Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria.

Argininosuccinate lyase (ASL) is required for the synthesis and channeling of L-arginine to nitric oxide synthase (NOS) for nitric oxide (NO) production. Congenital ASL deficiency causes argininosuccinic aciduria (ASA), the second most common urea-cycle disorder, and leads to deficiency of both ureagenesis and NO production. Subjects with ASA have been reported to develop long-term complications such as hypertension and neurocognitive deficits despite early initiation of therapy and the absence of documented hyperammonemia. In order to distinguish the relative contributions of the hepatic urea-cycle defect from those of the NO deficiency to the phenotype, we performed liver-directed gene therapy in a mouse model of ASA. Whereas the gene therapy corrected the ureagenesis defect, the systemic hypertension in mice could be corrected by treatment with an exogenous NO source. In an ASA subject with severe hypertension refractory to antihypertensive medications, monotherapy with NO supplements resulted in the long-term control of hypertension and a decrease in cardiac hypertrophy. In addition, the NO therapy was associated with an improvement in some neuropsychological parameters pertaining to verbal memory and nonverbal problem solving. Our data show that ASA, in addition to being a classical urea-cycle disorder, is also a model of congenital human NO deficiency and that ASA subjects could potentially benefit from NO supplementation. Hence, NO supplementation should be investigated for the long-term treatment of this condition.

Developmental assessment of infants with biliary atresia: differences between boys and girls.

OBJECTIVE: The aim of the present study was to investigate whether male and female infants with biliary atresia (BA) differ cognitively and to confirm previously documented developmental lags in infants with BA before liver transplantation. METHODS: With the Mullen Scales of Early Learning, we examined 21 female and 12 male infants (ages 3-20 months) with BA, comparing scores across indices by sex and correlating Mullen Scales of Early Learning scores with standard clinical and biochemical parameters. RESULTS: Overall, both boys and girls were found to be vulnerable to developmental lags in the areas of expressive language (EL) and gross motor skills. In comparison with their male peers, girls were found to be weaker in the area of visual reception skills (P=0.05) with a trend found for EL (P=0.08). Girls were also found to have higher C-bilirubin levels and to be of shorter length. Growth parameters were found to be correlated with EL scores. International normalized ratio was found to be correlated with gross motor performance and with a trend also noted for fine motor skills. Age at Kasai predicted receptive language skills. CONCLUSIONS: As has been shown, infants with BA appear to be vulnerable to developmental lags before transplantation. In particular, female infants appear to be vulnerable to cognitive and skill delays in comparison with their male peers. C-bilirubin levels may play a role in this increased vulnerability for females.

Language and motor skills are impaired in infants with biliary atresia before transplantation.

OBJECTIVE: To test the hypothesis that in very young patients with biliary atresia, cognitive deficits are apparent before transplantation. STUDY DESIGN: With the Mullen Scales of Early Learning (Mullen), we examined 15 infants (mean age, 7.8 months) with biliary atresia, correlating Mullen scores with standard clinical and biochemical parameters. RESULTS: Overall, participants displayed significant delays in gross motor and language skills, and fine motor and visual reasoning skills were relatively preserved. The international normalized ratio correlated inversely with gross (P < .01) and fine (P < .05) motor skills. Growth parameters correlated positively with expressive language ability, but length of hospitalization and mode of feeding did not. Age at performance of the Kasai procedure was found to correlate with receptive language performance (P < .05). CONCLUSIONS: Very young children with biliary atresia display a characteristic profile of early developmental deficits before transplantation. These findings suggest that early intervention and aggressive nutritional management should be the standard of care to minimize neurocognitive effects.

Neurocognitive functioning of a child with partial trisomy 6 and monosomy 21.

This case study describes the neurocognitive presentation of a child with identified genetic abnormalities of trisomy 6 and monosomy 21 who was evaluated as part of a standard medical protocol for cochlear implantation following diagnosis of profound sensorineural hearing loss. This child received neurocognitive testing prior to cochlear implantation and approximately 12 months post-activation of his cochlear implant. While he has not fully developed oral language, his presentation suggested improvement in overall skills since the activation of the cochlear implant; however, less than would be expected for a typically developing child.

