Doctors can now use a person’s genetic sequence as the basis for rational drug selection—a sign of how far personalized genomics has come in recent years. A case report published today in the New England Journal of Medicine illustrates the strength of this approach.
The paper describes an extended Saudi Arabian family in which many young siblings suffered from a Parkinson’s-like condition affecting their movement. The children had normal levels of neurotransmitters dopamine and serotonin in their spinal fluid, suggesting they should have been healthy. The unique circumstances prompted researchers to use the latest advances in genomic sequencing to identify a mutation in the SLC18A2 gene, which encodes the protein vesicular monoamine transporter 2, or VMAT2, as the cause of the disease.
A team led by Berge Minassian, a neurologist at the Hospital for Sick Children in Toronto, successfully pinpointed the mutation and treated the symptoms in these siblings. “I am certain that in the next few years patients walking into children’s hospitals will have their whole genomes sequenced,” says Minassian. Until now, magnetic resonance imaging (MRI) has been the primary diagnostic tool for people with neurological diseases.
The study’s initial patient was a 16-year-old girl first diagnosed with muscle weakness when she was just four months old. She sat for the first time when she was two and a half years old, began crawling at four and walking—and only with difficulty—at the very late age of 13. Her symptoms resembled Parkinson’s disease, but all her metabolic and MRI tests came back normal. Doctors also ran tests on her 2-year-old sister who suffered from similar symptoms and a red flag showed up in the toddler’s urine, where dopamine levels were below average. The physicians then gave the 16-year-old and her three younger siblings levodopa-carbidopa, a dopamine precursor used to treat Parkinson’s. They were puzzled, though, when the conditions worsened in all four.
Genome sequencing of the four siblings and four additional cousins identified a single mutation in VMAT2, a protein that works like a molecular pump to package dopamine and serotonin into structures called vesicles inside the nerve cell. The vesicles bind to the cell membrane and export these neurotransmitters into the synapse—the space between two neurons—where they initiate neurotransmission.
The researchers compared cells with mutant VMAT2 against those with a normal version of the protein. Those with mutant VMAT2 packaged only 2 pmol/mg of serotonin over a period of ten minutes, whereas cells with normal VMAT2 packaged 28 pmol/mg over the same time period. “These very important neuromediators can no longer be secreted at the synapse so you have a loss of function at the synapse,” says Minassian, noting that neurotransmitter accumulation inside the neuron is also toxic to the cell. Combined, these factors lead to the Parkinsonian symptoms.
This insight explained why the initial treatment of the siblings hadn’t worked: levodopa-carbidopa is a dopamine precursor molecule that is taken up by the cell and processed into dopamine inside the vesicle. Because mutant VMAT2 was unable to package these precursors into vesicles, they exacerbated the condition by raising the levels of dopamine trapped inside the youngsters’ neurons. The team then treated the four siblings with pramipexole, a drug that acts like a dopamine mimic to activate a neuron’s dopamine receptors, to restore neurotransmission. Within one week, all four siblings showed improvement in learning ability, muscle tone, posture, coordination and speech. The younger siblings benefited more from the treatment because their nervous systems had not suffered as much damage from the disease as in their older siblings.
This study focused on a single mutation in the dopamine and serotonin pathways, paving the way for rational drug selection in other single-gene disorders. However, more complex disorders might not see as swift a benefit. “I don’t think we are at that stage yet for other neurodegenerative targets, particularly in dominant disorders where the relationship between mutation and function is less clear,” says Mark Cookson, a neuroscientist at the US National Institute on Aging in Bethesda, Maryland.
In the end, says Minassian, the best treatments will come with our increased understanding of disease pathophysiology, made possible by advances in personalized genomics and genetic diagnosis.