Long-Term Neurobehavioral and Quality of Life Outcomes of Critically Ill Children after Glycemic Control.

OBJECTIVES: To investigate adaptive skills, behavior, and quality health-related quality of life in children from 32 centers enrolling in the Heart And Lung Failure-Pediatric INsulin Titration randomized controlled trial. STUDY DESIGN: This prospective longitudinal cohort study compared the effect of 2 tight glycemic control ranges (lower target, 80-100 mg/dL vs higher target, 150-180 mg/dL) 1-year neurobehavioral and health-related quality of life outcomes. Subjects had confirmed hyperglycemia and cardiac and/or respiratory failure. Patients aged 2-16 years old enrolled between April 2012 and September 2016 were studied at 1 year after intensive care discharge. The primary outcome, adaptive skills, was assessed using the Vineland Adaptive Behavior Scale. Behavior and health-related quality of life outcomes were assessed as secondary outcomes using the Pediatric Quality of Life and Child Behavior Checklist at baseline and 1-year follow-up. Group differences were evaluated using regression models adjusting for age category, baseline overall performance, and risk of mortality. RESULTS: Of 369 eligible children, 358 survived after hospital discharge and 214 (60%) completed follow-up. One-year Vineland Adaptive Behavior Scale-II composite scores were not different (mean ± SD, 79.9 ± 25.5 vs 79.4 ± 26.9, lower vs higher target; P = .20). Improvement in Pediatric Quality of Life total health from baseline was greater in the higher target group (adjusted mean difference, 8.2; 95% CI, 1.1-15.3; P = .02). CONCLUSIONS: One-year adaptive behavior in critically ill children with lower vs higher target glycemic control did not differ. The higher target group demonstrated improvement from baseline in overall health. This study affirms the lack of benefit of lower glucose targeting. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01565941.

Executive Functioning in the Dystrophinopathies and the Relation to Underlying Mutation Position.

OBJECTIVES: The aim of this study was to investigate executive skills in children with dystrophinopathy and to examine the association between executive functions and dystrophin gene mutation position. METHODS: Fifty boys with dystrophinopathy (mean age, 11 years 0 months; ages range, 5 to 17 years) completed measures of intellectual functioning (IF), working memory and executive functioning [including Digit Span (working memory) and measures from the NIH Toolbox (selective attention/inhibitory control, set shifting, working memory, and processing speed)]. Parents completed the Behavior Rating Inventory of Executive Function (BRIEF). Mutation positions were categorized into three groups (upstream exon 30, 31-62, and downstream exon 63). Paired-samples t tests compared performance on executive measures to IF, and a one-way (three-group) multivariate analysis of covariance compared cognitive performance with mutation location controlling for motor functioning. RESULTS: Mean performance on all executive measures was significantly lower than IF. Parents were also more likely to rate their child with dystrophinopathy as having clinically significant executive difficulties on the Shift, Emotional Control, and Behavior Regulation indices of the BRIEF. Mutation analyses resulted in small groups limiting power to detect subtle differences. Those with a downstream mutation position had significantly poorer performance on IF and Total Digit Span, but not on other measures of executive function including behavior. CONCLUSIONS: Individuals with dystrophinopathy have executive skill deficits, but they are not generally associated with more distal mutations. (JINS, 2019, 25, 146-155).

Executive Skills and Academic Achievement in the Dystrophinopathies.

OBJECTIVES: To examine academic performance in dystrophinopathy as a function of dystrophin gene mutation position as well as intellectual function, executive skills, socioeconomic status (SES), behavior, and physical ability. METHODS: In a cross-sectional study, boys with dystrophinopathy (ages 5-17; n=50) completed tests of academics (Woodcock-Johnson-III: spelling, reading, calculation and total scores), executive functioning (selective attention/inhibitory control, set shifting, working memory, and processing speed), single word comprehension and nonverbal reasoning. Motor skills were assessed and parents provided demographic information and child behavioral assessments. Dystrophin gene mutation positions were dichotomized into groups (upstream versus downstream of exon 43, location of isoforms previously linked to intellectual impairment). Genetic mutation groups were compared on measures of academic achievement, and multiple regression analyses examined unique and joint contributions of executive skills, intelligence quotient (IQ), SES, motor abilities, behavior, and mutation positions to academic outcomes. RESULTS: Academic performance was slightly, yet significantly, lower than IQ and varied as a function of dystrophin gene position, wherein boys possessing the downstream mutation exhibited greater impairment than boys with the upstream mutation. Digit span forward (indexing verbal span), but no other measure of executive function, contributed significant variance to total academic achievement, spelling and calculation. CONCLUSIONS: Weak academic performance is associated with dystrophinopathy and is more common in downstream mutations. A specific deficit in verbal span may underlie inefficiencies observed in children with dystrophinopathy and may drive deficits impacting academic abilities. (JINS, 2018, 24, 928-938).