Neurodevelopmental functioning in children being evaluated for heart transplant prior to 2 years of age.

Cardiac defects represent the most common type of birth defect and children with these abnormalities are known to experience a variety of developmental and neuropsychological delays. Children receiving heart transplants may be at the highest risk for delays as they tend to represent the most severely ill patients with heart disease. This study investigates neurocognitive and adaptive functioning in 20 children under 2 years of age who were undergoing evaluation for heart transplant, comparing their performance to that of normative samples. The results indicate delays across various domains of neurocognition, including general cognitive, receptive language, expressive language, fine motor, and gross motor skills. In addition, adaptive and social-emotional functioning fell significantly below that of normative samples. No significant differences were found when comparing the test performance of patients with congenital heart defects (n = 12) to patients with cardiomyopathy (n = 8). Secondary analyses investigating the impact of genetic conditions, premature birth, and non-English language dominance showed minor changes in results across some domains, although this may have been due, at least in part, to decreased power to detect differences. Overall, this study's results support the need for early evaluation, intensive intervention (e.g., speech, occupational, and physical therapy), and continued monitoring of these patients' neurodevelopmental/neuropsychological functioning over time. Future research should examine longitudinal changes in development using both pre- and post-transplant data and should investigate the impact of early intervention.

Cognition in children with sensorineural hearing loss: etiologic considerations.

OBJECTIVES: A considerable amount of literature has documented the impact of hearing impairment on spoken language skills in deaf children referred for cochlear implantation. Critical areas of neurocognitive development in the acquisition of visual (manual) language also appear to be impacted, although the evidence is less robust. The present study focused on the development of visual and fine motor skills in a sample of preschool-age children diagnosed with sensorineural hearing loss with no known neurologic conditions (n=36). STUDY DESIGN: Analysis of data collected as part of a standardized screening process for cochlear implantation at an academic medical center. METHOD: Children underwent a standardized neuropsychological assessment battery. Children were classified into three groups based on the etiology of their deafness (Connexin=15, Structural Malformation=11, and Unknown=10). RESULTS/CONCLUSIONS: Correlational analyses replicated previous research on the reduction in visual reception and fine motor skills as deaf children age. Children with genetic (Connexin) etiology exhibited a significant reduction in fine motor skills with age, whereas those with an etiology of Structural Abnormality exhibited a significant reduction in visual reception skills with age. Results of planned comparisons conducted as part of a multivariate analysis of variance (Skill x Group) indicated that the Connexin group was significantly better than the Unknown group with regard to fine motor skills. Implications for these findings and future studies are discussed.

Neuropsychological functioning in preschool-aged children undergoing evaluation for organ transplant.

OBJECTIVE: The purpose of this study was to review the current literature on neuropsychological functioning in two groups of children requiring organ transplants (liver or heart) and present recent clinical data collected through the liver and cardiac transplantation programs at a large pediatric academic medical center. METHOD: Data included in this study came from 18 patients who completed evaluations for heart transplant (n = 8) or liver transplant (n = 10) between the ages of 2 and 6 years (inclusive). Measures examining neurocognitive, emotional-behavioral, and adaptive functioning were collected as part of standard pre-transplant clinical neuropsychological evaluations. Within each organ group, mean scores were calculated and compared with normative population mean scores using one sample t-tests. In addition, non-parametric binomial tests were calculated to examine whether the proportion of individuals falling more than one standard deviation below the population mean was significantly greater in the patient groups than the normative population base rate of 16%. RESULTS: Patients in both groups performed below normative expectation in several neurocognitive and adaptive domains. However, neither group showed significant difficulties in behavioral or emotional regulation. CONCLUSIONS: Results from this study document cognitive delays in preschool-aged children undergoing evaluations for liver transplant or heart transplant, highlighting the importance of intervention and long-term monitoring of these two patient populations, as well as the need for neuropsychologist involvement with transplant teams.

Nonverbal cognitive development in children with cochlear implants: relationship between the Mullen Scales of Early Learning and later performance on the Leiter International Performance Scales-Revised.

