropsychological outcomes of patients and examined clinical covariates that influenced cognition. METHODS: A diverse cohort with mut, cblA, or cblB subtypes of isolated MMA (N = 43), ages 2 to 32 years, were evaluated at a single center over a 6-year period. The influence of clinical, laboratory, and metabolic parameters on neuropsychological testing results was determined. RESULTS: Early-onset mut patients (n = 21) manifested the most severe neurocognitive impairments, with a mean ± SD full-scale IQ (FSIQ) of 71.1 ± 14.75. Late-onset mut patients (n = 6) had a mean FSIQ of 88.5 ± 27.62. cblA (n = 7), cblB (n = 6), and mut patients diagnosed prenatally or by newborn screening (n = 3) obtained mean FSIQs in the average range (100.7 ± 10.95, 96.6 ± 10.92, and 106.7 ± 6.66, respectively). Hyperammonemia at diagnosis and the presence of a seizure disorder were associated with a lower FSIQ (P = .001 and P = .041, respectively), but other clinical variables, including basal ganglia injury and mutation status, did not. FSIQ remained stable over longitudinal testing (n = 10). Decreased scores on processing speed, compared with all other intellectual domains, emerged as a specific neurocognitive manifestation. CONCLUSIONS: The neurocognitive outcomes seen in isolated MMA are highly variable. An earlier age of disease onset, the presence of hyperammonemia at diagnosis, and a history of seizures were associated with more severe impairment. In all patient subtypes, selective deficits in processing speed were present.

Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes.

OBJECTIVE: Blocking interleukin-1 with anakinra in patients with the autoinflammatory syndrome neonatal-onset multisystem inflammatory disease (NOMID) reduces systemic and organ-specific inflammation. However, the impact of long-term treatment has not been established. This study was undertaken to evaluate the long-term effect of anakinra on clinical and laboratory outcomes and safety in patients with NOMID. METHODS: We conducted a cohort study of 26 NOMID patients ages 0.80-42.17 years who were followed up at the NIH and treated with anakinra 1-5 mg/kg/day for at least 36 months. Disease activity was assessed using daily diaries, questionnaires, and C-reactive protein level. Central nervous system (CNS) inflammation, hearing, vision, and safety were evaluated. RESULTS: Sustained improvements in diary scores, parent's/patient's and physician's global scores of disease activity, parent's/patient's pain scores, and inflammatory markers were observed (all P<0.001 at 36 and 60 months). At 36 and 60 months, CNS inflammation was suppressed, with decreased cerebrospinal fluid white blood cell counts (P=0.0026 and P=0.0076, respectively), albumin levels, and opening pressures (P=0.0012 and P<0.001, respectively). Most patients showed stable or improved hearing. Cochlear enhancement on magnetic resonance imaging correlated with continued hearing loss. Visual acuity and peripheral vision were stable. Low optic nerve size correlated with poor visual field. Bony lesions progressed. Adverse events other than viral infections were rare, and all patients continued to receive the medication. CONCLUSION: These findings indicate that anakinra provides sustained efficacy in the treatment of NOMID for up to 5 years, with the requirement of dose escalation. Damage progression in the CNS, ear, and eye, but not bone, is preventable. Anakinra is well tolerated overall.

Serotonin 1A receptors, depression, and memory in temporal lobe epilepsy.

PURPOSE: Memory deficits and depression are common in patients with temporal lobe epilepsy (TLE). Previous positron emission tomography (PET) studies have shown reduced mesial temporal 5HT1A-receptor binding in these patients. We examined the relationships among verbal memory performance, depression, and 5HT1A-receptor binding measured with 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl) cyclohexane carboxamide (18FCWAY) PET in a cross-sectional study. METHODS: We studied 40 patients (24 male; mean age 34.5 ± 10.7 years) with TLE. Seizure diagnosis and focus localization were based on ictal video-electroencephalography (EEG) recording. Patients had neuropsychological testing with Wechsler Adult Intelligence Score III (WAIS III) and Wechsler Memory Score III (WMS III) on stable antiepileptic drug (AED) regimens at least 24 h since the last seizure. Beck Depression Inventory (BDI) scores were obtained. We performed interictal PET with 18FCWAY, a fluorinated derivative of WAY 100635, a highly specific 5HT1A ligand, and structural magnetic resonance imaging (MRI) scans to estimate partial volume and plasma free fraction corrected 18FCWAY volume of distribution (V/f1). KEY FINDINGS: Hippocampal V/f1 was significantly lower in area ipsilateral than contralateral to the epileptic focus (73.7 ± 27.3 vs. 95.4 ± 28.4; p < 0.001). We found a significant relation between both left hippocampal 18FCWAY V/f1 (r = 0.41; p < 0.02) and left hippocampal volume (r = 0.36; p < 0.03) and delayed auditory memory score. On multiple regression, there was a significant effect of the interaction of left hippocampal 18FCWAY V/f1 and left hippocampal volume on delayed auditory memory, but not of either alone. High collinearity was present. In an analysis of variance including the side of the seizure focus, the effect of left hippocampal 18FCWAY V/f1 but not focus laterality retained significance. Mean BDI was 8.3 ± 7.0. There was a significant inverse relation between BDI and 18FCWAY V/f1 ipsilateral to the patient's epileptic focus (r = 0.38 p < 0.02). There was no difference between patients with a right or left temporal focus. There was no relation between BDI and immediate or delayed auditory memory. SIGNIFICANCE: Our study suggests that reduced left hippocampal 5HT1A-receptor binding may play a role in memory impairment in patients with TLE.