Zika Virus-Associated Cognitive Impairment in Adolescent, 2016.

Incidence of neurologic manifestations associated with Zika virus infection has been increasing. In 2016, neuropsychological and cognitive changes developed in an adolescent after travel to a Zika virus-endemic area. Single-photon emission computed tomography and neuropsychological testing raised the possibility that Zika virus infection may lead to neuropsychiatric and cognitive symptoms.

Digit Span Performance in Children with Dystrophinopathy: A Verbal Span or Working Memory Contribution?

OBJECTIVES: In a large cohort of boys with dystrophinopathies and their unaffected siblings, we examined whether consistently observed performance on digit span is due primarily to a verbal span or executive deficit. We additionally assessed whether digit span performance contributed to the observed variability in reading performance noted in this population. METHODS: Performance of 170 boys with dystrophinopathy was compared to 95 unaffected sibling controls on measures of verbal function, reading, and digit span. Maximum digit span forward (DSF) and backward (DSB) lengths were converted to Z-scores using normative data. Independent sample t tests, analysis of variance, and hierarchical multiple regression were run (α=0.05). RESULTS: Probands performed worse than controls on digit span, even after accounting for differences in general verbal function (p<.0001). Differences were significant for both DSF (p<.005) and DSB (p<.0001) span length, and an interaction effect yielded significantly worse DSB compared with DSF (p=.01). Reading performance was also lower in probands (p<.0001). The contribution of general level of verbal function, and forward and backward span lengths, did not vary between groups. CONCLUSIONS: In boys with dystrophinopathy, decreased performance on digit span appears to be due to both decreased span forward (measuring verbal span only) and backward (measuring verbal span and working memory). The extent to which sibling controls exhibited better performance compared to the probands was significantly greater for backward span when compared with forward span. Thus, immediate verbal memory and executive control are differentially compromised among boys with dystrophinopathy, and both of these abilities independently contribute to reading performance. (JINS, 2016, 22, 777-784).

Cognitive functioning one month and one year following febrile status epilepticus.

OBJECTIVE: The objective of this study was to determine early developmental and cognitive outcomes of children with febrile status epilepticus (FSE) one month and one year after FSE. METHODS: One hundred ninety four children with FSE were evaluated on measures of cognition, receptive language, and memory as part of the FEBSTAT study and compared with 100 controls with simple febrile seizures (FSs). RESULTS: Children with FSE did not differ dramatically on tasks compared with FS controls at one month after FSE but demonstrated slightly weaker motor development (p=0.035) and receptive language (p=0.034) at one year after FSE. Performances were generally within the low average to average range. Within the FSE cohort, non-White children performed weaker on many of the tasks compared with Caucasian children. At the one-year visit, acute hippocampal T2 findings on MRI were associated with weaker receptive language skills (p=0.0009), and human herpes virus 6 or 7 (HHV6/7) viremia was associated with better memory performances (p=0.047). CONCLUSION: Febrile status epilepticus does not appear to be associated with significant cognitive impairment on early developmental measures, although there is a trend for possible receptive language and motor delay one year after FSE. Further follow-up, which is in progress, is necessary to track long-term cognitive functioning.

Autistic Traits Associated with the Fragile X Premutation Allele: The Neurodevelopmental Profile.

Although most individuals who carry the Fragile X premutation allele, defined as 55-200 CGG repeats on the X-linked FMR1 gene (Fragile X Messenger Ribonucleoprotein 1 gene), do not meet diagnostic criteria for autism spectrum disorder, there is a suggestion of increased behaviors associated with subtle autistic traits. More autism associated characteristics have been reported among adults than children. This may highlight a possible worsening developmental trajectory, variable findings due to research quality or differences in number of studies done in adults vs children, rather than true developmental changes. This review is designed to examine the neurodevelopmental profile associated with the premutation allele from a developmental perspective, focused on autistic traits.

