Kim M. Cecil

X-Linked Creatine-Transporter Gene (SLC6A8) Defect: A New Creatine-Deficiency Syndrome

We report the first X-linked creatine-deficiency syndrome caused by a defective creatine transporter. The male index patient presented with developmental delay and hypotonia. Proton magnetic-resonance spectroscopy of his brain revealed absence of the creatine signal. However, creatine in urine and plasma was increased, and guanidinoacetate levels were normal. In three female relatives of the index patient, mild biochemical abnormalities and learning disabilities were present, to various extents. Fibroblasts from the index patient contained a hemizygous nonsense mutation in the gene SLC6A8 and were defective in creatine uptake. The three female relatives were heterozygous for this mutation in SLC6A8, which has been mapped to Xq28.

Decreased Brain Volume in Adults with Childhood Lead Exposure

Background Although environmental lead exposure is associated with significant deficits in cognition, executive functions, social behaviors, and motor abilities, the neuroanatomical basis for these impairments remains poorly understood. In this study, we examined the relationship between childhood lead exposure and adult brain volume using magnetic resonance imaging (MRI). We also explored how volume changes correlate with historic neuropsychological assessments. Methods and Findings Volumetric analyses of whole brain MRI data revealed significant decreases in brain volume associated with childhood blood lead concentrations. Using conservative, minimum contiguous cluster size and statistical criteria (700 voxels, unadjusted p < 0.001), approximately 1.2% of the total gray matter was significantly and inversely associated with mean childhood blood lead concentration. The most affected regions included frontal gray matter, specifically the anterior cingulate cortex (ACC). Areas of lead-associated gray matter volume loss were much larger and more significant in men than women. We found that fine motor factor scores positively correlated with gray matter volume in the cerebellar hemispheres; adding blood lead concentrations as a variable to the model attenuated this correlation. Conclusions Childhood lead exposure is associated with region-specific reductions in adult gray matter volume. Affected regions include the portions of the prefrontal cortex and ACC responsible for executive functions, mood regulation, and decision-making. These neuroanatomical findings were more pronounced for males, suggesting that lead-related atrophic changes have a disparate impact across sexes. This analysis suggests that adverse cognitive and behavioral outcomes may be related to leads effect on brain development producing persistent alterations in structure. Using a simple model, we found that blood lead concentration mediates brain volume and fine motor function.

Pediatric Sports-Related Concussion Produces Cerebral Blood Flow Alterations

Objectives: The pathophysiology of sports-related concussion (SRC) is incompletely understood. Human adult and experimental animal investigations have revealed structural axonal injuries, decreases in the neuronal metabolite N-acetyl aspartate, and reduced cerebral blood flow (CBF) after SRC and minor traumatic brain injury. The authors of this investigation explore these possibilities after pediatric SRC. Patients And Methods: Twelve children, ages 11 to 15 years, who experienced SRC were evaluated by ImPACT neurocognitive testing, T1 and susceptibility weighted MRI, diffusion tensor imaging, proton magnetic resonance spectroscopy, and phase contrast angiography at <72 hours, 14 days, and 30 days or greater after concussion. A similar number of age- and gender-matched controls were evaluated at a single time point. Results: ImPACT results confirmed statistically significant differences in initial total symptom score and reaction time between the SRC and control groups, resolving by 14 days for total symptom score and 30 days for reaction time. No evidence of structural injury was found on qualitative review of MRI. No decreases in neuronal metabolite N-acetyl aspartate or elevation of lactic acid were detected by proton magnetic resonance spectroscopy. Statistically significant alterations in CBF were documented in the SRC group, with reduction in CBF predominating (38 vs 48 mL/100 g per minute; P = .027). Improvement toward control values occurred in only 27% of the participants at 14 days and 64% at >30 days after SRC. Conclusions: Pediatric SRC is primarily a physiologic injury, affecting CBF significantly without evidence of measurable structural, metabolic neuronal or axonal injury. Further study of CBF mechanisms is needed to explain patterns of recovery.

The evaluation of human breast lesions with magnetic resonance imaging and proton magnetic resonance spectroscopy.

