Severity and duration of dysglycemia and brain injury among patients with neonatal encephalopathy.

Background: Evidence is needed to inform thresholds for glycemic management in neonatal encephalopathy (NE). We investigated how severity and duration of dysglycemia relate to brain injury after NE. Methods: A prospective cohort of 108 neonates ≥36 weeks gestational age with NE were enrolled between August 2014 and November 2019 at the Hospital for Sick Children, in Toronto, Canada. Participants underwent continuous glucose monitoring for 72 h, MRI at day 4 of life, and follow-up at 18 months. Receiver operating characteristic curves were used to assess the predictive value of glucose measures (minimum and maximum glucose, sequential 1 mmol/L glucose thresholds) during the first 72 h of life (HOL) for each brain injury pattern (basal ganglia, watershed, focal infarct, posterior-predominant). Linear and logistic regression analyses were used to assess the relationship between abnormal glycemia and 18-month outcomes (Bayley-III composite scores, Child Behavior Checklist [CBCL] T-scores, neuromotor score, cerebral palsy [CP], death), adjusting for brain injury severity. Findings: Of 108 neonates enrolled, 102 (94%) had an MRI. Maximum glucose during the first 48 HOL best predicted basal ganglia (AUC = 0.811) and watershed (AUC = 0.858) injury. Minimum glucose was not predictive of brain injury (AUC <0.509). Ninety-one (89%) infants underwent follow-up assessments at 19.0 ± 1.7 months. A glucose threshold of >10.1 mmol/L during the first 48 HOL was associated with 5.8-point higher CBCL Internalizing Composite T-score (P = 0.029), 0.3-point worse neuromotor score (P = 0.035), 8.6-fold higher odds for CP diagnosis (P = 0.014). While the glucose threshold of >10.1 mmol/L during the first 48 HOL was associated with higher odds of the composite outcome of severe disability or death (OR 3.0, 95% CI 1.0-8.4, P = 0.042), it was not associated with the composite outcome of moderate-to-severe disability or death (OR 0.9, 95% CI 0.4-2.2, P = 0.801). All associations with outcome lost significance after adjusting for brain injury severity. Interpretation: Maximum glucose concentration in the first 48 HOL is predictive of brain injury after NE. Further trials are needed to assess if protocols to control maximum glucose concentrations improve outcomes after NE. Funding: Canadian Institutes for Health Research, National Institutes of Health, and SickKids Foundation.

Seizure Burden and Neurologic Outcomes After Neonatal Encephalopathy.

BACKGROUND AND OBJECTIVES: Seizures are common during neonatal encephalopathy (NE), but the contribution of seizure burden (SB) to outcomes remains controversial. This study aims to examine the relationship between electrographic SB and neurologic outcomes after NE. METHODS: This prospective cohort study recruited newborns ≥36 weeks postmenstrual age around 6 hours of life between August 2014 and November 2019 from a neonatal intensive care unit (NICU). Participants underwent continuous electroencephalography for at least 48 hours, brain MRI within 3-5 days of life, and structured follow-up at 18 months. Electrographic seizures were identified by board-certified neurophysiologists and quantified as total SB and maximum hourly SB. A medication exposure score was calculated based on all antiseizure medications given during NICU admission. Brain MRI injury severity was classified based on basal ganglia and watershed scores. Developmental outcomes were measured using the Bayley Scales of Infant Development, Third Edition. Multivariable regression analyses were performed, adjusting for significant potential confounders. RESULTS: Of 108 enrolled infants, 98 had continuous EEG (cEEG) and MRI data collected, of which 5 were lost to follow-up, and 6 died before age 18 months. All infants with moderate-severe encephalopathy completed therapeutic hypothermia. cEEG-confirmed neonatal seizures occurred in 21 (24%) newborns, with a total SB mean of 12.5 ± 36.4 minutes and a maximum hourly SB mean of 4 ± 10 min/h. After adjusting for MRI brain injury severity and medication exposure, total SB was significantly associated with lower cognitive (-0.21, 95% CI -0.33 to -0.08, p = 0.002) and language (-0.25, 95% CI -0.39 to -0.11, p = 0.001) scores at 18 months. Total SB of 60 minutes was associated with 15-point decline in language scores and 70 minutes for cognitive scores. However, SB was not significantly associated with epilepsy, neuromotor score, or cerebral palsy (p > 0.1). DISCUSSION: Higher SB during NE was independently associated with worse cognitive and language scores at 18 months, even after adjusting for exposure to antiseizure medications and severity of brain injury. These observations support the hypothesis that neonatal seizures occurring during NE independently contribute to long-term outcomes.

