Parkinson’s Disease (Nalls, 2019) – Is Parkinson’s genetic?

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Nebula Genomics DNA Report for Parkinson’s Disease

Is Parkinson’s genetic? We created a DNA report based on a study that attempted to answer this question. Below you can see a SAMPLE DNA report. To get your personalized DNA report, purchase our Whole Genome Sequencing!

Sample report on Parkinson's from Nebula Genomics
Sample report on Parkinson's variants from Nebula Genomics

Additional Information

What is Parkinson’s? (Part 1 of Is Parkinson’s genetic?)

Parkinson’s disease or PD is a result of the slow, progressive loss of nerve cells. The characteristic symptoms are akinesia (reduction or loss of voluntary movement), rigor, and tremors. Currently, there is no cure for this degenerative disease of the nervous system, although the symptoms are treatable.  

Parkinson’s disease is characterized by the predominant loss of dopamine-producing neurons (brain cells) in the substantia nigra region in the brain. The lack of the neurotransmitter dopamine ultimately leads to a reduction in the activating effect of the basal ganglia on the cerebral cortex and thus to the noticeable movement disorders.

Non-Parkinson's and Parkinson's brain
Parkinson’s is associated with the loss of dopamine in the substantia nigra. Wikipedia. CCAttribution 3.0 Unported

There are a number of classifications of Parkinson’s disease based on disease origin and progression. These categories include:

  • Idiopathic Parkinson’s syndrome (IPS) (most frequent)
  • Familial Parkinson syndrome (genetic, hereditary forms, rare, named after the respective gene locus (i.e. PARK1)
  • Symptomatic (secondary) Parkinson’s syndromes
  • Drug-induced (i.e. neuroleptics with dopamine antagonism)
  • Vascular parkinsonism, as in cerebral microangiopathy (Binswanger’s disease)
  • Post-traumatic (ie. boxer’s encephalopathy)
  • Toxin-induced (i.e. carbon monoxide, manganese, MPTP)
  • Inflammatory (e.g., after encephalitis lethargica, also in diffuse pathogen-related brain diseases such as advanced HIV encephalopathy)
  • Metabolic (Wilson’s disease)
  • Parkinsonian syndromes in the context of other neurodegenerative diseases (atypical Parkinsonian syndromes)
  • Multisystem atrophy
  • Progressive supranuclear gaze palsy
  • Corticobasal degeneration
  • Lewy body dementia

Epidemiology (Part 2 of Is Parkinson’s genetic?)

According to the Parkinson’s Foundation, the disease affects more than 10 million people worldwide. According to their projections, nearly one million will be living with Parkinson’s disease in the United States by 2020, which is more than the combined number of people diagnosed with multiple sclerosis, muscular dystrophy and Lou Gehrig’s disease (or Amyotrophic Lateral Sclerosis).

Approximately 60,000 Americans are diagnosed with PD each year.

A map of deaths due to the disease in 2012
Deaths from Parkinson’s disease in 2012 per million persons. Statistics from WHO. Wikipedia. CCAttribution-Share Alike 4.0 International

Incidence of Parkinson’s disease increases with age, but an estimated four percent of people with PD are diagnosed before age 50. Men are 1.5 times more likely to have Parkinson’s disease than women.

Symptoms (Part 3 of Is Parkinson’s genetic?)

The disease begins gradually and progresses throughout life. The symptoms become more severe as the disease progresses and are therefore more easily recognizable. The most common form of Parkinson’s disease typically begins unilaterally, in one side of the body. It is therefore not uncommon for shoulder pain and unilateral muscle tension to occur, prompting the patient to first see an orthopedist.

According to the Parkinson’s Foundation, ten early symptoms include:

  1. Tremor
  2. Small handwriting
  3. Loss of smell
  4. Trouble sleeping
  5. Trouble moving or walking
  6. Constipation
  7. A soft or low voice
  8. Masked face
  9. Dizziness or fainting
  10. Stooping or hunching over

As the disease progresses, Parkinson’s disease is defined by the cardinal symptoms of bradykinesia (slow movement) or akinesia (loss or impairment of the power of voluntary movement) and one of the other three leading symptoms (rigidity, tremor, postural instability).

