Science 11, May 2007

Frozen faces
The syndrome is named for Paul Julius Möbius, a German neurologist who published an early description of it in 1888. (He was also the grandson of August Ferdinand Möbius, the mathematician of Möbius strip fame.) According to a statement developed at the conference, the syndrome’s defining characteristics are facial weakness and impaired ability to move the eyes to the side – symptoms that are present at birth and don’t worsen with age. Researchers estimate that Möbius syndrome occurs in 1 of every 50,000 live births, affecting boys and girls equally often.

The core symptoms of Möbius syndrome point to defects in two cranial nerves: the abducens nerve, which innervates the lateral rectus muscles that rotate the eyes toward the side of the head; and the facial nerve, which innervates the muscles of the face. Yet, there doesn’t seem to be a single neuropathological signature of the disorder.

At the conference, George Padberg, a neurologist at the University Medical Center in Nijmegen, the Netherlands, described magnetic resonance imaging studies he and colleagues have done to visualize the nervous system in people with Möbius syndrome, as well as findings from electrophysiological tests of nerve function. This work has revealed a variety of defects. In some patients, the cranial nerves appear to be damaged or even missing. Others have abnormalities in the brainstem that include – and often extend beyond – the region where the abducens and facial nerves originate. Based on these and other findings, Padberg suspects that Möbius syndrome results from genetic miscues that derail the embryonic development of the brainstem.

But the search for the relevant genes has yielded little fruit so far. The rarity of the disorder, coupled with the fact that only about 2% of cases are inherited, makes it difficult to find a sufficient number of subjects for genetic linkage studies, says Ethylin Wang Jabs, a geneticist at Johns Hopkins University in Baltimore, Maryland. The complexity of the disorder and lack of precise diagnostic criteria have also complicated matters, Jabs says. Padberg’s group, for example, has published studies identifying regions of chromosome 3 and chromosome 10 as likely loci of genes related to inherited Möbius syndrome in two Dutch families, but other researchers point out that individuals in these families lack the eye-movement irregularities necessary to qualify as true cases of Möbius syndrome. (Padberg now agrees.)

Now that there’s a more precise definition of the disorder, the next step for finding Möbius genes, Jabs and others say, will be to create a central database in which researchers can share clinical and genetic data on Möbius patients. Jabs has started a database that now includes clinical data and/or DNA samples from 89 people with Möbius syndrome and more than 100 relatives, and other research teams have similar data.

Researchers are also looking to related disorders and mouse models of brain development for clues. At the conference, Elizabeth Engle, a pediatric neurologist at Children’s Hospital Boston, described her team’s research on several inherited neurological conditions that share symptoms with Möbius syndrome. Athabascan brainstem dysgenesis syndrome (ABDS), named for the Native American population in which it was first described in 2003, causes impaired lateral eye movements and sometimes facial weakness as well. Similar symptoms had been reported in mice lacking a gene called Hoxa1, one of a family of genes that guide embryonic development. People with ABDS inherit a truncated copy of the human version of the gene, HOXA1, Engle and colleagues reported in 2005 in Nature Genetics. It’s possible that spontaneous mutations in HOXA1 could be involved in Möbius syndrome, Engle says, but so far no one has looked. Jabs has been screening her Möbius patients for mutations in two other Hox genes, HOXB1 and HOXB2, based on findings of facial nerve abnormalities in mice lacking these genes. So far, however, nothing has turned up.

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