Chronic Iron Deficiency and Cognitive Function in Early Childhood.

BACKGROUND AND OBJECTIVES: A landmark longitudinal study, conducted in Costa Rica in the 1980s, found that children with chronic iron deficiency compared with good iron status in infancy had 8 to 9 points lower cognitive scores, up to 19 years of age. Our objective was to examine this association in a contemporary, high-resource setting. METHODS: This was a prospective observational study of children aged 12 to 40 months screened with hemoglobin and serum ferritin. All parents received diet advice; children received oral iron according to iron status. After 4 months, children were grouped as: chronic iron deficiency (iron deficiency anemia at baseline or persistent nonanemic iron deficiency) or iron sufficiency (IS) (IS at baseline or resolved nonanemic iron deficiency). Outcomes measured at 4 and 12 months included the Early Learning Composite (from the Mullen Scales of Early Learning) and serum ferritin. RESULTS: Of 1478 children screened, 116 were included (41 chronic, 75 sufficient). Using multivariable analyses, the mean between-group differences in the Early Learning Composite at 4 months was -6.4 points (95% confidence interval [CI]: -12.4 to -0.3, P = .04) and at 12 months was -7.4 points (95% CI: -14.0 to -0.8, P = .03). The mean between-group differences in serum ferritin at 4 months was 14.3 µg/L (95% CI: 1.3-27.4, P = .03) and was not significantly different at 12 months. CONCLUSIONS: Children with chronic iron deficiency, compared with children with IS, demonstrated improved iron status, but cognitive scores 6 to 7 points lower 4 and 12 months after intervention. Future research may examine outcomes of a screening strategy on the basis of early detection of iron deficiency using serum ferritin.

Deep intronic variant in MVK as a cause for mevalonic aciduria initially presenting as non-syndromic retinitis pigmentosa.

Non-syndromic retinitis pigmentosa (NSRP) is a clinically and genetically heterogeneous group of disorders characterized by progressive degeneration of the rod and cone photoreceptors, often leading to blindness. The evolving association of syndromic genes to cause NSRP and the increasing role of intronic variants in explaining missing heritability in genetic disorders present challenges in establishing conclusive clinical and genetic diagnoses. This study sought to identify and validate the causative genetic variant(s) in a 13-year-old male initially diagnosed with NSRP. Genome sequencing identified a pathogenic missense variant in MVK [NM_000431.3:c.803T>C (p.Ile268Thr)], in trans with a novel intronic variant predicted to create a new donor splice site (c.768+71C>A). Proband cDNA analysis confirmed the inclusion of the first 68 base pairs of intron 8 that resulted in a frameshift in MVK (r.768_769ins[768+1_768+68]) and significantly reduced the expression of reference transcript (17.6%). Patient re-phenotyping revealed ataxia, cerebellar atrophy, elevated urinary mevalonate and LTE4 , in keeping with mild mevalonic aciduria and associated syndromic retinitis pigmentosa. Leakage of reference transcript likely explains the milder phenotype observed in our patient. This is the first association of a deep intronic splice variant to cause MVK-related disorder. This report highlights the importance of variant validation and patient re-phenotyping in establishing accurate diagnosis in the era of genome sequencing.

Quantitative brain MRI morphology in severe and attenuated forms of mucopolysaccharidosis type I.