AbstractPurpose. MR spectroscopy (MRS) assists in lesion characterization and diagnosis when combined with magnetic resonance imaging (MRI). Cancerous lesions demonstrate elevated composite choline levels arising from increased cellular proliferation. Our study investigated if MR spectroscopy of the breast would be useful for characterizing benign and malignant lesions. Materials and methods. Single voxel proton MR spectroscopy (MRS) was acquired as part of an MR imaging protocol in 38 patients referred upon surgical consultation. The MR spectra were read independently in a blinded fashion without the MR images by three spectroscopists. The MRI exam was interpreted in two settings: (a) as a clinical exam with detailed histories and results from previous imaging studies such as mammography or ultrasound included and (b) as a blinded study without prior histories or imaging results. Results. Elevated choline levels were demonstrated by MRS in 19 of the 23 confirmed cancer patients. The sensitivity and specificity for determining malignancy from benign breast disease with MRS alone were 83 and 87%, respectively, while a blinded MRI review reported 95 and 86%, respectively. Conclusions. Proton MR spectroscopy provides a noninvasive, biochemical measure of metabolism. The technique can be performed in less than 10min as part of an MRI examination. MRI in combination with MRS may improve the specificity of breast MR and thereby, influence patient treatment options. This may be particularly true with less experienced breast MRI readers. In exams where MRI and MRS agree, the additional confidence measure provided by MRS may influence the course of treatment.

X-linked creatine transporter defect: an overview.

Summary: In 2001 we identified a new inborn error of metabolism caused by a defect in the X-linked creatine transporter SLC6A8 gene mapped at Xq28 (SLC6A8 deficiency, McKusick 300352). An X-linked creatine transporter defect was presumed because of (1) the absence of creatine in the brain as indicated by proton magnetic resonance spectroscopy (MRS); (2) the elevated creatine levels in urine and normal guanidinoacetate levels in plasma, ruling out a creatine biosynthesis defect; (3) the absence of an improvement on creatine supplementation; and (4) the fact that the pedigree suggested an X-linked disease. Our hypothesis was proved by the presence of a hemizygous nonsense mutation in the male index patient and by the impaired creatine uptake by cultured fibroblasts. Currently, at least 7 unrelated families (13 male patients and 13 carriers) with a SLC6A8 deficiency have been identified. Four families come fromone metropolitan area. This suggests that SLC6A8 deficiency may have a relatively high incidence. The hallmarks of the disorder are X-linked mental retardation, expressive speech and language delay, epilepsy, developmental delay and autistic behaviour. In approximately 50% of the female carriers, learning disabilities of varying degrees have been noted.

Irreversible brain creatine deficiency with elevated serum and urine creatine: A creatine transporter defect?

Recent reports highlight the utility of in vivo magnetic resonance spectroscopy (MRS) techniques to recognize creatine deficiency syndromes affecting the central nervous system (CNS). Reported cases demonstrate partial reversibility of neurologic symptoms upon restoration of CNS creatine levels with the administration of oral creatine. We describe a patient with a brain creatine deficiency syndrome detected by proton MRS that differs from published reports. Metabolic screening revealed elevated creatine in the serum and urine, with normal levels of guanidino acetic acid. Unlike the case with other reported creatine deficiency syndromes, treatment with oral creatine monohydrate demonstrated no observable increase in brain creatine with proton MRS and no improvement in clinical symptoms. In this study, we report a novel brain creatine deficiency syndrome most likely representing a creatine transporter defect. Ann Neurol 2001;49:401–404

Proton magnetic resonance spectroscopy of the frontal lobe and cerebellar vermis in children with a mood disorder and a familial risk for bipolar disorders.

OBJECTIVE Few studies have examined the neurochemical abnormalities that might be associated with pediatric bipolar disorder. The aim of this study was to use magnetic resonance spectroscopy to evaluate several brain regions implicated in bipolar disorder in children with a mood disorder and a familial risk for bipolar disorder. We hypothesized that these children would exhibit neurochemical differences compared with healthy children of parents without a psychiatric disorder. Specifically, decreased N-acetylaspartate (NAA) and creatine and phosphocreatine (Cr) of the prefrontal cortex and cerebellar vermis would reflect impairments in neuronal function and cellular metabolism, and elevated myo-inositol (mI) would reflect impaired phosphoinositide metabolism, potentially representing early markers of neurophysiologic changes that might underlie the development of bipolar disorder. METHODS Children with a mood disorder and at least one parent with bipolar disorder (n = 9) and healthy children (n = 10) group matched for age (8-12 years), race, sex, education, and Tanner stage were evaluated using the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia. Proton magnetic resonance spectroscopy was acquired using 8-cc volumes within the frontal cortex, frontal white matter, and the cerebellar vermis. Metabolite ratios (NAA/Cr, cholines (Cho)/Cr, mI/Cr, NAA/Cho, NAA/mI, and Cho/mI) and concentrations (NAA, Cr, Cho, and mI) were calculated and compared between groups. RESULTS The trend in concentration levels of NAA and Cr was approximately 8% lower for children with a mood disorder than healthy children within the cerebellar vermis. The frontal cortex in children with a mood disorder revealed elevated mI concentration levels, approximately 16% increased, compared with healthy children. CONCLUSIONS Similar to findings in adults with bipolar disorders, neurochemical abnormalities within the frontal cortex and the cerebellar vermis were present in this preliminary comparison of children with a mood disorder and a familial risk for bipolar disorder. Larger sample sizes are needed to replicate these findings.

