Research: Research Interests

print this page | close window

Walker Warburg Syndrome

The association of hydrocephalus with lissencephaly and eye abnormalities was first described by Walker in 1942. Later, Warburg reported that this syndrome was inherited as an autosomal recessive disorder, meaning that it occurs when an individual has received 2 malfunctioning copies of a gene, one from each parent. Over time, we have learned more about the specific malformations present in what is now known as the Walker Warburg Syndrome.

The primary features in the brain are type II lissencephaly and cerebellar malformations, often leading to hydrocephalus. Many children also present with encephalocele. Lissencephaly literally means "smooth brain" - without the typical folds or gyri that increase the overall surface area of the brain. Type II lissencephaly is not entirely smooth. Instead, the brain's outer layers (the cerebral cortex) are disorganized and form a bumpy or "cobblestone" appearance. Hydrocephalus refers to "water on the brain". This can occur if there is a blockage preventing fluid in the ventricles of the brain from draining properly. In Walker Warburg Syndrome, this blockage can result from abnormalities of the cerebellum. Sometimes, children with Walker Warburg Syndrome will be described with a Dandy-Walker malformation. Dandy-Walker malformation is not a specific diagnosis but means that there is a cyst in the 4th ventricle of the brain and associated cerebellar malformations. Encephalocele is a defect in the bone of the skull allowing some of the brain to protrude through this opening. Not all children with Walker Warburg Syndrome will have all of these findings, but the type II lissencephaly seems to be present in almost everyone. There are many possible eye abnormalities including microphthalmia (very small eyes), macrophthalmia (very large eyes), cataracts, glaucoma, and abnormal retinas.

Since the original description of Walker Warburg Syndrome in 1942, we have discovered that most children have a muscular dystrophy in addition to the eye and brain findings. This muscular dystrophy presents as significantly low muscle tone with poor reflexes. It can be detected by measuring the level of some muscle enzymes.

As with other types of lissencephaly, there is a range of severity with some children having severe illness and others having milder Walker Warburg Syndrome. Some children with severe Walker Warburg Syndrome die in the 1st year of life while those with mild Walker Warburg Syndrome may do much better.

As mentioned earlier, Walker Warburg Syndrome is an autosomal recessive disorder and occurs when a child receives two malfunctioning copies of the gene involved in this condition. Most children are born to parents who are "silent carriers" of a gene mutation that may never have presented itself in the family before. All of our genes occur in pairs, with one gene of each pair coming from each parent. We believe that all of us carry genes that have the potential to cause genetic disorders if an individual inherits two copies of those genes. If two parents who are carriers of the same malfunctioning gene (silent carriers) have a child, there is a 1 in 4, or 25%, chance that the child will inherit 2 copies and will have the disorder. This same chance exists with each pregnancy the couple has together.

Recently, our laboratory, in conjunction with a group in the Netherlands, reported the discovery of a gene associated with Walker Warburg Syndrome. This gene, known as POMT1, codes for a protein known as O-mannosyltransferase 1, an enzyme involved in adding sugars to proteins. In the research done so far, changes (mutations) in the POMT1 gene were seen in 6 of 30 individuals with Walker Warburg Syndrome. Because 24 of the individuals studied did not have any apparent changes within this gene or in the regulation of this gene, it is presumed that there is at least one another, as yet unidentified, gene involved in causing Walker Warburg Syndrome. Research is ongoing in our laboratory to identify any other Walker Warburg Syndrome genes.


MRIs: T1 Axial | T1 Axial | T2 Axial | T2 Axial | T1 Sagittal | T1 Sagittal


If you have a child who you think may have this condition and you would like us to review the diagnosis, please contact our research coordinator by e-mail at walshlab@bidmc.harvard.edu or by phone at (617) 919-4371.