Reading skills over time among children with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked progressive neuromuscular disorder with a distinct cognitive profile including decreased verbal span. Children with DMD are also at risk for lower scores on academic achievement tests and increased behavioral problems. Longitudinal analyses generally reveal a stable intellectual profile, although attention and behavioral problems may negatively impact longitudinal IQ scores. To date, no study has reported on reading over time in DMD. Reading performance was assessed longitudinally in children with DMD, examining for potential contributions to the trajectory. Retrospective data analysis on assessments completed at baseline, year 2, and year 4 on 26 boys with DMD and 27 unaffected sibling controls (age at baseline: DMD 8 ± 1.4, controls 9 ± 2.6) indicated that children with DMD performed slightly, yet significantly, worse than controls on reading skills, but the longitudinal trajectory of reading skills for children with DMD and controls was not significantly different. Verbal span at time 1 was uniquely associated with later reading skills in children with DMD. Behavior was not associated with declines. The results confirm that children with DMD underperform on reading tasks and align with previous research suggesting that cognitive skills in DMD are stable over time.

Intrasubject variability of sustained attention is associated with elevated self-reported attention deficits in women with a fragile X premutation allele.

OBJECTIVE: Women with a fragile X premutation (PM) self-report higher rates of attention difficulties than women without a PM; however, results of studies using objective measures of attention are inconsistent. The present study assessed whether intrasubject variability during a sustained attention task better predicted functional outcomes in women with a PM than the previously published standard reaction time and accuracy variables. METHOD: We analyzed continuous performance test, a computerized measure of sustained attention, and the Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale Report (CAARS) data from 273 women with a PM and 175 women without a PM aged 18-50 years. Separate analyses using Pearson correlations and independent t tests were performed on the full range of coefficient of variation (CV) of reaction time scores and the subset of scores that showed higher variability. RESULTS: Performance variability of sustained attention measured by the continuous performance test was associated with functional outcomes measured by the CAARS in women with a PM but not women without a PM. Specifically, the CV in those with higher variability was correlated with two CAARS subscale scores (p = .006). Independent t tests showed significant differences in CV between CAARS scores dichotomized for the presence of subclinical symptoms for two subscales (p ≤ .001-.007). Correlation between the full range of CV scores and the CAARS Inattention/Memory Problems subscale approached significance (p = .012). CONCLUSIONS: Findings highlight the importance of including intrasubject variability in analyzing attention in clinical populations as a more sensitive objective measure associated with reported symptoms and to assist in predicting functional outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS).

Glut1 deficiency syndrome (Glut1 DS) was originally described in 1991 as a developmental encephalopathy characterized by infantile onset refractory epilepsy, cognitive impairment, and mixed motor abnormalities including spasticity, ataxia, and dystonia. The clinical condition is caused by impaired glucose transport across the blood brain barrier. The past 5 years have seen a dramatic expansion in the range of clinical syndromes that are recognized to occur with Glut1 DS. In particular, there has been greater recognition of milder phenotypes. Absence epilepsy and other idiopathic generalized epilepsy syndromes may occur with seizure onset in childhood or adulthood. A number of patients present predominantly with movement disorders, sometimes without any accompanying seizures. In particular, paroxysmal exertional dyskinesia is now a well-documented clinical feature that occurs in individuals with Glut1 DS. A clue to the diagnosis in patients with paroxysmal symptoms may be the triggering of episodes during fasting or exercise. Intellectual impairment may range from severe to very mild. Awareness of the broad range of potential clinical phenotypes associated with Glut1 DS will facilitate earlier diagnosis of this treatable neurologic condition. The ketogenic diet is the mainstay of treatment and nourishes the starving symptomatic brain during development.

Longitudinal assessment of skill development in children with first febrile seizure.

To determine whether first febrile seizure (FS) has detrimental effects on development, 159 children (aged 6 months to 5 years) with FS were compared to 142 controls on measures of cognition, motor ability, and adaptive behavior. Participants were identified through the emergency department in an urban, low-income community. Children were evaluated within one month of the ED visit and one year later, and difference in performance over one year was examined. Performance did not differ between cases and controls on measures of cognition (baseline: p=0.5, one year: p=0.2, change over time: p=0.1) or motor skills (baseline: p=0.9, one year: p=0.7, change over time, p=0.6). The adaptive behavior composite score did not differ by FS case status at baseline (p=0.2) or one year later (p=0.6); however, between-group differences over time approached significance (p=0.05). Findings support the idea that first FS does not pose developmental or behavioral consequences in a low socioeconomic environment.

