Risk factors for preoperative periventricular leukomalacia in term neonates with hypoplastic left heart syndrome are patient related.

BACKGROUND: Preoperative brain injury is common in neonates with complex congenital heart disease. Increasing evidence suggests a complex interaction of prenatal and postnatal risk factors for development of brain white matter injury, called periventricular leukomalacia (PVL), in neonates with complex congenital heart disease. To date, there remains a limited understanding of the risk factors contributing to preoperative PVL in hypoplastic left heart syndrome (HLHS). METHODS: Neonates with HLHS or HLHS variants from 3 prospective magnetic resonance imaging studies (2003-2010) were selected for this cohort. Preoperative brain magnetic resonance imaging was performed the morning of the surgery. Stepwise multilogistic regression of patient characteristics, mode of delivery (cesarean section vs vaginal), time of diagnosis (prenatal vs postnatal), HLHS subtypes, brain total maturation score, time to surgery, individual averaged daily preoperative blood gases, and complete blood cell count values was used to determine significant associations. RESULTS: A total of 57 neonates with HLHS were born at 38.7 ± 2.3 weeks; 86% (49/57) had a prenatal diagnosis, with 31% (18/57) delivered by cesarean section. HLHS with aortic atresia (AA) was common in this cohort, 71% (41/57). Preoperative PVL was identified in 19% (11/57). Male patients with AA (P = .004) were at higher risk for PVL. Lower total brain maturation score was also identified as a strong predictor for preoperative PVL (P = .005). CONCLUSIONS: In neonates with HLHS, nonmodifiable patient-related factors, including male sex with AA (lack of antegrade blood flow) and lower total brain maturation score, placed neonates at the greatest risk for preoperative white matter injury.

Long-term follow-up after gene therapy for canavan disease.

Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 10(11) vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.

Plasma biomarkers associated with the apolipoprotein E genotype and Alzheimer disease.

BACKGROUND: A blood-based test that could be used as a screen for Alzheimer disease (AD) may enable early intervention and better access to treatment. OBJECTIVE: To apply a multiplex immunoassay panel to identify plasma biomarkers of AD using plasma samples from the Alzheimer's Disease Neuroimaging Initiative cohort. DESIGN: Cohort study. SETTING: The Biomarkers Consortium Alzheimer's Disease Plasma Proteomics Project. PARTICIPANTS: Plasma samples at baseline and at 1 year were analyzed from 396 (345 at 1 year) patients with mild cognitive impairment, 112 (97 at 1 year) patients with AD, and 58 (54 at 1 year) healthy control subjects. MAIN OUTCOME MEASURES: Multivariate and univariate statistical analyses were used to examine differences across diagnostic groups and relative to the apolipoprotein E (ApoE) genotype. RESULTS: Increased levels of eotaxin 3, pancreatic polypeptide, and N-terminal protein B-type brain natriuretic peptide were observed in patients, confirming similar changes reported in cerebrospinal fluid samples of patients with AD and MCI. Increases in tenascin C levels and decreases in IgM and ApoE levels were also observed. All participants with Apo ε3/ε4 or ε4/ε4 alleles showed a distinct biochemical profile characterized by low C-reactive protein and ApoE levels and by high cortisol, interleukin 13, apolipoprotein B, and gamma interferon levels. The use of plasma biomarkers improved specificity in differentiating patients with AD from controls, and ApoE plasma levels were lowest in patients whose mild cognitive impairment had progressed to dementia. CONCLUSIONS: Plasma biomarker results confirm cerebrospinal fluid studies reporting increased levels of pancreatic polypeptide and N-terminal protein B-type brain natriuretic peptide in patients with AD and mild cognitive impairment. Incorporation of plasma biomarkers yielded high sensitivity with improved specificity, supporting their usefulness as a screening tool. The ApoE genotype was associated with a unique biochemical profile irrespective of diagnosis, highlighting the importance of genotype on blood protein profiles.

Phase measurement of cognitive impairment specific to radiotherapy.