The saccadic and neurological deficits in type 3 Gaucher disease.

UNLABELLED: Our objective was to characterize the saccadic eye movements in patients with type 3 Gaucher disease (chronic neuronopathic) in relationship to neurological and neurophysiological abnormalities. For approximately 4 years, we prospectively followed a cohort of 15 patients with Gaucher type 3, ages 8-28 years, by measuring saccadic eye movements using the scleral search coil method. We found that patients with type 3 Gaucher disease had a significantly higher regression slope of duration vs amplitude and peak duration vs amplitude compared to healthy controls for both horizontal and vertical saccades. Saccadic latency was significantly increased for horizontal saccades only. Downward saccades were more affected than upward saccades. Saccade abnormalities increased over time in some patients reflecting the slowly progressive nature of the disease. Phase plane plots showed individually characteristic patterns of abnormal saccade trajectories. Oculo-manual dexterity scores on the Purdue Pegboard test were low in virtually all patients, even in those with normal cognitive function. Vertical saccade peak duration vs amplitude slope significantly correlated with IQ and with the performance on the Purdue Pegboard but not with the brainstem and somatosensory evoked potentials. We conclude that, in patients with Gaucher disease type 3, saccadic eye movements and oculo-manual dexterity are representative neurological functions for longitudinal studies and can probably be used as endpoints for therapeutic clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00001289.

Unrelated umbilical cord blood transplant for juvenile metachromatic leukodystrophy: a 5-year follow-up in three affected siblings.

Unrelated umbilical cord blood transplantation (UCBT) was used to treat three siblings with juvenile metachromatic leukodystrophy (jMLD). The efficacy of this therapy was measured over a 5-year period with serial neurological examinations, neuroimaging, nerve conduction studies (NCS), and neuropsychological evaluations (NPE). Outcomes were a function of disease stage at time of UCBT with alteration of disease course occurring in the first 2 years after UCBT and then subsequent halting of progression and stabilization of symptoms and disease.

Cortical mapping and frameless stereotactic navigation in the high-field intraoperative magnetic resonance imaging suite.

Frameless stereotactic neuronavigation provides tracking of surgical instruments on radiographic images and orients the surgeon to tumor margins at surgery. Bipolar electrical stimulation mapping (ESM) delineates safe limits for resection of brain tumors adjacent to eloquent cortex. These standard techniques could complement the capability of intraoperative MR (iMR) imaging to evaluate for occult residual disease during surgery and promote more complete tumor removal. The use of frameless neuronavigation in the high-field iMR imaging suite requires that a few pieces of standard equipment be replaced by nonferromagnetic instruments. Specific use of ESM in a high-field iMR imaging suite has not been reported in the literature. To study whether frameless neuronavigation and electrical stimulation mapping could be successfully integrated in the high-field iMR imaging suite, the authors employed these modalities in 10 consecutive cases involving patients undergoing conscious craniotomy for primary brain tumors located in or adjacent to eloquent cortices. Equipment included a custom high-field MR imaging-compatible head holder and dynamic reference frame attachment, a standard MR imaging-compatible dynamic reference frame, a standard MR imaging machine with a table top that could be translated to a pedestal outside the 5-gauss line for the operative intervention, and standard neuronavigational and cortical stimulation equipment. Both ESM and frameless stereotactic guidance were performed outside the 5-gauss line. The presence of residual neoplasm was evaluated using iMR imaging; resection was continued until eloquent areas were encountered or iMR imaging confirmed complete removal of any residual tumor. Mapping identified essential language (5 patients), sensory (6), and motor (7) areas. The combined use of frameless stereotactic navigation, ESM, and iMR imaging resulted in complete radiographic resection in 7 cases and resection to an eloquent margin in 3 cases. Postoperative MR imaging confirmed final iMR imaging findings. No patient experienced a permanent new neurological deficit. Familiar techniques such as frameless navigation and ESM can be rapidly, inexpensively, safely, and effectively integrated into the high-field iMR imaging suite.

