30% of the patients received a definitive diagnosis
using whole-exome sequencing.
Genetic testing may be important for patient counseling.
For instance, if a patient has a family history of Huntington’s disease and develops symptoms suggestive of
Huntington’s disease, a normal test result is therapeutic,
Dr. Jinnah said. Normal results may be false negatives,
however. For example, next-generation sequencing
methods are not suitable for detecting certain problems
like large insertions, duplications, triplet disorders, and
certain genes, and neurologists should consider whether
other tests may be useful.
If a genetic test yields a pathologic result, it can inform prognosis and guide family counseling and planning. Furthermore, some inherited disorders have life-altering treatments.
Neurologists are familiar with typical and atypical
presentations of Wilson’s disease because the disorder
has highly effective treatments. But recent studies have
identified lesser-known disorders that may be equally im-
portant to recognize. “How many of us are routinely testing
these same cases for disorders of manganese transporters?”
Dr. Jinnah asked. “It is relatively new information, but the
clinical scenario is virtually identical.”
The International Parkinson and Movement Disorder
Society’s Rare Movement Disorders Task Force sought to
determine how many treatable genetic movement disor-
ders have been identified. The task force found more than
30 disorders with specific treatments—including vitamins,
dietary interventions, trigger avoidance, and drugs—that
can have “a dramatic impact on the patient’s clinical
course,” Dr. Jinnah said. “All of them are quite rare, but
we do not want to miss them, because they are treatable.”
Investigators identify more treatable disorders each year.
Interpreting Ambiguous Results
Another practical concern for neurologists is the interpreta-
tion of variants of unknown significance (VOUS) in genetic
test results. “It means that a change or variant in the normal
gene was discovered by the laboratory, but the change has
never been described in association with the disease that
you are interested in,” Dr. Jinnah said. “As a result, the
laboratory cannot tell you whether it is relevant or not.”
Neurologists might be inclined to tell a patient that
they “found something weird in their DNA,” but this
approach “consolidates the patient’s concern that they
have some mysterious disorder that none of the doctors
can figure out, even the experts,” he said. Nor should
neurologists tell a patient that the VOUS is not signifi-
cant, because that is not what VOUS means.
A VOUS is comparable to a radiology report that
says, “Clinical correlation is advised.” That phrase leads
neurologists to compare neuroimaging to the clinical
phenotype and ask whether the imaging findings make
sense. “A VOUS is no different from this,” he said. Neu-
rologists cannot explain all genetic variants, just as neu-
rologists cannot explain all of the spots on a brain scan.
“We have to get comfortable with the fact that we do
not have answers for everything and that there will be
some ambiguities when we are done.”
Genetics is logical and straightforward, and edu-
cational sessions are available at conferences for neu-
rologists who are interested in learning more about
genetic testing, Dr. Jinnah said. Neurologists also can
refer patients to experts. “This referral must be a col-
laboration,” he said. “People in human genetics are
not trained in movement disorders, and many of them
have no formal training in neurology. They need your
careful phenotypic exam to point them in the direction
of ataxia tests, parkinsonism tests, or dystonia tests.”
Genetic testing often is expensive, not readily avail-
able, and not covered by insurance, but this situation
may change, Dr. Jinnah said. He likened the situation
of genetic testing today to that of MRI in the 1980s.
“Only a few centers in the world had [MRI]. It was
extremely expensive. Now, MRI scanners are every-
where, and everybody uses it because it is so valuable
in clinical medicine,” he said. “I suspect that in a few
years, we will see the same with genetic tests.” NR
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