Velo-Cardio-Facial Syndrome

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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
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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

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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

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Common Cognitive Deficits in VCFS

• Psychomotor and perceptual deficits
• Learning and memory disabilities
• Emotional abnormalities (flat affect and poor
  social interaction).
• High incidence for schizophrenia and/or bipolar
  disorder in adult (30 VCFS patients develop
  schizophrenia)

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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.

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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

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VCFS Schizophrenia Candidate Genes

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

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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

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Aims

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

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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)

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Potential Challenges for Atlas Based Scripts

• Brain atrophy
• Congenital abnormalities
• Brain asymmetry
• White matter lesions

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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