PURPOSE: Memory impairment is an early-delayed effect of radiotherapy (RT). The prospective longitudinal measurement of the cognitive phase effects from RT was conducted on treated and untreated brain tumor patients. The study design investigated semantic vs. perceptual and visual vs. verbal memory to determine the most disease-specific measure of RT-related changes and understanding of the neurotoxicity from RT to the brain. METHODS AND MATERIALS: Tests of memory that had previously shown RT-related phasic changes were compared with experimental tests of memory to test hypotheses about cognition targeted to the neural toxicity of RT. The results from 41 irradiated and 29 nonirradiated patients with low-grade, supratentorial tumors were analyzed. The methods controlled for comorbid white matter risk, recurrence, interval after treatment, and age (18-69 years). The effects were examined before RT and at three points after RT to 1 year using a mixed effects model that included interval, group, surgical status, medication use, practice, and individual random effects. Four new tests of memory and other candidate cognitive tests were investigated, and a post hoc analysis of a comprehensive battery of tests was performed to identify the cognitive processes most specific to RT. RESULTS: The RT effects on memory were identified in the treated group only; among the new tests of memory and the complete neurocognitive battery, the RT effects were significant only for delayed recall (p < 0.009) and interval to recognize (p < 0.002). Tumor location was not related to the treatment effect. Memory decline was specific to retrieval of semantic memories; a double dissociation of semantic from perceptual visual memory was demonstrated in the RT group. CONCLUSIONS: These results implicate memory dependent on the semantic cortex and the hippocampal memory system. A cognitive measurement that is brief but specific to neural mechanisms is effective and feasible for studies of RT damage.

Adolescent obesity as a risk factor for high-level nicotine addiction in young women.

PURPOSE: Obesity and cigarette smoking are two of the most frequent and preventable causes of disease and death in the United States; both are often established during youth. We hypothesized that obese, adolescent girls would be at higher risk for nicotine addiction in young adulthood, and that particular individual and social factors would mediate this association. METHODS: Students surveyed in the National Longitudinal Study of Adolescent Health (Add Health), a nationally representative school-based and in-home survey conducted in three waves, comprised the sample. More than 4,000 respondents were used for the multivariate linear and logistic regression analyses used to determine the association between obesity and level of nicotine addiction. Potential mediation effects of the association were also examined. RESULTS: Obesity doubled the risk of the highest level of nicotine addiction after controlling for demographic factors, parent and friend smoking, and baseline smoking (OR, 2.12; 95% CI, 1.22-3.68). Family smoking was the strongest predictor of nicotine addiction (OR, 4.72; 95% CI, 2.89-7.72). Grade point average was a partial mediator of this relationship (OR, .48; 95% CI, .32-.74). CONCLUSIONS: Obese, adolescent females are at increased risk for high-level nicotine addiction in young adulthood as compared with their nonobese peers. Grade point average partially mediates the association, and may represent a confluence of factors including increased absenteeism, social marginalization, biases, and lack of confidence in academic ability. Obese, adolescent females may require targeted interventions to address their risk of subsequent high-level nicotine addiction, especially if risk factors such as parental smoking and poor school performance are present.

Brain maturation is delayed in infants with complex congenital heart defects.

OBJECTIVE: Small head circumferences and white matter injury in the form of periventricular leukomalacia have been observed in populations of infants with severe forms of congenital heart defects. This study tests the hypothesis that congenital heart defects delay in utero structural brain development. METHODS: Full-term infants with hypoplastic left heart syndrome or transposition of the great arteries were prospectively evaluated with preoperative brain magnetic resonance imaging. Patients with independent risk factors for abnormal brain development (shock, end-organ injury, or intrauterine growth retardation) were excluded. Outcome measures included head circumferences and the total maturation score on magnetic resonance imaging. Total maturation score is a previously validated semiquantitative anatomic scoring system used to assess whole brain maturity. The total maturation score evaluates 4 parameters of maturity: (1) myelination, (2) cortical infolding, (3) involution of glial cell migration bands, and (4) presence of germinal matrix tissue. RESULTS: The study cohort included 29 neonates with hypoplastic left heart syndrome and 13 neonates with transposition of the great arteries at a mean gestational age of 38.9 +/- 1.1 weeks. Mean head circumference was 1 standard deviation below normal. The mean total maturation score for the cohort was 10.15 +/- 0.94, significantly lower than reported normative data in infants without congenital heart defects, corresponding to a delay of 1 month in structural brain development. CONCLUSION: Before surgery, term infants with hypoplastic left heart syndrome and transposition of the great arteries have brains that are smaller and structurally less mature than expected. This delay in brain development may foster susceptibility to periventricular leukomalacia in the preoperative, intraoperative, and postoperative periods.