Methodologically, longitudinal assessment of cognitive development in young children has proven difficult because few measures span infancy through school age. This matter is further complicated when the child presents with a sensory deficit such as hearing loss. Few measures are validated in this population, and children who are evaluated for cochlear implantation are often reevaluated annually. The authors sought to evaluate the predictive validity of subscales of the Mullen Scales of Early Learning (MSEL) on Leiter International Performance Scales-Revised (LIPS-R) Full-Scale IQ scores. To further elucidate the relationship of these two measures, comparisons were also made with the Vineland Adaptive Behavior Scale-Second Edition (VABS), which provides a measure of adaptive functioning across the life span. Participants included 35 children (14 female, 21 male) who were evaluated both as part of the precandidacy process for cochlear implantation using the MSEL and VABS and following implantation with the LIPS-R and VABS. Hierarchical linear regression revealed that the MSEL Visual Reception subdomain score significantly predicted 52% of the variance in LIPS-R Full-Scale IQ scores at follow-up, F(1, 34) = 35.80, p < .0001, R (2) = .52, ß = .72. This result suggests that the Visual Reception subscale offers predictive validity of later LIPS-R Full-Scale IQ scores. The VABS was also significantly correlated with cognitive variables at each time point.

Cognitive outcomes and familial stress after cochlear implantation in deaf children with and without developmental delays.

OBJECTIVE: The benefits of cochlear implantation for children with developmental delays (DD) often are unclear. We compared cognition, adaptive behavior, familial stress, and communication in children with and without DD. STUDY DESIGN: Retrospective review. SETTING: Two tertiary care pediatric hospitals. PATIENTS: Two hundred four children who underwent cochlear implantation assessed before and more than 1 year after implantation. MAIN OUTCOME MEASURES: The Mullen Scales of Early Learning (MSEL), vineland adaptive behavior scales (VABS), Parental Stress Index, and Preschool Language Scale. RESULTS: We developed a specific definition of DD for hearing-impaired children based upon diagnostic and statistical manual of mental disorders, fourth edition, criteria for mental retardation; 60 children met the criteria for DD, and 144 children did not. Before implantation, multiple linear regression demonstrated that children with DD had lower scores in every domain of the MSEL and VABS (p < 0.05), but no differences in any domains of the parental stress index and preschool language scale (p > 0.1) compared with children without DD. After implantation, children without DD demonstrated significant improvements in intelligence as measured by the MSEL and age-appropriate improvements in adaptive behavior as evaluated by the VABS, and their familial stress levels were not increased after cochlear implantation. In contrast, children with DD underwent implantation at a later age and demonstrated less comprehensive developmental improvements after cochlear implantation and higher stress levels. However, when the age differences were taken into account using multiple linear regression analyses, the differences between the 2 cohorts were reduced. CONCLUSION: These data indicate that our definition of DD is a reliable method of stratifying deaf children. Although children with DD have a normal developmental rate of adaptive behavior after cochlear implantation, their developmental rate of intelligence is lower, and they have higher stress levels than children without DD. However, our data suggest that if children with DD could be implanted as early as children without DD, their intelligence and stress outcomes would be improved.

Intelligence, parental depression, and behavior adaptability in deaf children being considered for cochlear implantation.

Cognitive ability and behavioral adaptability are distinct, yet related, constructs that can impact childhood development. Both are often reduced in deaf children of hearing parents who do not provide sufficient language and communication access. Additionally, parental depression is commonly observed due to parent-child communication difficulties that can lead to parents' feelings of inadequacy and frustration. We sought to assess whether adaptive behavior in deaf children was associated with nonverbal intelligence and parental depression. Parents of precochlear implant patients seen for neuropsychological assessment were administered the Parenting Stress Index and Vineland Behavior Adaptive Scales to obtain measures of parental distress and child's behavioral adaptability. Precochlear implant patients' cognitive functioning was assessed via the Mullen Scales of Early Learning or the Leiter International Performance Scale-Revised, depending on the child's age at the time of testing. Regardless of age or neurological status, the deaf child's adaptive behavior consistently showed a strong relationship with intelligence. Moderate correlation between parental depression and the child's adaptive behavior was observed only in the younger group. The relationship between parental depression and communication subscale was moderated by intelligence for deaf children without neurological complications. The findings provide important implications for promoting family-centered interventions with early communication and language development.