Genetic factors may hinder treatment in Parkinson’s caused by gene: Case
After a good initial response, woman's symptoms severely worsened
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- A case report from Japan suggests that genetic factors may hinder treatment for people with Parkinson's caused by a VPS13C gene mutation.
- After successful initial treatment with medication and DBS, a woman with early-onset Parkinson's experienced rapidly worsening symptoms.
- This case shows that genetic testing is crucial before deep brain stimulation in early-onset Parkinson's, per researchers.
A woman diagnosed with early-onset Parkinson’s disease — later found to be caused by a mutation in the VPS13C gene — initially responded well to medication and deep brain stimulation (DBS), but then experienced rapid worsening of both her motor and nonmotor symptoms, ultimately leaving her unable to live independently.
According to clinicians, the woman’s case suggests that genetic factors may limit how well treatment works for people whose Parkinson’s is due to specific disease-related genes. Further, the team cautioned that DBS surgery in people with early-onset Parkinson’s is best done only after genetic testing.
“The VPS13C genotype [genetic makeup] is a critical factor in prognosticating DBS outcomes,” the scientists wrote. “Clinicians must inform patients and families that medium-to-long-term outcomes are uncertain because of possible rapid motor, cognitive, and psychiatric decline.”
A report detailing the woman’s treatment, titled “Deep brain stimulation in VPS13C-associated Parkinson’s disease: a longitudinal case study,” was published in the journal Clinical Parkinsonism & Related Disorders by a quintet of researchers in Japan.
While the causes of Parkinson’s aren’t fully understood, the neurodegenerative disease is sometimes due to genetic mutations, such as those in the VPS13C gene. This gene encodes VPS13C, a protein that helps maintain lysosomes, which are structures that break down waste in cells.
When VPS13C is mutated, misfolded proteins build up and become toxic to nerve cells, potentially contributing to the progressive loss of nerve cells.
Woman’s symptoms began at age 24, leading to diagnosis
In Japan, a woman without a family history of Parkinson’s began experiencing symptoms at age 24 and was soon diagnosed with early-onset Parkinson’s. At first, her symptoms were mild, and included abnormal toe curling and stiffness on the left side of her body. She began treatment with pramipexole dihydrochloride, marketed in the U.S. as Mirapex ER.
In Parkinson’s, symptoms are caused by a loss of dopamine, a chemical in the brain that helps control movement. Pramipexole dihydrochloride works by mimicking the activity of dopamine in the brain. Over time, however, the medication effects began to wear off, and symptoms become more difficult to control.
That was the case for this woman, who often experienced off episodes, or times when symptoms return or worsen between two doses of medication.
During off times, she became unable to move, but her symptoms eased with rescue doses of levodopa, which the body can use to produce dopamine, or Apokyn (apomorphine), which mimics dopamine.
However, “management was challenging, requiring complex medication adjustments,” the researchers wrote. “Although the patient was able to go outdoors during on periods, severe daytime off periods frequently rendered the patient bedbound and unable to handle medication packaging or leave the restroom.”
By age 30, her doctors recommended DBS, a surgical procedure in which electrodes are placed in a part of the brain called the subthalamic nucleus. A small device then sends electrical signals to help normalize neural activity, which can ease motor symptoms.
Initially, DBS worked well, and the woman returned to daily activities, the researchers noted.
Genetic testing 9 years after diagnosis revealed gene mutation
At age 33, genetic testing identified an unknown, disease-causing mutation in the VPS13C gene as the reason for the woman’s early Parkinson’s.
A couple of years later, and despite medication and DBS, she developed worsening motor symptoms, including difficulty walking, frequent falls, and slurred speech.
According to the researchers, these findings support “genetic testing before DBS.”
At the same time, she developed cognitive and psychiatric symptoms and “became unable to distinguish between numbers and alphabets on a keyboard,” the researchers wrote. Her “work performance … deteriorated due to frequent errors.”
She also developed apathy (lack of motivation),as well as anhedonia, or an inability to feel pleasure. Further, she now had reduced control over behavior, which led to inappropriate actions, among other issues.
By age 36, her cognitive function had declined severely. She needed constant supervision and could no longer live independently. On one occasion, “the patient was found wandering in public in a state of undress (wearing only underwear) and was detained by the police for safety and hospitalized,” the researchers wrote.
[The findings in this case support] genetic testing before DBS.
Brain scans did not show progressive loss of brain tissue. Clinicians also tried MIBG cardiac scintigraphy, which uses a tracer to see how well the autonomic nervous system, which controls internal organs and automatic functions such as heart rate and blood pressure, is working. That testing showed loss of nerve supply to the heart over just seven years, according to the researchers.
Per the team, “the present case is consistent with brain-first [Parkinson’s],” in which misfolded proteins first form in the brain, rather than in the gut, causing the disease to progress faster. This distinction refers to two proposed pathways of Parkinson’s disease, in which symptoms may begin in the brain or the digestive system before spreading throughout the body.
Further research is needed to determine whether mutations in the VPS13C gene are always associated with brain-first Parkinson’s, the researchers stated.
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