Parachute mitral valve: morphologic descriptors, associated lesions, and outcomes after biventricular repair.

OBJECTIVE: In "true" parachute mitral valve, mitral valve chordae insert into one papillary muscle. In parachute-like asymmetric mitral valve, most or all chordal attachments are to one papillary muscle. This study compared morphologic features, associated lesions, and palliation strategies of the two parachute mitral valve and dominant papillary muscle types and examined interventions and midterm outcomes in patients with biventricular circulation. METHODS: Echocardiography and autopsy databases were reviewed to identify patients with "true" parachute mitral valve or parachute-like asymmetric mitral valve from January 1987 to January 2006. Predictors of palliation strategy in the entire cohort, mitral stenosis on initial echocardiogram, and mortality in the biventricular cohort were determined with logistic regression. RESULTS: Eighty-six patients with "true" parachute mitral valve (n = 49) or parachute-like asymmetric mitral valve (n = 37) were identified. Chordal attachments to the posteromedial papillary muscle were more common (73%). The presence "true" parachute mitral valve (P = .008), hypoplastic left ventricle (P < .001), and two or more left-sided obstructive lesions (P = .002) predicted univentricular palliation. Among 49 patients maintaining biventricular circulation at follow-up, 8 died median follow-up 6.4 years (7 days-17.8 years). Multivariate analysis revealed that "true" parachute mitral valve was associated with mitral stenosis on initial echocardiogram (P = .03), and "true" parachute mitral valve (P = .04) and conotruncal anomalies (P = .0003) were associated with mortality. Progressive mitral stenosis was found in 11 patients; 2 underwent mitral valve interventions, and 1 died. CONCLUSION: Nearly two thirds of this parachute mitral valve cohort underwent biventricular palliation. Some progression of mitral stenosis occurred, although mitral valve intervention was rare. "True" parachute mitral valve was associated with mitral stenosis on initial echocardiogram. "True" parachute mitral valve and conotruncal anomalies were associated with mortality in the biventricular population.

Preoperative brain injury in transposition of the great arteries is associated with oxygenation and time to surgery, not balloon atrial septostomy.

BACKGROUND: Preoperative brain injury is an increasingly recognized phenomenon in neonates with complex congenital heart disease. Recently, reports have been published that associate preoperative brain injury in neonates with transposition of the great arteries with the performance of balloon atrial septostomy (BAS), a procedure that improves systemic oxygenation preoperatively. It is unclear whether BAS is the cause of brain injury or is a confounder, because neonates who require BAS are typically more hypoxemic. We sought to determine the relationship between preoperative brain injury in neonates with transposition of the great arteries and the performance of BAS. We hypothesized that brain injury results from hypoxic injury, not from the BAS itself. METHODS AND RESULTS: Infants with transposition of the great arteries (n=26) were retrospectively included from a larger cohort of infants with congenital heart disease who underwent preoperative brain MRI as part of 2 separate prospective studies. Data collected included all preoperative pulse oximetry recordings, all values from preoperative arterial blood gas measurements, and BAS procedure data. MRI scans were performed on the day of surgery, before the surgical repair. Of the 26 neonates, 14 underwent BAS. No stroke was seen in the entire cohort, whereas 10 (38%) of 26 patients were found to have hypoxic brain injury in the form of periventricular leukomalacia. Periventricular leukomalacia was not associated with BAS; however, neonates with periventricular leukomalacia had lower preoperative oxygenation (P=0.026) and a longer time to surgery (P=0.028) than those without periventricular leukomalacia. CONCLUSIONS: Preoperative brain injury in neonates with transposition of the great arteries is associated with hypoxemia and longer time to surgery. We found no association between BAS and brain injury.

Accuracy of intraoperative transesophageal echocardiography in the prediction of future neo-aortic valve function after the Ross procedure in children and young adults.