OBJECTIVE: To assess our hypothesis that brain macrostructure is different in individuals with mucopolysaccharidosis type I (MPS I) and healthy controls (HC), we conducted a comprehensive multicenter study using a uniform quantitative magnetic resonance imaging (qMRI) protocol, with analyses that account for the effects of disease phenotype, age, and cognition. METHODS: Brain MRIs in 23 individuals with attenuated (MPS IA) and 38 with severe MPS I (MPS IH), aged 4-25 years, enrolled under the study protocol NCT01870375, were compared to 98 healthy controls. RESULTS: Cortical and subcortical gray matter, white matter, corpus callosum, ventricular and choroid plexus volumes in MPS I significantly differed from HC. Thicker cortex, lower white matter and corpus callosum volumes were already present at the youngest MPS I participants aged 4-5 years. Age-related differences were observed in both MPS I groups, but most markedly in MPS IH, particularly in cortical gray matter metrics. IQ scores were inversely associated with ventricular volume in both MPS I groups and were positively associated with cortical thickness only in MPS IA. CONCLUSIONS: Quantitatively-derived MRI measures distinguished MPS I participants from HC as well as severe from attenuated forms. Age-related neurodevelopmental trajectories in both MPS I forms differed from HC. The extent to which brain structure is altered by disease, potentially spared by treatment, and how it relates to neurocognitive dysfunction needs further exploration.

Establishing a core outcome set for mucopolysaccharidoses (MPS) in children: study protocol for a rapid literature review, candidate outcomes survey, and Delphi surveys.

BACKGROUND: Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases characterized by chronic, progressive multi-system manifestations with varying degrees of severity. Disease-modifying therapies exist to treat some types of MPS; however, they are not curative, underscoring the need to identify and evaluate co-interventions that optimize functioning, participation in preferred activities, and quality of life. A Canadian pediatric MPS registry is under development and may serve as a platform to launch randomized controlled trials to evaluate such interventions. To promote the standardized collection of patient/family-reported and clinical outcomes considered important to patients/families, health care providers (HCPs), and policymakers, the choice of outcomes to include in the registry will be informed by a core outcome set (COS). We aim to establish a patient-oriented COS for pediatric MPS using a multi-stakeholder approach. METHODS: In step 1 of the six-step process to develop the COS, we will identify relevant outcomes through a rapid literature review and candidate outcomes survey. A two-phase screening approach will be implemented to identify eligible publications, followed by extraction of outcomes and other pre-specified data elements. Simultaneously, we will conduct a candidate outcomes survey with children with MPS and their families to identify outcomes most important to them. In step 2, HCPs experienced in treating patients with MPS will be invited to review the list of outcomes generated in step 1 and identify additional clinically relevant outcomes. We will then ask patients/families, HCPs, and policymakers to rate the outcomes in a set of Delphi Surveys (step 3), and to participate in a subsequent consensus meeting to finalize the COS (step 4). Step 5 involves establishing a set of outcome measurement instruments for the COS. Finally, we will disseminate the COS to knowledge users (step 6). DISCUSSION: The proposed COS will inform the choice of outcomes to include in the MPS registry and, more broadly, promote the standardized collection of patient-oriented outcomes for pediatric MPS research. By involving patients/families from the earliest stage of the research, we will ensure that the COS will be relevant to those who will ultimately benefit from the research. TRIAL REGISTRATION: PROSPERO CRD42021267531 , COMET.

Randomized Trial of Oral Iron and Diet Advice versus Diet Advice Alone in Young Children with Nonanemic Iron Deficiency.

OBJECTIVE: To compare the effects of 2 treatment options on neurodevelopmental and laboratory outcomes in young children with nonanemic iron deficiency. STUDY DESIGN: A blinded, placebo-controlled, randomized trial of children 1-3 years with nonanemic iron deficiency (hemoglobin ≥110 g/L, serum ferritin <14 µg/L) was conducted in 8 primary care practices in Toronto, Canada. Interventions included ferrous sulfate or placebo for 4 months; all parents received diet advice. The primary outcome was the Early Learning Composite (ELC) using the Mullen Scales of Early Learning (mean 100, SD 15). Secondary outcomes included serum ferritin. Measurements were obtained at baseline and 4 and 12 months. Sample size was calculated to detect a between-group difference of 6-7 points in ELC. RESULTS: At enrollment (n = 60), mean age was 24.2 (SD 7.4) months and mean serum ferritin was 10.0 (SD 2.4) µg/L. For ELC, the mean between-group difference at 4 months was 1.1 (95% CI -4.2 to 6.5) and at 12 months was 4.1 (95% CI -1.9 to 10.1). For serum ferritin, at 4 months, the mean between-group difference was 16.9 µg/L (95% CI 6.5 to 27.2), and no child randomized to ferrous sulfate had a serum ferritin <14 µg/L (0% vs 31%, P = .003). CONCLUSIONS: For young children with nonanemic iron deficiency, treatment options include oral iron and/or diet advice. We remain uncertain about which option is superior with respect to cognitive outcomes; however, adding ferrous sulfate to diet advice resulted in superior serum ferritin outcomes after 4 months. Shared decision-making between practitioners and parents may be considered when selecting either option. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01481766.

