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Velo-Cardio-Facial Syndrome

Velo-Cardio-Facial Syndrome. PRINCIPAL INVESTIGATOR: Marek Kubicki, MD, PhD INVESTIGATORS: Zora Kikinis, PhD Sylvain Bouix, PhD Marc Niethammer, PhD Martha Shenton, PhD Christine Finn, MD Raju Kucherlapati, MD RESEARCH ASSISTANT: Doug Markant, BA. Velo-Cardio-Facial Syndrome (VCFS).

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Velo-Cardio-Facial Syndrome

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  1. Velo-Cardio-Facial Syndrome PRINCIPAL INVESTIGATOR: Marek Kubicki, MD, PhD INVESTIGATORS: Zora Kikinis, PhD Sylvain Bouix, PhD Marc Niethammer, PhD Martha Shenton, PhD Christine Finn, MD Raju Kucherlapati, MD RESEARCH ASSISTANT: Doug Markant, BA

  2. Velo-Cardio-Facial Syndrome (VCFS) • Condition defined by Sphrintzen in 1978 • Chromosome 22 q11.2 deletion. Deletion of 1.5 to 3 Mb (single copies of 30 to 45 genes missing) • Prevalence 1 in every 4000 newborns

  3. VCFS Symptoms • "velum" latin meaning soft palate Cleft palate, small or aplastic tonsils, hypernasal speech • “kardia" greek meaning heart VSD , right sided aortic arch, tetralogy of Fallot, aberrant subclavian artery • "facial" latin having to do with the face maxillary excess, malar flatness, facial asymmetry, thin upper lip, prominent nasal root, large nasal tip, pinched, hypoplastic base

  4. Common Cognitive Deficits in VCFS • Psychomotor and perceptual deficits • Learning and memorydisabilities • Emotional abnormalities (flat affect and poor social interaction). • High incidence for schizophrenia and/or bipolar disorder in adult(30%VCFS patients developschizophrenia)

  5. Neuroimaging Findings in VCFS • MRI case reports (most) • - high frequency of nonspecific white matter hyperintensities (30% of cases) • - cavum septi pellucidi (in 45% of cases) • MRI quantitative reports (few) • - Reduced volumes of regions related to language and verbal memory (superior temporal gyrus, hippocampus, amygdala and parietal lobe). • - Increased volume and posterior displacement of the corpus callosum • DTI (two studies) • - Reduced anisotropy in frontal, parietal, and temporal white matter • - Reduced anisotropy in white matter tracts connecting frontal and temporal lobes • - Reduced anisotropy in inferior parietal lobule which is correlated with scores from the arithmetic subscale of the WISC/WAIS, after co-varying for IQ and age of subjects.

  6. Neuroimaging Findings in VCFS Cases with Schizophrenia • MRI (3 studies, only one with IQ matched populations) • - Decreased total gray and white matter volumes • - Increased total and sulcal CSF volumes. • - Decreased frontal, temporal and parietal gray matter volumes • - Increased corpus callosum volume • Based on scarce findings, VCFS investigators proposed a model, in which a deficiency in frontal maturation leads to a vulnerability for schizophrenia among individuals with VCFS • DTI • - None

  7. VCFS Schizophrenia Candidate Genes • COMT (controls dopamine degradation in prefrontal cortex, related to attention and memory) • RTN4R(also known as Nogo-66 Receptor, related toaxonal regeneration and plasticity as well as myelin) • PRODH (one of the enzymes to convert proline to glutamate)   • ZDH8 • SNAP29 • TBX1

  8. Project • Subject recruitment • Psychological interview • DNA analysis, genotyping of the 22q11.2 region • Brain imaging (MRI and DTI on 3T) • Analysis of imaging data, and genetic correlations

  9. Aims • Etiology of schizophrenia and related diseases • Prognosis of mental health diseases in VCFS • Early intervention

  10. Hypotheses • Regions that we want to study with MRI • DLPC (COMT) • Orbital Frontal Gyrus (emotion) • Cingulate Gyrus (attention, emotion) • Hippocampus (memory, learning) Tracts that we want to study with DTI • Fornix (memory) • Arcuate Fasciculus (language) • Cingulum Bundle (attention) • Uncinate Fasciculus (emotion, affective flattening)

  11. Potential Challenges for Atlas Based Scripts • Brain atrophy • Congenital abnormalities • Brain asymmetry • White matter lesions

  12. Velo-Cardio-Facial Syndrome (VCFS) as a Genetic Model for Schizophrenia. PRINCIPAL INVESTIGATOR: Marek Kubicki, MD, PhD INVESTIGATORS: Zora Kikinis, PhD Sylvain Bouix, PhD Marc Niethammer, PhD Christine Finn, MD Raju Kucherlapati, MD Martha Shenton, PhD RESEARCH ASSISTANT: Doug Markant, BA • BACKGROUND: • VCFS is a rare genetic syndrome (single copies of 30-45 genes on 22 chromosome are missing) • 30% of patients with VCFS develop schizophrenia • AIMS: • To characterize anatomical similarities and dissimilarities between VCFS and Schizophrenia • To find “schizophrenia” genes • DATA: • DTI, MRI, haplotypes, neuropsychology

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