OBJECTIVE: Neo-aortic insufficiency (neo-AI) has been noted following the Ross procedure. The purpose of this study was to evaluate the ability of intraoperative transesophageal echocardiography (TEE) to predict future neo-AI in pediatric patients undergoing the Ross from January 1995 to December 2003, who had an intraoperative TEE, and discharge and follow-up transthoracic (TTE) echocardiograms. DESIGN: Retrospective case series. PATIENTS: All patients who underwent the Ross procedure at Children's Hospital of Philadephia between January 1995 and December 2003, and had an intraoperative TEE, discharge, and follow-up (>6 months) transthoracic echocardiogram (TTE) (by July 1, 2004) were included. OUTCOME MEASURES: Grade of neo-AI was assessed on intraoperative TEE, discharge, and follow-up TTE echocardiogram reports. RESULTS: Follow-up was available in 99/115 (86%) survivors. Median age at Ross was 9.3 years (4 days-34 years). No patient had more than mild neo-AI on intraoperative TEE. At discharge, 2 patients (2%) had moderate neo-AI. At most recent follow-up (median 4.2 years, 8 months-9.3 years), 21 patients (21%) had moderate or greater neo-AI; 9 underwent neo-aortic reintervention. The presence of any neo-AI on intraoperative TEE had 100% sensitivity and negative predictive value for diagnosing moderate or greater neo-AI at discharge. Patients who had mild neo-AI on TEE were more likely to have moderate or greater neo-AI at most recent follow-up than those patients with no neo-AI on TEE (9% vs. 30%, P = 0.01). CONCLUSION: Intraoperative TEE is an excellent screening tool for the presence of significant neo-AI at the time of hospital discharge. Neo-AI progresses over time after Ross procedure and is more likely to progress in those patients with neo-AI on intraoperative TEE. However, predictive validity decreases over time as neo-AI progresses.

The development of the pediatric cardiac quality of life inventory: a quality of life measure for children and adolescents with heart disease.

OBJECTIVE: Mortality after surgery for congenital heart disease (CHD) has decreased. Quality of life (QOL) assessment in survivors has become increasingly important. The purpose of this project was to create the Pediatric Cardiac Quality of Life Inventory (PCQLI). METHODS: Items were generated through nominal groups of patients, parents, and providers. The pilot PCQLI was completed by children (age 8-12), adolescents (age 13-18), and their parents at three cardiology clinics. Item reduction was performed through analysis of items, principal components, internal consistency (IC), and patterns of correlation. RESULTS: A total of 655 patient-parent pairs completed the pilot PCQLI. Principal components identified included: impact of disease (ID); psychosocial impact (PI); and emotional environment (EE). After item reduction ID and PI had excellent IC (ID = 0.88-0.91; PI = 0.78-0.85) and correlated highly with each other (0.81-0.90) and with the total score (TS) (ID = 0.95-0.96; PI = 0.87-0.93). EE was not correlated with ID, PI, or TS and was removed from the final forms. Two-ventricle CHD patients had a higher TS than single-ventricle CHD patients across all forms (P < 0.001). CONCLUSION: The PCQLI has patient and parent-proxy forms, has wide age range, and discriminates between CHD subgroups. The ID and PI subscales of the PCQLI have excellent IC and correlate well with each other and the TS.

The relationship between neo-aortic root dilation, insufficiency, and reintervention following the Ross procedure in infants, children, and young adults.

OBJECTIVES: The purpose of this study was to describe the relationship between neo-aortic root size, neo-aortic insufficiency (AI), and reintervention at mid-term follow-up. BACKGROUND: Data on neo-aortic valve function and growth after the Ross procedure in children are limited. METHODS: A total of 74 of 119 Ross patients from January 1995 to December 2003 had > or =2 follow-up echocardiograms at our institution and were included. Neo-aortic dimensions were converted to z-scores and modeled over time. Kaplan-Meier analysis was used to assess freedom from neo-aortic outcomes, and predictors were identified through multivariate analysis. RESULTS: Median age at Ross was 9 years (range 3 days to 34 years). Over 4.7 years (range 3 months to 9.3 years) follow-up, there was disproportionate enlargement of the neo-aortic root (z-score increase of 0.75/year [p < 0.0001]). Neo-AI progressed > or =1 grade in 36% of patients and > or =2 grades in 15%. Nine patients (12%) had neo-aortic reintervention at 2.0 years (range 1.1 to 9.5 years) after the Ross procedure owing to severe neo-AI (n = 7), neo-aortic root dilation (n = 1), and neo-aortic pseudoaneurysm (n = 1). At 6 years after the Ross procedure, freedom from neo-aortic reintervention was 88%. Freedom from neo-aortic root z-score >4 was only 3% and from moderate or greater neo-AI was 60%. Longer follow-up time was associated with neo-aortic root dilation (p < 0.0001). Prior ventricular septal defect (VSD) repair predicted neo-AI (p = 0.02) and reintervention (p = 0.03). Prior aortic valve replacement (p = 0.002) also predicted neo-AI. Neo-aortic root dilation was not associated with neo-AI or reintervention. CONCLUSIONS: At mid-term follow-up after the Ross procedure, neo-aortic root size increases significantly out of proportion to somatic growth, and neo-AI is progressive. Prior VSD repair and aortic valve replacement were associated with neo-AI and reintervention.