Person Ability Scores as an Alternative to Norm-Referenced Scores as Outcome Measures in Studies of Neurodevelopmental Disorders.

Although norm-referenced scores are essential to the identification of disability, they possess several features which affect their sensitivity to change. Norm-referenced scores often decrease over time among people with neurodevelopmental disorders who exhibit slower-than-average increases in ability. Further, the reliability of norm-referenced scores is lower at the tails of the distribution, resulting in floor effects and increased measurement error for people with neurodevelopmental disorders. In contrast, the person ability scores generated during the process of constructing a standardized test with item response theory are designed to assess change. We illustrate these limitations of norm-referenced scores, and relative advantages of ability scores, using data from studies of autism spectrum disorder and creatine transporter deficiency.

Association between Serum Ferritin and Cognitive Function in Early Childhood.

In infants 1-3 years of age, we found higher serum ferritin values associated with higher cognitive function, as measured by the Mullen Scales of Early Learning (P = .02 for the nonlinear relationship). A serum ferritin of 17 µg/L corresponded to the maximum level of cognition, beyond which there was no meaningful improvement. TRIAL REGISTRATION: Clinicaltrials.gov NCT01481766 and NCT01869530.

Attention and corpus callosum volumes in individuals with mucopolysaccharidosis type I.

OBJECTIVE: Previous research suggests attention and white matter (WM) abnormalities in individuals with mucopolysaccharidosis type I (MPS I); this cross-sectional comparison is one of the first to examine the relationship of WM structural abnormalities as measured by corpus callosum (CC) volumes with attention scores to evaluate this relationship in a larger sample of patients with MPS I. METHODS: Volumetric MRI data and performance on a computerized measure of sustained attention were compared for 18 participants with the severe form of MPS I (MPS IH), 18 participants with the attenuated form of MPS I (MPS IATT), and 60 typically developing age-matched controls. RESULTS: The MPS I groups showed below-average mean attention scores (p < 0.001) and smaller CC volumes (p < 0.001) than controls. No significant associations were found between attention performance and CC volume for controls. Attention was associated with posterior CC volumes in the participants with MPS IH (p = 0.053) and total (p = 0.007) and anterior (p < 0.001) CC volumes in participants with MPS IATT. CONCLUSIONS: We found that attention and CC volumes were reduced in participants with MPS I compared to typically developing controls. Smaller CC volumes in participants with MPS I were associated with decreased attention; such an association was not seen in controls. While hematopoietic cell transplantation used to treat MPS IH may compound these effects, attention difficulties were also seen in the MPS IATT group, suggesting that disease effects contribute substantially to the clinical attentional difficulties seen in this population.

Long-term outcome of patients with X-linked adrenoleukodystrophy: A retrospective cohort study.

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder associated with leukodystrophy, myeloneuropathy and adrenocortical insufficiency. We performed a retrospective cohort study to evaluate long-term outcome of patients with X-ALD. METHOD: All patients with X-ALD diagnosed between 1989 and 2012 were included. Electronic patient charts were reviewed for clinical features, biochemical investigations, molecular genetic testing, neuroimaging, long-term outcome and treatment. RESULTS: Forty-eight patients from 18 unrelated families were included (15 females; 33 males). Seventeen patients were symptomatic at the time of the biochemical diagnosis including 14 with neurocognitive dysfunction and 3 with Addison disease only. Thirty-one asymptomatic individuals were identified by positive family history of X-ALD. During follow-up, eight individuals developed childhood cerebral X-ALD (CCALD), one individual developed adrenomyeloneuropathy (AMN), six individuals developed Addison disease only, and five individuals remained asymptomatic. Direct sequencing of ABCD1 confirmed the genetic diagnosis in 29 individuals. Seven patients with CCALD underwent hematopoietic stem cell transplantation (HSCT). Nine patients lost the follow-up. There was no correlation between clinical severity score, Loes score and elevated degree of elevated very long chain fatty acid (VLCFA) levels in CCALD. CONCLUSION: Our study reports forty-eight new patients with X-ALD and their long-term outcome. Only 35% of the patients presented with neurological features or Addison disease. The remaining individuals were identified due to positive family history. Close monitoring of asymptomatic males resulted in early HSCT to prevent progressive lethal neurodegenerative disease. Identification of patients with X-ALD is important to improve neurodevelopmental outcome of asymptomatic males.

