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UC San Diego Electronic Theses and Dissertations (2007)

ABSTRACT OF THE DISSERATION

Reduced microstructural white matter integrity in a genetic metabolic disorder:

A diffusion tensor MRI study

by

Sunita Bava

Doctor of Philosophy in Clinical Psychology

University of California, San Diego,

San Diego State University, 2007

Professor Doris Trauner, Chair

Infantile nephropathic cystinosis is a genetic metabolic disorder in which cystine accumulates continuously in lysosomes, forming intracellular crystals throughout various organs in the body, including the kidneys, liver, thyroid, and brain. Cognitive deficits are particularly evident in the visuospatial domain and are accompanied by impairments in arithmetic and tactile recognition. Though the genetic causes and behavioral expression of this disorder are well characterized, the underlying neuropathological features are only grossly defined. The available literature suggests that cerebral white matter may be preferentially affected in this group, as cystine crystals have been identified in oligodendrocytes and perivascular macrophages. Within this context, the current study used diffusion tensor MRI to investigate whether early processes in this disorder contribute to selective neuropathological changes. Accordingly, white matter integrity in the dorsal visual pathway (the "where" system) was examined in a young group (ages 3-7 years) of children with cystinosis (n = 24) and compared to an age-matched group of typically developing children (n = 24). A secondary aim of this study was to characterize the relationship between diffusion fractional anisotropy (FA), visuospatial functioning and white blood cell cystine level (an indicator of disease load).

Voxel-based analysis identified reduced FA primarily in bilateral inferior parietal white matter in children with cystinosis. Other areas bearing similar attenuations in anisotropy were found in the right mid-temporal and subgyral frontal regions. To expand this approach on a single-subject level, a region-of-interest (ROI) analysis was conducted focusing on parietal and temporal subregions, corresponding to the neuroanatomical visual pathways. In addition to changes in the inferior parietal lobule (IPL) as identified by voxel-level analysis, results of ROI analysis indicated bilaterally decreased FA in the superior parietal lobule (SPL). These findings occurred in the context of nonsignificant differences in FA in inferior temporal regions. A concomitant increase in the apparent diffusion coefficient (MD) in bilateral SPL and IPL was evident in the cystinosis group, with comparable MD values in inferior temporal white matter. Together, this pattern of findings is consistent with the hypothesized dissociation between the dorsal and ventral pathways in children with cystinosis.

Results of multiple regression analysis revealed an interaction between age and FA, which when decomposed into simple effects, indicated a stronger relationship between FA and visuospatial functioning for older cystinosis children. Specifically, decremented performance on a task of visual-motor integration was associated with reduced FA in the right IPL in school-aged children with cystinosis (age > 5 years, n = 13, r = .74). Spearman correlations between white blood cell cystine level and MD in the right IPL (r = .46) and SPL (r = .50) were evident across the entire cystinosis group. In addition, correlations between cystine level and bilateral parietal MD became apparent in school-aged children, suggesting a progressive effect of cystine accumulation in addition to early white matter changes.

Taken together, significant attenuations in FA suggest that the genetic deletion underlying cystinosis results in early and regionally selective neuropathological changes which may involve myelin-forming oligodendroglia or their precursors. Contrary to expectations, relationships between anisotropy, cognitive performance, and cystine level, were only present in the older children of our group. These findings suggest that the accumulation of cystine over time may constitute a secondary progressive effect that interferes with white matter maturation. Moreover, the extent of cognitive deficit observed in children with cystinosis may result from an interaction of both the static and progressive processes in this condition.