Midterm outcomes and predictors of reintervention after the Ross procedure in infants, children, and young adults.

OBJECTIVES: This study assessed the type, time course, and risk factors for right and left ventricular outflow tract reinterventions after the Ross procedure in a population of infants, children, and young adults. METHODS: Patients who underwent the Ross procedure between January 1995 and June 2004 were included (n = 121 consecutive patients). Kaplan-Meier and hazard analyses of right and left ventricular outflow tract reinterventions were performed, and predictors of reintervention were identified through multivariate analysis. RESULTS: The median age at the Ross procedure was 8.2 years (4 days to 34 years); 20% were aged less than 1 year. Half of the patients had isolated aortic valve disease; the other half had complex left-sided heart disease. Early mortality (<30 days) was 2.5% (n = 3). There were 2 late deaths (1.7%). Follow-up (median 6.5 years [2.5 months to 10.4 years]) was available for 96% of survivors (n = 111). Right ventricular outflow tract reintervention (n = 22 in 15 patients) was performed 2.0 years (2.0 weeks to 9.8 years) after the Ross procedure because of stenosis in 19 of 22 cases. Freedom from right ventricular outflow tract reintervention at 8 years was 81%. Smaller homograft size was the strongest predictor (P < .001) of right ventricular outflow tract reintervention. Left ventricular outflow tract reintervention (n = 15 in 15 patients) was performed 2.8 years (1.0 months to 11.6 years) after the Ross procedure because of severe neoaortic insufficiency in 10 of 15 patients. Freedom from left ventricular outflow tract reintervention at 8 years was 83%. Native pulmonary valve abnormalities (P < .01), original diagnosis of aortic insufficiency (P < .01), prior aortic valve replacement (P = .01), and prior ventricular septal defect repair (P = .04) predicted left ventricular outflow tract reintervention. CONCLUSIONS: At midterm follow-up after the Ross procedure, interim mortality is rare. Neoaortic insufficiency and right ventricle to pulmonary artery conduit obstruction are common postoperative sequelae, requiring reintervention in one quarter of patients.

Distribution of a 3.5-mL (1.0%) C31G vaginal gel using magnetic resonance imaging.

C31G (Savvy) has been developed as a topical vaginal microbicide with broad-spectrum antibacterial and antiviral properties. The objective of this study was to evaluate the distribution of a 1.0% concentration of (3.5 mL) C31G vaginal gel in the human pelvis using magnetic resonance imaging (MRI). Gel delivery with a standard applicator was primarily to the upper vagina and was well tolerated. Vaginal mucosal coverage at 18 min was excellent with 92% linear coverage and 75% surface contact coverage of the vagina. The upper vagina was almost completely covered and gel was also noted in the lower vagina. Coverage 6 h after application was substantially decreased, with 60% of maximal linear coverage and 41% surface contact. There was a very minimal coverage of the vaginal mucosa noted 24 h following insertion. Simulated intercourse resulted in relatively little change in overall distribution at all three time points. Repeat application of the gel may be necessary if intercourse has not occurred within the first few hours after initial insertion.

Preoperative cerebral blood flow is diminished in neonates with severe congenital heart defects.