New Paradigm for the Treatment of Glucose Transporter 1 Deficiency Syndrome: Low Glycemic Index Diet and Modified High Amylopectin Cornstarch.

OBJECTIVE: Glucose transporter 1 deficiency syndrome is an autosomal, dominantly inherited neurometabolic disorder caused by mutations in the SLC2A1 gene. Decreased glucose transport into the brain results in seizures and cognitive dysfunction. The ketogenic diet is the treatment of choice, but complicated with compliance problems. Stabilization of blood glucose levels by low glycemic index diet and modified high amylopectin cornstarch would provide steady-state glucose transport into the brain to prevent seizures and cognitive dysfunction in patients with glucose transporter 1 deficiency syndrome as an alternative treatment. PATIENT: We report a new glucose transporter 1 deficiency syndrome patient (c.988C>T; p. Arg330X in the SLC2A1) treated with modified high amylopectin cornstarch (Glycosade) and low glycemic index diet because of compliance problems with the ketogenic diet. She was diagnosed at 11.5 years of age and was treated with the ketogenic diet between ages 12 and 18 years. RESULTS: She was started on modified high amylopectin cornstarch at bedtime and low glycemic index diet with meals and snacks every 3-4 hours. Within the first 6 months of therapy, she improved in her seizures and cognitive functions, but experienced compliance problems afterwards. Neuropsychological assessment was stable at 12 months of therapy. CONCLUSION: This diet was easy to apply compared with the ketogenic diet and resulted in stable neuropsychological functioning of this glucose transporter 1 deficiency syndrome patient. Modified high amylopectin cornstarch and low glycemic index diet might be an alternative treatment in glucose transporter 1 deficiency syndrome patients with compliance problems to the ketogenic diet treatment, but additional patients should be treated to prove usefulness of this new treatment.

An internal pilot study for a randomized trial aimed at evaluating the effectiveness of iron interventions in children with non-anemic iron deficiency: the OptEC trial.

BACKGROUND: The OptEC trial aims to evaluate the effectiveness of oral iron in young children with non-anemic iron deficiency (NAID). The initial sample size calculated for the OptEC trial ranged from 112-198 subjects. Given the uncertainty regarding the parameters used to calculate the sample, an internal pilot study was conducted. The objectives of this internal pilot study were to obtain reliable estimate of parameters (standard deviation and design factor) to recalculate the sample size and to assess the adherence rate and reasons for non-adherence in children enrolled in the pilot study. METHODS: The first 30 subjects enrolled into the OptEC trial constituted the internal pilot study. The primary outcome of the OptEC trial is the Early Learning Composite (ELC). For estimation of the SD of the ELC, descriptive statistics of the 4 month follow-up ELC scores were assessed within each intervention group. The observed SD within each group was then pooled to obtain an estimated SD (S2) of the ELC. Correlation (ρ) between the ELC measured at baseline and follow-up was assessed. Recalculation of the sample size was performed using analysis of covariance (ANCOVA) method which uses the design factor (1- ρ(2)). Adherence rate was calculated using a parent reported rate of missed doses of the study intervention. CONCLUSION: The new estimate of the SD of the ELC was found to be 17.40 (S2). The design factor was (1- ρ2) = 0.21. Using a significance level of 5%, power of 80%, S2 = 17.40 and effect estimate (Δ) ranging from 6-8 points, the new sample size based on ANCOVA method ranged from 32-56 subjects (16-28 per group). Adherence ranged between 14% and 100% with 44% of the children having an adherence rate ≥ 86%. Information generated from our internal pilot study was used to update the design of the full and definitive trial, including recalculation of sample size, determination of the adequacy of adherence, and application of strategies to improve adherence. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01481766 (date of registration: November 22, 2011).