Quality of life in children and adolescents 1-year after cure of Cushing syndrome: a prospective study.

OBJECTIVE: Cushing syndrome (CS) in children is associated with symptoms that may impair health related quality of life (HRQL). There are no prospective reports of HRQL in children with CS. METHODS: Prospective study of 40 children (mean age 13 +/- 3.2 years) with CS evaluated prior to and 1-year post-treatment. The Child Health Questionnaire (CHQ) was used to assess HRQL; Wechsler Intelligence Scale for Children (WASI) was used to assess cognitive function, and patient-reported symptoms were assessed with a CS symptom checklist. RESULTS: Active CS was associated with low physical and psychosocial summary scores compared to US population data (P < 0.001). Despite improvement from pre- to 1-year postcure, residual impairment remained in physical summary and function, and role-physical, global health and emotional impact (parent) scores. Incomplete recovery of adrenal function at 1-year post-treatment was associated with impaired scores. WASI IQ scores declined and a correlation was noted between age at first evaluation and IQ score changes. Most self-reported CS symptoms showed improvement, but forgetfulness, unclear thinking and decreased attention span did not improve after cure of CS. CONCLUSION: CS in children and adolescents is associated with impaired HRQL, with residual impairment 1 year after cure. Our results also suggest that younger children are more likely to experience negative changes in cognitive function. HRQL is an important outcome measure in children and adolescents with CS and identification of factors that contribute to HRQL may help to diminish the physical and psychological burden of disease in this population of patients.

Cognitive outcome in treated patients with chronic neuronopathic Gaucher disease.

OBJECTIVE: To investigate the spectrum and prevalence of cognitive deficits among children with type 3 (chronic neuronopathic) Gaucher disease (GD). STUDY DESIGN: A case review study identified 32 children (male/female; 17:15) with type 3 GD who had received enzyme replacement therapy (ERT) or a bone marrow transplant. The diagnosis of GD was established by enzymatic assay and DNA testing. Subjects were assessed with standard neuropsychological testing, and data from the most recent evaluation were included. RESULTS: Neuropsychometric assessments demonstrated a wide spectrum of full-scale IQ scores ranging from 39 to 124 (mean 75). About 60% of subjects had intellectual skills below average. There were significant discrepancies between verbal and performance IQ, with a range between -6 and 38 points (P = .02). This gap was more prominent in older subjects, with better performance in the verbal areas. No correlation was observed between intelligence measures and genotype or the extent of systemic involvement. The dosage, age at initiation, and the length of ERT had no significant effect on IQ scores. CONCLUSIONS: In type 3 GD, cognitive deficits, characterized by visual-spatial dysfunction, are common but underappreciated and appear resistant to ERT.

Neuropsychological functioning in adolescent children of mothers with a history of bipolar or major depressive disorders.

BACKGROUND: Growing evidence demonstrates an association of neuropsychological deficits with mood disorders, but it is not yet clear whether these deficits are risk factors or are concomitant with the symptoms. This study examines the neuropsychological functioning of a group of adolescent offspring who are at risk for a mood disorder by virtue of being raised by mothers who have been diagnosed with major depressive disorder (MDD) or bipolar disorder (BPD). METHODS: Adolescent offspring of mothers with BPD (n = 43) or MDD (n = 72) and of psychiatrically well parents (n = 50) completed a battery of neuropsychological tests to assess executive functioning, memory, and attention. RESULTS: Children of mothers with BPD showed deficits in executive functioning and selective deficits in spatial memory and attention, in comparison with children of well mothers. Deficits were not found for children of MDD mothers. CONCLUSIONS: Knowledge of these neurocognitive processes could aid ultimately in determining whether neurocognitive deficits precede BPD, whether unique profiles are associated with various types of mood disorders, and who may benefit from interventions.

A prospective high-risk study of the association among maternal negativity, apparent frontal lobe dysfunction, and the development of bipolar disorder.