OBJECTIVE: Impaired neurodevelopmental outcome represents a major morbidity for survivors of infant heart surgery for congenital heart defects. Previous studies in these neonates have reported preoperative microcephaly, periventricular leukomalacia, and other findings. The hypothesis of this study is that preoperative cerebral blood flow is substantially diminished and might relate to preoperative neurologic conditions. METHODS: Preoperative brain magnetic resonance imaging was performed. Cerebral blood flow measurements in infants with congenital heart defects were obtained by using a novel noninvasive magnetic resonance imaging technique, pulsed arterial spin-label perfusion magnetic resonance imaging. Cerebral blood flow was measured before the operation under standard ventilation and repeated after increased carbon dioxide. RESULTS: A total of 25 term infants were studied. The average age at the time of the operation was 4.4 +/- 4.6 days. Congenital heart defects varied widely. Microcephaly occurred in 24% (6/25). Baseline cerebral blood flow was 19.7 +/- 9.2 mL . 100 g -1 . min -1 (8.0-42.2 mL . 100 g -1 . min -1 ). Five patients had cerebral blood flow measurements of less than 10 mL . 100 g -1 . min -1 . Mean hypercarbic cerebral blood flow increased to 40.1 +/- 20.3 mL . 100 g -1 . min -1 (11.4-94.0 mL . 100 g -1 . min -1 , P < .001). Pairwise analyses found that low hemoglobin levels were associated with higher baseline cerebral blood flow values ( P = .04). Periventricular leukomalacia occurred in 28% (7/25) and was associated with decreased baseline cerebral blood flow values ( P = .05) and a smaller change in cerebral blood flow with hypercarbia ( P = .003). CONCLUSIONS: Structural brain abnormalities are common in these neonates before surgical intervention. Preoperative cerebral blood flow for this cohort was low and drastically reduced in some patients. Low cerebral blood flow values were associated with periventricular leukomalacia. Carbon dioxide reactivity was preserved but might be compromised by some aspects of the cardiac anatomy. The full spectrum of cerebral blood flow measurements with this technique in congenital heart defects and their long-term significance require continued investigation.

The predictive value of longitudinal neuropsychologic assessment in the early detection of brain tumor recurrence.

BACKGROUND: Neuropsychologic tests are widely used to predict the course of progressive neurologic diseases, and recent research has demonstrated the specificity of cognitive measures, even in relatively diffuse diseases. However, the cognitive effects of brain tumors of similar histology and location are known to be highly variable. The authors used the specificity of cognitive function principle to compare two models for the early detection of low-grade brain tumor recurrence prior to detection with clinically scheduled neuroimaging. METHODS: To test the feasibility of these prediction models, 34 patients with supratentorial, low-grade brain tumors prospectively were administered serial comprehensive neuropsychologic examinations; 11 patients developed recurrent tumors during the series and 23 patients did not. A general model based on tests sensitive to malignancy and white matter disease was compared with a tumor-specific model based on indices related to each patient's tumor locus. A Cox proportional hazards model was used to identify the predictor variables that significantly changed immediately prior to recurrence. RESULTS: Only the tumor-specific model achieved statistical significance (P < 0.02). A tumor-specific index decline of 1 standard deviation indicated a 5-fold increase in the probability of tumor recurrence. CONCLUSIONS: Although this method needs to be tested with more frequent and regular observations and with a larger sample, these results provide evidence of the feasibility of the subject-specific model as a predictor of recurrence. The evidence of the predictive value of a tumor-specific model is consistent with studies that identify only limited, brain structure-specific cognitive decline from broad neuropsychologic batteries.

Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain.

This clinical protocol describes virus-based gene transfer for Canavan disease, a childhood leukodystrophy. Canavan disease, also known as Van Bogaert-Bertrand disease, is a monogeneic, autosomal recessive disease in which the gene coding for the enzyme aspartoacylase (ASPA) is defective. The lack of functional enzyme leads to an increase in the central nervous system of the substrate molecule, N-acetyl-aspartate (NAA), which impairs normal myelination and results in spongiform degeneration of the brain. No effective treatment currently exists; however, virus-based gene transfer has the potential to arrest or reverse the course of this otherwise fatal condition. This procedure involves neurosurgical administration of approximately 900 billion genomic particles (approximately 10 billion infectious particles) of recombinant adeno-associated virus (AAV) containing the aspartoacylase gene (ASPA) directly to affected regions of the brain in each of 21 patients with Canavan disease. Pre- and post-delivery assessments include a battery of noninvasive biochemical, radiological, and neurological tests. This gene transfer study represents the first clinical use of AAV in the human brain and the first instance of viral gene transfer for a neurodegenerative disease.