VANCOUVER—Researchers’ under- standing of genetic causes of movement disorders is advancing rapidly. “The
ability to generate data has almost surpassed our ability to understand and use it
in the clinic,” said Buz Jinnah, MD, PhD,
at the 21st International Congress of Parkinson’s Disease and Movement Disorders.
A recent study underscores the swift
evolution of the field. Investigators compared the diagnostic ability of a dystonia
gene panel with that of experts who formulated a diagnostic workup without the use of gene
panel analysis. In a cohort of 61 patients, the gene
panel led to more genetic diagnoses and did so faster
and at less cost on average, compared with experts using traditional methods.
Neurologists face practical questions, such as which
patients need genetic testing, which tests they should
perform, and how the results influence clinical management, said Dr. Jinnah, Professor of Neurology, Human
Genetics, and Pediatrics at Emory University School of
Medicine in Atlanta. Neurologists once considered Wilson’s disease to have the only genetic cause of movement
disorders that significantly changed treatment. Now, researchers have identified more than 30 genetic movement disorders with specific, effective treatments.
Does a Patient Need Genetic Testing?
Not all patients need genetic testing. In some cases, the
need for genetic testing is obvious, but in other cases, it
is not so clear, Dr. Jinnah said. Certain features increase
suspicion for a genetic disorder, such as family history,
unusually young age of onset, and combinations of features that fit a recognized syndrome.
Genetic testing also may be warranted in presumed
acquired cases. “Methodical studies of these so-called
acquired cases reveal a high proportion of genetic ex-
planation for them,” he said. “We typically think of
cerebral palsy as an acquired disorder…. But the stud-
ies are now showing that about a third of these cases
have a genetic explanation.”
Single-gene sequencing, chromosomal
microarray, and tests for deletions or in-
sertions are available, as well as next-gen-
eration sequencing methods with broader
reach. Next-generation techniques include
gene panels that can test hundreds of genes
associated with a disease, whole-exome se-
quencing, and whole-genome sequencing.
Choosing a Test
Experts tend to use one of three strategies to select which genetic test to perform. One approach entails identifying red flags—“telltale clinical
features that point to a specific diagnosis or group of
diagnoses,” said Dr. Jinnah.
Another approach involves pattern recognition. Syndromic combinations may lead a neurologist “straight to
a single gene test to confirm the diagnosis” if a patient
has a classic presentation of a genetic disease.
The third approach uses diagnostic algorithms. “
Depending on the presence or absence of various clinical features …
[an algorithm] tells you which gene or collection of genes
you need to test for,” he said.
Each strategy has limitations, however. It is difficult to remember all of the red flags and syndromic
patterns, and many disorders lack red flags. Atypical
syndromes can be misleading, and atypical presentations that have been reported in the literature for
decades “continue to surprise us,” Dr. Jinnah said.
Researchers have published various diagnostic algorithms for dystonia, parkinsonism, and ataxia, and
none of them is perfect.
Several studies have shown the potential of next-generation genetic testing. A report from the NIH’s
Undiagnosed Diseases Program found that 25% of
patients in the program reached a diagnosis within
a few weeks using whole-exome sequencing. “Their
conclusion was that these agnostic methods need to
be used earlier in the diagnostic process,” he said.
A similar study in Canada evaluated the use of
whole-exome sequencing in 362 children with disorders that experts had not been able to diagnose. About
How to Keep Pace With Genetic
Advances in Movement Disorders
Buz Jinnah, MD, PhD