Neurocognition across the spectrum of mucopolysaccharidosis type I: Age, severity, and treatment.

OBJECTIVES: Precise characterization of cognitive outcomes and factors that contribute to cognitive variability will enable better understanding of disease progression and treatment effects in mucopolysaccharidosis type I (MPS I). We examined the effects on cognition of phenotype, genotype, age at evaluation and first treatment, and somatic disease burden. METHODS: Sixty patients with severe MPS IH (Hurler syndrome treated with hematopoietic cell transplant and 29 with attenuated MPS I treated with enzyme replacement therapy), were studied with IQ measures, medical history, genotypes. Sixty-seven patients had volumetric MRI. Subjects were grouped by age and phenotype and MRI and compared to 96 normal controls. RESULTS: Prior to hematopoietic cell transplant, MPS IH patients were all cognitively average, but post-transplant, 59% were below average, but stable. Genotype and age at HCT were associated with cognitive ability. In attenuated MPS I, 40% were below average with genotype and somatic disease burden predicting their cognitive ability. White matter volumes were associated with IQ for controls, but not for MPS I. Gray matter volumes were positively associated with IQ in controls and attenuated MPS I patients, but negatively associated in MPS IH. CONCLUSIONS: Cognitive impairment, a major difficulty for many MPS I patients, is associated with genotype, age at treatment and somatic disease burden. IQ association with white matter differed from controls. Many attenuated MPS patients have significant physical and/or cognitive problems and receive insufficient support services. Results provide direction for future clinical trials and better disease management.

Optimizing early child development for young children with non-anemic iron deficiency in the primary care practice setting (OptEC): study protocol for a randomized controlled trial.

BACKGROUND: Three decades of research suggests that prevention of iron deficiency anemia (IDA) in the primary care setting may be an unrealized and unique opportunity to prevent poor developmental outcomes in children. A longitudinal study of infants with IDA showed that the developmental disadvantage persists long term despite iron therapy. Early stages of iron deficiency, termed non-anemic iron deficiency (NAID), provide an opportunity for early detection and treatment before progression to IDA. There is little research regarding NAID, which may be associated with delayed development in young children. The aim of this study is to compare the effectiveness of four months of oral iron treatment plus dietary advice, with placebo plus dietary advice, in improving developmental outcomes in children with NAID and to conduct an internal pilot study. METHODS/DESIGN: From a screening cohort, those identified with NAID (hemoglobin ≥110 g/L and serum ferritin <14 µg/L) are invited to participate in a pragmatic, multi-site, placebo controlled, blinded, parallel group, superiority randomized trial. Participating physicians are part of a primary healthcare research network called TARGet Kids! Children between 12 and 40 months of age and identified with NAID are randomized to receive four months of oral iron treatment at 6 mg/kg/day plus dietary advice, or placebo plus dietary advice (75 per group). The primary outcome, child developmental score, is assessed using the Mullen Scales of Early Learning at baseline and at four months after randomization. Secondary outcomes include an age appropriate behavior measure (Children's Behavior Questionnaire) and two laboratory measures (hemoglobin and serum ferritin levels). Change in developmental and laboratory measures from baseline to the end of the four-month follow-up period will be analyzed using linear regression (analysis of covariance method). DISCUSSION: This trial will provide evidence regarding the association between child development and NAID, and the effectiveness of oral iron to improve developmental outcomes in children with NAID. The sample size of the trial will be recalculated using estimates taken from an internal pilot study. TRIAL REGISTRATION: This trial was registered with Clinicaltrials.gov (identifier: NCT01481766 ) on 22 November 2011.

Cognitive, medical, and neuroimaging characteristics of attenuated mucopolysaccharidosis type II.