Proton Magnetic Resonance Spectroscopy in the Frontal and Temporal Lobes of Neuroleptic Naive Patients with Schizophrenia

Studies with proton magnetic resonance spectroscopy (MRS) have reported abnormalities in N-acetyl-aspartate (NAA), amino acids (AA) and choline (Cho) to creatine (Cr) ratios associated with schizophrenia. We report data on the three ratios in a sample of 18 neuroleptic naive patients with first-episode schizophrenia (eight studied in the dorsolateral prefrontal and 10 in the midtemporal lobe) and 24 healthy controls (14 studied in prefrontal and 10 in midtemporal lobes). Frontal lobe proton spectra were acquired with the stimulated-echo acquisition mode (STEAM) pulse sequence (echo time 21 ms, repetition time 2 s). Temporal lobe proton spectra were acquired with the point-resolved spectroscopy (PRESS) pulse sequence (echo time 16–21 ms, repetition time 2 s). Upon comparison with normal controls, NAA/Cr ratios were reduced in patients both for the frontal and the temporal lobe. By contrast, Cho/Cr ratios were slightly elevated in frontal and reduced in temporal lobes; whereas, AA/Cr ratios were normal in frontal and markedly increased in the temporal lobe. The reduced NAA/Cr ratios suggest lower neuronal viability in patients and is consistent with findings of reduced brain volume in both frontal and temporal regions.

Diffusion Tensor MR Imaging Reveals Persistent White Matter Alteration after Traumatic Brain Injury Experienced during Early Childhood

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) can noninvasively quantify white matter (WM) integrity. Although its application in adult traumatic brain injury (TBI) is common, few studies in children have been reported. The purposes of this study were to examine the alteration of fractional anisotropy (FA) in children with TBI experienced during early childhood and to quantify the association between FA and injury severity. MATERIALS AND METHODS: FA was assessed in 9 children with TBI (age = 7.89 ± 1.00 years; Glasgow Coma Scale [GCS] = 10.11 ± 4.68) and a control group of 12 children with orthopedic injuries without central nervous system involvement (age = 7.51 ± 0.95 years). All of the subjects were at minimum 12 months after injury. We examined group differences in a series of predetermined WM regions of interest with t test analysis. We subsequently conducted a voxel-wise comparison with Spearman partial correlation analysis. Correlations between FA and injury severity were also calculated on a voxel-wise basis. RESULTS: FA values were significantly reduced in the TBI group in genu of corpus callosum (CC), posterior limb of internal capsule (PLIC), superior longitudinal fasciculus (SLF), superior fronto-occipital fasciculus (SFO), and centrum semiovale (CS). GCS scores were positively correlated with FA in several WM areas including CC, PLIC, SLF, CS, SFO, and inferior fronto-occipital fasciculus (IFO). CONCLUSION: This DTI study provides evidence that WM integrity remains abnormal in children with moderate-to-severe TBI experienced during early childhood and that injury severity correlated strongly with FA.

Magnetic resonance spectroscopy of the pediatric brain.

Proton magnetic resonance (MR) spectroscopy is a complementary method to MR imaging for understanding disease processes in the pediatric brain. By demonstrating the presence of various metabolites in the sampled tissue, MR spectroscopy helps in the understanding of abnormalities detected by MR imaging or clinical examination. This capability is especially pertinent in the pediatric brain, where the manifestation of pathology is superimposed upon a background of normal or abnormal brain development. In this article, we review the major metabolites demonstrated by MR spectroscopy and present examples of MR spectra obtained in various pathological processes encountered in children.