In a previous paper, the authors found that impairment on the Wisconsin Card Sorting Test (WCST) in adolescence was predictive of bipolar disorder in young adulthood among offspring of mothers with bipolar illness. In the present study, the authors explore the contribution of maternal characteristics, beyond maternal mood disorder, to the prediction of offspring dysfunction on the WCST. Results showed that maternal bipolar disorder and maternal negativity were both predictive of impaired performance on the WCST during adolescence. The contribution of maternal negativity to offspring WCST impairment was not better explained by maternal personality disorder, mother's functional impairment, family loading for bipolar disorder, or offspring disruptive behavioral disturbance. Findings did not support a moderator model. However, support was found for a mediation model in which maternal negativity contributed to risk for offspring bipolar disorder through its negative association with apparent frontal lobe functioning, as measured by the WCST. Findings are discussed from the perspective of a vulnerability-stress model. In addition, the authors consider the possibility that maternal negativity and offspring impairment on the WCST may be reflective of a common heritable trait.

A prospective study of the association among impaired executive functioning, childhood attentional problems, and the development of bipolar disorder.

Studies of adults who have been diagnosed with, and treated for, bipolar disorder have shown that these patients exhibit impairment on measures of executive functioning. However, it is unclear whether executive dysfunction precedes the diagnosis of bipolar illness, or develops subsequent to its onset. Moreover, investigators have failed to control for the effects of premorbid attentional problems on cognitive performance in these patients. The present authors explored these questions using data from a longitudinal prospective study of individuals at risk for major mood disorder. Results revealed that 67% of participants who met criteria for bipolar disorder in young adulthood showed impairment on the Wisconsin Card Sorting Test (WCST) when they were assessed during adolescence, as compared with 17% of individuals with no major mood diagnosis, and 19% with unipolar depression. This association between performance on the WCST and bipolar illness was not accounted for by high rates of premorbid attentional disturbance. In fact, among participants with early attentional problems, only those who ultimately developed bipolar disorder exhibited impairment on the WCST. Early attentional problems that preceded unipolar depression or no mood disorder were not associated with executive dysfunction.

Cognitive function in patients with chronic granulomatous disease: a preliminary report.

Chronic granulomatous disease is an inherited immunodeficiency in which phagocytes fail to generate superoxide and its metabolites, resulting in severe recurrent infections and frequent hospitalizations. Chronic illness and frequent hospitalizations can affect growth and development as well as social and educational opportunities. Since no data have been reported on cognitive functioning in patients with this illness, the authors sought to examine cognitive function in a group of patients with chronic granulomatous disease. A retrospective chart review of 26 patients seen and followed at the National Institutes of Health who had received cognitive testing at the request of parent or staff was performed. Demographic information including medical, psychiatric, and developmental histories was gathered. Six patients (23%) were found to have an IQ of 70 or below, indicative of cognitive deficits, and all of those patients had defects in the membrane-linked cytochrome b558. The prevalence of cognitive deficits in this selected population of chronic granulomatous disease patients was high. The determination of the true distribution of cognitive functioning in the general chronic granulomatous disease population is important, since cognitive deficits have implications for educational planning and potential therapies such as transplantation and gene therapy in children.

Gonadal mosaicism in severe Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS, MIM #146510) is characterized by central and postaxial polydactyly, hypothalamic hamartoma (HH), bifid epiglottis, imperforate anus, renal abnormalities, and pulmonary segmentation anomalies. It is inherited in an autosomal dominant pattern. Here, we describe a family with two affected children manifesting severe PHS with mental retardation, behavioral problems, and intractable seizures. Both parents are healthy, with normal intelligence, and have no malformations on physical, laryngoscopic, and cranial MRI exam. The atypical presentation of these children and the absence of parental manifestations suggested an autosomal recessive mode of inheritance or gonadal mosaicism. Sequencing of GLI3 revealed a two nucleotide deletion in exon 15 (c.3385_3386delTT) predicting a frameshift and premature stop at codon 1129 (p.F1129X) in the children while both parents have wild type alleles. Genotyping with GLI3 intragenic markers revealed that both children inherited the abnormal allele from their mother thus supporting gonadal mosaicism as the underlying mechanism of inheritance (paternity was confirmed). This is the first reported case of gonadal mosaicism in PHS. The severe CNS manifestations of these children are reminiscent of children with non-syndromic HH who often have progressive mental retardation with behavioral problems and intractable seizures. We conclude that the phenotypic spectrum of PHS can include severe CNS manifestations and that recurrence risks for PHS should include a proviso for gonadal mosaicism, though the frequency cannot be calculated from a single case report. Published 2003 Wiley-Liss, Inc.