Association of maternal exposure to Superstorm Sandy and maternal cannabis use with development of psychopathology among offspring: the Stress in Pregnancy Study.

BACKGROUND: Early-life adverse experiences can elevate the magnitude of the risk of developmental psychopathology, but the potential synergistic effects of multiple factors have not been well studied. AIMS: To determine whether prenatal exposures to maternal stress (Superstorm Sandy) and maternal cannabis use synergistically alter the risk of developmental psychopathology. METHOD: The study included 163 children (53.4% girls), longitudinally tracked (ages 2-5 years) in relation to the effects of two early-life adverse exposures (Superstorm Sandy and maternal cannabis use). Offspring were grouped by exposure status (neither, only maternal cannabis use, only Superstorm Sandy or both). DSM-IV disorders for offspring were derived from structured clinical interviews; caregiver-reported ratings of family stress and social support were also assessed. RESULTS: A total of 40.5% had been exposed to Superstorm Sandy and 24.5% to maternal cannabis use. Offspring exposed to both (n = 13, 8.0%), relative to those exposed to neither, had a 31-fold increased risk of disruptive behavioural disorders (DBDs) and a seven-fold increased risk of anxiety disorders. The synergy index demonstrated that offspring with two exposures had synergistic elevation in risk of DBDs (synergy index, 2.06, P = 0.03) and anxiety disorders (synergy index, 2.60, P = 0.004), compared with the sum of single risks. Offspring with two exposures had the highest parenting stress and lowest social support. CONCLUSIONS: Our findings are consistent with the double-hit model suggesting that offspring with multiple early-life adverse exposures (Superstorm Sandy and maternal cannabis use) have synergistically increased risks of mental health problems. Given the increasing frequency of major natural disasters and cannabis use, especially among women under stress, these findings have significant public health implications.

Distribution of febrile seizure duration and associations with development.

OBJECTIVE: In prior studies of febrile seizures (FSs), prolonged FSs were defined, absent empirical evidence, as lasting 10 or 15 minutes or more. We assessed the distribution of FS duration in a cohort with first FSs, and the association between FS duration and baseline characteristics of the children. METHODS: We calculated the observed cumulative probability, S(t), that a FS would last at least t minutes, S(t) = exp(-t/τ). Data were also fit using a model obtained as the sum of 2 exponential distributions (S[t] = αexp[-t/τ(1) ] + [1 - α]exp[-t/τ(2) ]). After assessing the best fit, the cutoff defining long FS was determined. Logistic regression was used to examine associations between long FSs and baseline characteristics, behavior, and development. RESULTS: In 158 children with a first FS, median duration was 4.0 minutes. Duration of FS was best fit by a 2-component mixture exponential model. Using this model, we identified 1 population that accounts for 82.3% of FSs and has a mean duration of 3.8 minutes (short FS) and a second population that accounts for 17.7% of FSs and has a mean duration of 39.8 minutes (long FS). Long FSs were significantly associated with developmental delay (p = 0.010) and delays and younger age at first FS (p = 0.048). INTERPRETATION: Like the distribution of afebrile seizure duration in children, the distribution of first FS duration is best modeled by assuming 2 populations. Developmental delay and younger age are associated with prolonged FSs. Our data lend further support to defining 10 minutes as the upper limit for a simple FS.

Visual memory failure presages conversion to MELAS phenotype.

OBJECTIVE: To examine the correlation between verbal and visual memory function and correlation with brain metabolites (lactate and N-Acetylaspartate, NAA) in individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). METHODS: Memory performance and brain metabolites (ventricular lactate, occipital lactate, and occipital NAA) were examined in 18 MELAS, 58 m.3243A > G carriers, and 20 familial controls. Measures included the Selective Reminding Test (verbal memory), Benton Visuospatial Retention Test (visual memory), and MR Spectroscopy (NAA, Lactate). ANOVA, chi-squared/Fisher's exact tests, paired t-tests, Pearson correlations, and Spearman correlations were used. RESULTS: When compared to carriers and controls, MELAS patients had the: (1) most impaired memory functions (Visual: p = 0.0003; Verbal: p = 0.02), (2) greatest visual than verbal memory impairment, (3) highest brain lactate levels (p < 0.0001), and (4) lowest brain NAA levels (p = 0.0003). Occipital and ventricular lactate to NAA ratios correlated significantly with visual memory performance (p ≤ 0.001). Higher lactate levels (p ≤ 0.01) and lower NAA levels (p = 0.0009) correlated specifically with greater visual memory dysfunction in MELAS. There was little or no correlation with verbal memory. INTERPRETATION: Individuals with MELAS are at increased risk for impaired memory. Although verbal and visual memory are both affected, visual memory is preferentially affected and more clearly associated with brain metabolite levels. Preferential involvement of posterior brain regions is a distinctive clinical signature of MELAS. We now report a distinctive cognitive phenotype that targets visual memory more prominently and earlier than verbal memory. We speculate that this finding in carriers presages a conversion to the MELAS phenotype.