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Cover page: Reduced microstructural white matter integrity in a genetic metabolic disorder: A diffusion tensor MRI study
  • Article
  • Peer Reviewed
UC San Diego Previously Published Works (2022)
OBJECTIVES: The COVID-19 pandemic and the resulting social changes have made unprecedented changes in our lifetime with unknown repercussions on children with autism spectrum disorders. We sought to assess the effect of the COVID-19 pandemic and resulting social changes on boys with autism spectrum disorder. METHODS: We conducted a survey using the CRISIS-AFAR questionnaire of caregivers of a population of boys (n = 40) with moderate to severe autism spectrum disorder for changes in environment and behavior before and after the pandemic. RESULTS: We found several interesting findings, including an increase in self-injurious behaviors after the start of the pandemic, but not in the level of hyperactivity, anxiety, or aggressive behavior, or amount and frequency of stereotypies/repetitive behaviors in the children before and after the start of the pandemic. There was an increased difficulty in adjusting to new daily routines after the pandemic, as well as increased difficulty falling asleep. CONCLUSIONS: The study showed that a majority of boys with moderate/severe autism in our study were negatively affected by the pandemic across several domains. Additionally, this study highlights the need for educational and mental health resources to be prepared for similar events in the future.
    Cover page: Impact of COVID-19 Pandemic-Associated Social Changes on Boys with Moderate to Severe Autism.
    • Article
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    UC San Diego Previously Published Works (2002)
    The purpose of the present study was to describe in greater anatomical detail the changes in brain structure that occur during maturation between childhood and adolescence. High-resolution MRI, tissue classification, and anatomical segmentation of cortical and subcortical regions were used in a sample of 35 normally developing children and adolescents between 7 and 16 years of age (mean age 11 years; 20 males, 15 females). Each cortical and subcortical measure was examined for age and sex effects on raw volumes and on the measures as proportions of total supratentorial cranial volume. Results indicate age-related increases in total supratentorial cranial volume and raw and proportional increases in total cerebral white matter. Gray-matter volume reductions were only observed once variance in total brain size was proportionally controlled. The change in total cerebral white-matter proportion was significantly greater than the change in total cerebral gray-matter proportion over this age range, suggesting that the relative gray-matter reduction is probably due to significant increases in white matter. Total raw cerebral CSF volume increases were also observed. Within the cerebrum, regional patterns varied depending on the tissue (or CSF) assessed. Only frontal and parietal cortices showed changes in gray matter, white matter, and CSF measures. Once the approximately 7% larger brain volume in males was controlled, only mesial temporal cortex, caudate, thalamus, and basomesial diencephalic structures showed sex effects with the females having greater relative volumes in these regions than the males. Overall, these results are consistent with earlier reports and describe in greater detail the regional pattern of age-related differences in gray and white matter in normally developing children and adolescents.
      Cover page: Development of cortical and subcortical brain structures in childhood and adolescence: a structural MRI study
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      UC San Diego Previously Published Works (2010)
      Nephropathic cystinosis is a rare genetic metabolic disorder that results in accumulation of the amino acid cystine in lysosomes due to lack of a cystine-specific transporter protein. Cystine accumulates in cells throughout the body and causes progressive damage to multiple organs, including the brain. Neuromotor deficits have been qualitatively described in individuals with cystinosis. This study quantitatively examined fine-motor coordination in individuals with cystinosis. Brain magnetic resonance imaging (MRI) scans were also performed to determine whether structural changes were associated with motor deficits. Participants were 52 children and adolescents with infantile nephropathic cystinosis and 49 controls, ages 2–17 years, divided into preacademic and school-age groups. Results indicated that both the preacademic and school-age cystinosis groups performed significantly more poorly than their matched control groups on the Motor Coordination Test. Further, the level of performance was not significantly different between the preacademic and school-age groups. There were no significant differences in motor coordination scores based on MRI findings. This is the first study to document a persistent, nonprogressive, fine-motor coordination deficit in children and adolescents with cystinosis. The fact that these difficulties are present in the preschool years lends further support to the theory that cystinosis adversely affects neurological functioning early in development. The absence of a relationship between brain structural changes and motor function suggests that an alternative cause for motor dysfunction must be at work in this disorder.
        Cover page: Neurological impairment in nephropathic cystinosis: motor coordination deficits
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        • Peer Reviewed
        UC San Diego Previously Published Works (2014)
        Cystinosis is caused by mutations in the CTNS gene (17p13.2), which encodes for a lysosomal cystine/proton symporter termed cystinosin. It is the most common cause of inherited renal Fanconi syndrome in young children. Because of its rarity, the diagnosis and specific treatment of cystinosis are frequently delayed, which has a significant impact on the overall prognosis. In this document, we have summarized expert opinions on several aspects of the disease to improve knowledge and provide guidance for diagnosis and treatment.
          Cover page: Nephropathic cystinosis: an international consensus document
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          • Peer Reviewed
          UC San Diego Previously Published Works (2019)
          We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.
            Cover page: Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy
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