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Looks Like One, Quacks Like One, Decidedly Isn’t

News from the Johns Hopkins Department of Psychiatry and Behavioral Sciences

A rare Huntington’s look-alike could help the cause.

The irritability, the hours closeted in her bedroom and the mood swings would’ve been reason enough for the Taylors to bring their sister, Lavinia,* to a psychiatrist. But in this family, dismay comes before a diagnosis. They’ve seen their relatives’ progressive decline, watched as clumsiness, involuntary movements, odd behavior and thinking take over, and life fades away.

So, in 1995, when family history and a morning of neurological, cognitive and psychiatric exams at Hopkins’ Huntington’s disease (HD) clinic confirmed their sister’s troubles ahead, the Taylors weren’t surprised. Psychiatrist Russell Margolis and his colleagues, however, were. And that surprise has cleared an unusual path in Huntington’s research. 

Russ Margolis
“It’s taken us years to get this far,” says Russ Margolis, whose work with Dobrila Rudnicki shines a light on HD.

One offshoot of the 1993 discovery of the HD gene mutation was the appearance of a test to spot it in patient DNA, one that Hopkins was quick to include in patient workups. And data has mounted tying those with the disease to the characteristic mutation, a large repetition of a pattern of DNA bases—CAG,CAG,CAG and so on—called a repeat expansion. Researchers here found that the more repeats, the earlier the onset of Huntington’s disease. But nobody has been able to show how repeats lead to sure, irrevocable death of deep brain nuclei. That would be the veritable key to therapy.

Then, however, along comes Lavinia, who turned things around. “We hadn’t had any reason to believe she was different,” says Margolis. To anyone’s clinical eye, the African-American woman in her late 30s had HD; all the neurological, cognitive and behavioral symptoms were there. CT and MR images showed the same brain shrinkage. But Taylor was negative for the mutant HD gene. Yes, she had abnormally high repeat expansions, but of a different kind, a CTG,CTG pattern. Moreover, Margolis’ team found, the culprit mutation was on a different gene, on a different chromosome.

A field trip to the family’s North Carolina home told more. “We saw an illness nearly identical to Huntington’s visually, but with the key genetic difference only in affected family members,” says Margolis, who heads Hopkins’ Laboratory of Genetic Neurobiology. He estimates that the new disorder, called Huntington’s disease-like 2 (HDL2), claims less than 1 percent of those diagnosed with HD.

Now the team has identified 25 HDL2 families, many in South Africa. A half-dozen autopsies verify the strong similarities. But despite HDL2’s being both incurable and rare to boot, it holds unusual potential to explain HD. “We know it’s odd that such an uncommon disease has such importance,” says Margolis. “But its HD-like outcome suggests the two share a common pathway at some point—a place to focus our efforts to get at the major mechanisms and to target therapy, if we’re lucky, for both diseases.” 

Led by colleague Drobrila Rudnicki, Ph.D., Margolis’ team has begun crucial work to define how HDL2 and HD differ on a molecular level. Already there’s evidence that the odd repeats in the DNA spark appearance of a flawed RNA that, by itself, can damage neurons—a new and unsuspected agent of nervous system disease. Rudnicki has shown that nerve cells carrying HDL2 genes don’t survive. And direct contact with the abnormal RNA quickly kills nerve cells in cultures. Next, the group begins studies with their newly created HDL2 animal models—a useful result of a family’s help.

For information, call 410-614-4262.
*not her real name

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