Acute hyperglycemia produces transient improvement in glucose transporter type 1 deficiency.

OBJECTIVE: Glucose transporter type 1 deficiency syndrome (Glut1-DS) is characterized clinically by acquired microcephaly, infantile-onset seizures, psychomotor retardation, choreoathetosis, dystonia, and ataxia. The laboratory signature is hypoglycorrhachia. The 5-hour oral glucose tolerance test (OGTT) was performed to assess cerebral function and systemic carbohydrate homeostasis during acute hyperglycemia, in the knowledge that GLUT1 is constitutively expressed ubiquitously and upregulated in the brain. METHODS: Thirteen Glut1-DS patients completed a 5-hour OGTT. Six patients had prolonged electroencephalographic (EEG)/video monitoring, 10 patients had plasma glucose and serum insulin measurements, and 5 patients had repeated measures of attention, memory, fine motor coordination, and well-being. All patients had a full neuropsychological battery prior to OGTT. RESULTS: The glycemic profile and insulin response during the OGTT were normal. Following the glucose load, transient improvement of clinical seizures and EEG findings were observed, with the most significant improvement beginning within the first 30 minutes and continuing for 180 minutes. Thereafter, clinical seizures returned, and EEG findings worsened. Additionally, transient improvement in attention, fine motor coordination, and reported well-being were observed without any change in memory performance. INTERPRETATION: This study documents transient neurological improvement in Glut1-DS patients following acute hyperglycemia, associated with improved fine motor coordination and attention. Also, systemic carbohydrate homeostasis was normal, despite GLUT1 haploinsufficiency, confirming the specific role of GLUT1 as the transporter of metabolic fuel across the blood-brain barrier. The transient improvement in brain function underscores the rate-limiting role of glucose transport and the critical minute-to-minute dependence of cerebral function on fuel availability for energy metabolism.

Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort.

Mutations in the DMD gene, encoding the dystrophin protein, are responsible for the dystrophinopathies Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X-linked Dilated Cardiomyopathy (XLDC). Mutation analysis has traditionally been challenging, due to the large gene size (79 exons over 2.2 Mb of genomic DNA). We report a very large aggregate data set comprised of DMD mutations detected in samples from patients enrolled in the United Dystrophinopathy Project, a multicenter research consortium, and in referral samples submitted for mutation analysis with a diagnosis of dystrophinopathy. We report 1,111 mutations in the DMD gene, including 891 mutations with associated phenotypes. These results encompass 506 point mutations (including 294 nonsense mutations) and significantly expand the number of mutations associated with the dystrophinopathies, highlighting the utility of modern diagnostic techniques. Our data supports the uniform hypermutability of CGA>TGA mutations, establishes the frequency of polymorphic muscle (Dp427m) protein isoforms and reveals unique genomic haplotypes associated with "private" mutations. We note that 60% of these patients would be predicted to benefit from skipping of a single DMD exon using antisense oligonucleotide therapy, and 62% would be predicted to benefit from an inclusive multiexonskipping approach directed toward exons 45 through 55.

Longitudinal changes in clinical outcome measures in COL6-related dystrophies and LAMA2-related dystrophies.

