Brain imaging in urea cycle disorders

Abstract

Urea cycle disorders (UCD) represent a group of rare inborn errors of metabolism that carry a high risk of mortality and neurological morbidity resulting from the effects of accumulation of ammonia and other biochemical intermediates. These disorders result from single gene defects involved in the detoxification pathway of ammonia to urea. UCD include deficiencies in any of the six enzymes and two membrane transporters involved in urea biosynthesis. It has previously been reported that approximately half of infants who present with hyperammonemic coma in the newborn period die of cerebral edema; and those who survive 3days or more of coma invariably have intellectual disability [1]. In children with partial defects there is an association between the number and severity of recurrent hyperammonemic (HA) episodes (i.e. with or without coma) and subsequent cognitive and neurologic deficits [2]. However, the effects of milder or subclinical HA episodes on the brain are largely unknown. This review discusses the results of neuroimaging studies performed as part of the NIH funded Rare Diseases Clinical Research Center in Urea Cycle Disorders and focuses on biomarkers of brain injury in ornithine transcarbamylase deficiency (OTCD). We used anatomic imaging, functional magnetic resonance imaging (fMRI), diffusion-tensor imaging (DTI), and (1)H/(13)C magnetic resonance spectroscopy (MRS) to study clinically stable adults with partial OTCD. This allowed us to determine alterations in brain biochemistry associated with changes in cell volume and osmolarity and permitted us to identify brain biomarkers of HA. We found that white matter tracts underlying specific pathways involved in working memory and executive function are altered in subjects with OTCD (as measured by DTI), including those heterozygous women who were previously considered asymptomatic. An understanding of the pathogenesis of brain injury in UCD is likely to advance our knowledge of more common disorders of liver dysfunction.

Copyright 2010 Elsevier Inc. All rights reserved.

Figures

Figure 1

The relationship between the neuron and astrocyte glutamine handling. Glutamate in the synapse is taken up by the neuron, shuttled to the astrocytes and used to synthesize glutamine which then diffuses back to the neuron and is converted to glutamate. Glutamate, an excitatory neurotransmitter is used to make GABA, the major CNS inhibitory neurotransmitter.

Figure 2

STROOP and Comprehensive trials making test, part B show differences in subjects with OTCD and controls. The subjects are further separated into those who are symptomatic and asymptomatic.

Figure 3

White matter lesions seen in patients with OTCD. In the top panel are routine T2 weighted scans where the recognition of T2 hyperintensities is not obvious. In the bottom panel, after applying FLAIR imaging, the areas of T2 signal hyperintensity become more apparent.

Figure 4

Voxel locations chosen for 1H MRS; a) parietal white matter; b) posterior cingulate gray matter; c) thalamus; d) frontal white matter; e) frontal gray matter. (reprinted from Gropman AL, Fricke ST, Seltzer RR, Hailu A, et al (2008). Mol Genet Metab. 95(1-2):21-30).

Figure 5

Biochemical areas of significance in OTCD by brain region (reprinted from Gropman AL, Fricke ST, Seltzer RR, Hailu A, et al (2008). Mol Genet Metab. 95(1-2):21-30). These bar graphs demonstrate the concentrations of the major measured metabolites in brain in subjects and controls. Regions of significance between subjects and controls are shown as a p-value.

Figure 6

There is an inverse relationship between brain glutamine and myoinositol levels in subjects with OTCD as measured by 1H MRS. No such relationship was observed in the controls. (reprinted from Gropman AL, Fricke ST, Seltzer RR, Hailu A, et al (2008). Mol Genet Metab. 95(1-2):21-30)

Figure 7

This overlapping spectrum acquired by 1H MRS shows the major brain metabolite differences in subjects with OTCD and controls. The Black indicates an OTCD subject and the gray an age matched control subject (reprinted from Gropman AL, Fricke ST, Seltzer RR, Hailu A, et al (2008). Mol Genet Metab. 95(1-2):21-30).

Figure 8

Pedigree of OTCD family. The two probands are III-1 and III-3. Proband III-1 is asymptomatic and III-3 is symptomatic and presented at age 2.5 years with anorexia, vomiting and encephalopathy. Their mother II-2 is mildly symptomatic. There is a history of neonatal onset disease with lethality in a male. Case II.1 is an OTCD heterozygote who is clinically asymptomatic. Her sister, case III.3 presented at age 2-1/2 with anorexia, vomiting and encephalopathy. She experiences intermittent hyperammonemia and cognitive impairments. Their mother, case II.2, had vomiting and headache with onset of teen years (reprinted from Gropman AL, Fricke ST, Seltzer RR, Hailu A, et al (2008) Mol Genet Metab. 95(1-2):21-30).

Figure 9

This overlapping spectrum shows contributions from 1H MRS: An overlay of the two sisters and normal control is seen (Gropman AL, Seltzer RR, Yudkoff M, Sawyer A, et al (2008) Mol Genet Metab. 94(1):52-60).

Figure 10

13C-labeled substrates can be infused to enhance the MR signal obtained from a localized brain region. The high specificity of the 13C spectrum can be exploited, and the time course of labeled metabolites (shown in filled and partially filled circle) can be tracked through important metabolic pathways (figure compliments of Dr. Brian Ross, Huntington Medical Research Institute, Pasadena, CA).

Figure 11

Cingulum fibers are highlighted as having a decreased FA (see text).

Figure 12

Significant difference in FA between case subject (arginase deficiency) and normal controls in the pons.