UNLABELLED: The phenotype of attenuated mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, has not been previously studied in systematic manner. In contrast to the "severe" phenotype, the "attenuated" phenotype does not present with behavioral or cognitive impairment; however, the presence of mild behavior and cognitive impairment that might impact long-term functional outcomes is unknown. Previously, significant MRI abnormalities have been found in MPS II. Recent evidence suggests white matter abnormalities in many MPS disorders. METHODS: As the initial cross-sectional analysis of a longitudinal study, we studied the association of brain volumes and somatic disease burden with neuropsychological outcomes, including measures of intelligence, memory, and attention in 20 patients with attenuated MPS II with a mean age of 15.8. MRI volumes were compared to 55 normal controls. RESULTS: While IQ and memory were average, measures of attention were one standard deviation below the average range. Corpus callosum volumes were significantly different from age-matched controls, differing by 22%. Normal age-related volume increases in white matter were not seen in MPS II patients as they were in controls. Somatic disease burden and white matter and corpus callosum volumes were significantly associated with attention deficits. Neither age at evaluation nor age at starting treatment predicted attention outcomes. CONCLUSIONS: Despite average intelligence, attention is compromised in attenuated MPS II. Results confirm an important role of corpus callosum and cortical white matter abnormality in MPS II as well as the somatic disease burden in contributing to attention difficulties. Awareness by the patient and caregivers with appropriate management and symptomatic support will benefit the attenuated MPS II patient.

Long-term treatment outcome of two patients with pyridoxine-dependent epilepsy caused by ALDH7A1 mutations: normal neurocognitive outcome.

Pyridoxine-dependent epilepsy is an autosomal recessively inherited disorder of lysine catabolism caused by mutations in the ALDH7A1 gene. We report 2 patients with normal neurocognitive outcome (full-scale IQ of 108 and 74) and their more than 10 years' treatment outcome on pyridoxine monotherapy. Both patients had specific borderline impairments in visual processing speed. More long-term treatment outcome reports will increase our knowledge about the natural history of the disease.

Novel therapy for pyridoxine dependent epilepsy due to ALDH7A1 genetic defect: L-arginine supplementation alternative to lysine-restricted diet.

BACKGROUND AND HYPOTHESIS: Pyridoxine dependent epilepsy (PDE) due to mutations in the ALDH7A1 gene (PDE-ALDH7A1) is caused by α-aminoadipic-semialdehyde-dehydrogenase enzyme deficiency in the lysine pathway resulting in the accumulation of α-aminoadipic acid semialdehyde (α-AASA). Classical presentation is neonatal intractable seizures with a dramatic response to pyridoxine. Pyridoxine therapy does not prevent developmental delays in the majority of the patients. We hypothesized that L-arginine supplementation will decrease accumulation of α-AASA by competitive inhibition of lysine transport into the central nervous system and improve neurodevelopmental and neurocognitive functions in PDE-ALDH7A1. METHODS: A 12-year-old male with PDE-ALDH7A1 was treated with l-arginine supplementation as an innovative therapy. Treatment outcome was monitored by cerebral-spinal-fluid (CSF) α-AASA measurements at baseline, 6th and 12th months of therapy. Neuropsychological assessments were performed at baseline and 12th months of therapy. RESULTS: L-arginine therapy was well tolerated without side effects. CSF α-AASA was decreased 57% at 12th months of therapy. Neuropsychological assessments revealed improvements in general abilities index from 108 to 116 and improvements in verbal and motor functioning at 12th months of therapy. CONCLUSION: The short-term treatment outcome of this novel L-arginine supplementation therapy for PDE-ALDH7A1 was successful for biochemical and neurocognitive improvements.

The effects of maternal supplementation of polyunsaturated Fatty acids on visual, neurobehavioural, and developmental outcomes of the child: a systematic review of the randomized trials.

Polyunsaturated fatty acid (PUFA) use in pregnancy has been promoted as beneficial for visual and neurobehavioural development in the fetus. However, no systematic review of the randomized trials has been conducted. The objective of this review was to evaluate potential advantages of this regiment by reviewing all randomized trials in pregnancy. Methods. Systematic review of randomized controlled studies comparing cognitive and visual achievements among infants whose mothers were treated and untreated with PUFA during gestation. Results. Nine studies met the inclusion criteria, three focusing on visual and six on neurobehavioural development. Due to differing outcome measurements in the infants, the studies could not be combined into a formal meta-analysis. Synthesizing the existing data, for both visual and neurobehavioural development, most studies could not show sustained benefits to infant cognition or visual development. Conclusion. At the present time a recommendation to change practice and supplement all expecting mothers with PUFA to improve offspring vision or neurobehavioural function is not supported by existing evidence.