OBJECTIVE: To identify the rate of change of clinical outcome measures in children with 2 types of congenital muscular dystrophy (CMD), COL6-related dystrophies (COL6-RDs) and LAMA2-related dystrophies (LAMA2-RDs). METHODS: Over the course of 4 years, 47 individuals (23 with COL6-RD and 24 with LAMA2-RD) 4 to 22 years of age were evaluated. Assessments included the Motor Function Measure 32 (MFM32), myometry (knee flexors and extensors, elbow flexors and extensors), goniometry (knee and elbow extension), pulmonary function tests, and quality-of-life measures. Separate linear mixed-effects models were fitted for each outcome measurement, with subject-specific random intercepts. RESULTS: Total MFM32 scores for COL6-RDs and LAMA2-RDs decreased at a rate of 4.01 and 2.60 points, respectively, each year (p < 0.01). All muscle groups except elbow flexors for individuals with COL6-RDs decreased in strength between 1.70% (p < 0.05) and 2.55% (p < 0.01). Range-of-motion measurements decreased by 3.21° (p < 0.05) at the left elbow each year in individuals with LAMA2-RDs and 2.35° (p < 0.01) in right knee extension each year in individuals with COL6-RDs. Pulmonary function demonstrated a yearly decline in sitting forced vital capacity percent predicted of 3.03% (p < 0.01) in individuals with COL6-RDs. There was no significant change in quality-of-life measures analyzed. CONCLUSION: Results of this study describe the rate of change of motor function as measured by the MFM32, muscle strength, range of motion, and pulmonary function in individuals with COL6-RDs and LAMA2-RDs.

Duchenne muscular dystrophy: a cerebellar disorder?

Cyrulnik, S.C., and V.J. Hinton. Duchenne muscular dystrophy: A cerebellar disorder? NEUROSCI. BIOBEHAV. REV. Duchenne muscular dystrophy (DMD) is a genetic disorder that is often associated with cognitive deficits. These cognitive deficits have been linked to the absence of dystrophin, a protein product which is normally found in multiple tissues throughout the body. In the current paper, we argue that it is the absence of dystrophin in the cerebellum that is responsible for the cognitive deficits observed. We begin by reviewing data that document structural and functional abnormalities in the brains of individuals with DMD and mdx mice. We briefly review the cognitive deficits associated with DMD, and then present neuroimaging and neuropsychological evidence to indicate that the cerebellum is involved in the same aspects of cognition that are impaired in children with DMD. It is our contention that the development of brain pathways in the cerebellum (e.g., cerebro-cerebellar loops) without dystrophin may result in altered brain function presenting as cognitive deficits in DMD.

Cognitive and adaptive deficits in young children with Duchenne muscular dystrophy (DMD).

The goal of the current investigation was to examine adaptive behavior and cognitive skills in young children with Duchenne muscular dystrophy (DMD), a genetic disorder that causes progressive muscular weakness and concomitant cognitive deficits. Previous studies have documented specific language deficits in older children with DMD, but there are limited data on younger children. Twenty children with DMD who were between 3 and 6 years old and 20 unaffected family control children were recruited. Parents completed questionnaires relating to development and adaptive functioning, while children completed neuropsychological testing. Results of paired t tests indicate that children with DMD are rated as delayed relative to familial controls on measures of adaptive functioning, as assessed by the Vineland Adaptive Behavior Scales. Furthermore, children with DMD exhibit impairments on multiple measures of cognition, including measures of receptive language, expressive language, visuo-spatial skills, fine-motor skills, attention, and memory skills. Across all domains examined, the young children with DMD performed more poorly than their familial controls. These deficits appear to be more generalized than those reported in older children with this disorder. Dystrophin, a missing protein product, is hypothesized to be responsible for these cognitive and behavioral impairments.

Brain glucose supply and the syndrome of infantile neuroglycopenia.

OBJECTIVE: To describe neuroglycopenia as a specific syndrome caused by insufficient glucose availability during brain development. DESIGN: Neurologic examinations, neuropsychologic tests, biochemical methods, and functional imaging. PARTICIPANTS: Patients afflicted by genetic mutation of the cerebral glucose transporter type 1 and a patient afflicted by persistent infantile hypoglycemia (hyperinsulinism) matched to her healthy twin. RESULTS: The hallmark of the phenotype is the combination of infantile epilepsy and cerebellar and pyramidal tract dysfunction, together with permanent neuropsychologic abnormalities and reduced thalamocortical glucose uptake despite subsequent supply of energetic substrate. CONCLUSIONS: When neuroglycopenia-the lack of adequate glucose supply to the nervous system-occurs in the developing brain, thalamic and cortical metabolism mature aberrantly, causing epilepsy associated with other characteristic neurologic and behavioral disturbances, a pattern also reflected in functional images, as if there were a temporal window during which glucose were crucial for brain development. When maturation is complete, glucose merely serves as a fuel, and then, when deficient, it only causes unrelated disturbances.