September-October 2018

From Genes to Molecular Pathways: A Paradigm Shift in Understanding Brain Malformations


Alireza Radmanesh

Over the past decade, advances in MRI techniques and molecular biology have revolutionized our understanding of brain malformations. During this time, classifications for developmental malformations of the cortex, or those of the midbrain and hindbrain, have undergone a few revisions in light of the evolving understanding of their molecular mechanisms.1,2

In the early part of the past decade, much emphasis was placed on classifying genetic malformations based on the specific gene that was mutated. Therefore, authors grouped diseases from different mutations of the same gene together. For example, mutations of the GFAP gene associated with infantile macrocephaly and other mutations of GFAP associated with spinomedullary degeneration in adults were all classified as Alexander disease.

Despite the values of such classifications, many different genes involved in the same molecular pathway may cause a single clinical disorder. For example, Leigh syndrome could have many different genetic causes all of which result in defective oxidative metabolism and energy production.3,4

On the other hand, different mutations of the same gene could cause different phenotypes (different diseases), because proteins have complex structures with different components participating in different molecular pathways. Therefore, different mutations affecting different structural components of a protein could affect very different pathways and lead to distinct phenotypes.

In addition to different mutations of the same gene, epigenetic factors and environmental factors likely modulate clinical phenotypes, further complicating this tangled web. Therefore, sooner or later neuroscientists will need to reclassify diseases by how each specific mutation or epigenetic modification affects the function of the … more »

Genetics Vignette

Genetics of Von Hippel-Lindau Disease

Von Hippel-Lindau Disease

Raymond Tu

We have a research interest in relating imaging with genomics. Our brief review article, “Genetics of Von Hippel-Lindau Disease,” is an educational review for the radiologist to help link genotypes with imaging phenotypes.

Von Hippel-Lindau (VHL) disease is particularly interesting in that both molecular genetic sequencing and imaging play crucial roles in disease diagnosis and surveillance. … more »


Neuroradiologic Features of CASK Mutations

Jun-ichi Takanashi

Jun-ichi Takanashi

CASK belongs to the membrane-associated guanylate kinase protein family, which transfers phosphorus-containing groups (phosphotransferases) with a phosphate group as an acceptor; this is an important function during neuronal development. CASK regulates gene expression by interacting with a nucleosome assembly protein (CINAP) and the transcription factor TBR1 to form a complex that induces the transcription of genes … more »


Characteristic MR Imaging Findings of the Neonatal Brain in RASopathies

Mehmet N. Cizmeci

Our multicenter, observational study on RASopathies, was the first study to describe cranial MRI findings in infants with a RASopathy, and our starting point was an observation that the infants with Noonan syndrome had a very characteristic, steep tentorial configuration. Briefly, RASopathies are a group of rare genetic conditions with overlapping phenotypic features.1 There are over 15 … more »


Disorders of Microtubule Function in Neurons: Imaging Correlates

James Barkovich - MAP gene mutations

James Barkovich

I chose the topic of disorders of microtubule function because I was seeing a lot of patients with brain malformations due to mutations of tubulin genes (such as TUBA1A, TUBB2B, TUBG1, etc.) and microtubule-associated protein (MAP) genes (such as DCX, LIS1, and DYNCH1H1) and saw that they had characteristic features that could … more »

Head & Neck

Anatomic Malformations of the Middle and Inner Ear in 22q11.2 Deletion Syndrome: Case Series and Literature Review

Emmy Verheij

Although it is a relatively unknown syndrome, 22q11.2 deletion syndrome occurs rather frequently. The prevalence is estimated at 1: 2,000 – 4,000 live births. The great variability in phenotype makes it a very scientifically interesting syndrome because many different organs can be impacted. Balance disorder is one of the described features in this syndrome and it was thought … more »