Akinesia and/or bradykinesia

This general lack of movement is a prerequisite for the diagnosis of Parkinson’s disease. It is noticeable in all movements. Thus, the muscle play in the face is reduced, speech becomes quiet and unclear, swallowing is delayed, the dexterity of the hands decreases especially with fast movements (handwriting becomes smaller), the trunk movements are difficult, and the gait becomes small-stepped and shuffling.

In Parkinson’s, this slowness happens in different ways:

  • Reduction of automatic movements (such as blinking or swinging your arms when you walk)
  • Difficulty initiating movements (like getting up out of a chair)
  • General slowness in physical actions
  • The appearance of abnormal stillness or a decrease in facial expression

This translates into difficulty performing everyday functions, such as buttoning a shirt, cutting food or brushing your teeth.

Rigidity

This refers to muscle stiffness due to an increase in muscle tone. It is caused by an involuntary tensing of the entire striated musculature and often also leads to muscle pain. Outwardly visible is a slight flexion of the elbow joint, trunk and neck, and later of the knee joints.

Tremor

Alternating tension of opposing muscles produces a relatively slow tremor that decreases with movement. The tremor is more prominent on one side of the body.

Postural instability

Decreased stability in holding the body upright occurs due to a disturbance in the positional reflexes. The small but rapid reflex compensatory movements are delayed, resulting in gait and stance instability. The turning movement becomes unsteady and patients may start tripping. 

The various symptoms can be pronounced to different degrees in individual patients or be completely absent. Their occurrence and severity also change during the course of the day.

Symptoms of Parkinson's
Symptoms of Parkinson’s are often divided as motor and non-motor impairments. Wikipedia. CCAttribution-Share Alike 4.0 International

Patients may also experience other illnesses such as low blood pressure and sleep problems.

Causes (Part 4 of Is Parkinson’s genetic?)

Scientists believe that a combination of genetic and environmental factors play a role in the loss of dopamine in the brain and the following onset of Parkinson’s disease. The disease is very diverse among patients, with individuals differing in age onset, progression, and even treatment effectiveness. 

Dopamine deficiency

Parkinson’s disease is a degenerative disease of the extrapyramidal motor system (EPS) or basal ganglia. It involves the death of nerve cells in the pars compacta of the substantia nigra, which produce dopamine and transport it through their axons into the putamen. The first signs of disease are only noticed when approx. 55% to 60% of these dopaminergic cells have died.

The dopamine deficiency ultimately leads to an imbalance in the function of the basal ganglia in two ways. The messenger substance glutamate is relatively abundant. The globus pallidus internus ultimately inhibits the motor activation of the cerebral cortex by the thalamus. This leads to the main symptoms rigor, tremor and hypokinesia, but also to a slowing of mental processes (bradyphrenia).

In addition to the dopamine deficiency, changes in other neurotransmitters have also been observed. For example, serotonin, acetylcholine and norepinephrine deficiency was found in some regions of the brain stem.

Is Parkinson’s Genetic?

Research and identification of the inherited forms have shown that Parkinson’s disease is not a uniform disease, but a heterogeneous group of diseases with a spectrum of clinical and pathological manifestations (PARK1 to PARK13). Family history is an important risk factor. Monogenic forms of Parkinson’s disease are responsible for about five to ten percent of all patients who develop Parkinson’s disease. Among these, genetic mutations of the alpha-synuclein gene (SNCA gene, PARK1) are of particular interest.

The PARK1 locus was mapped in a large family with dominant inherited Parkinson’s disease and Lewy body pathology; two other point mutations with high penetrance were identified in large families but not in patients with sporadic Parkinson’s disease.

Remarkably, in 2007, SNCA aggregates were identified in a specific part of the brain called the presynaptic fraction of human brain tissue. Possibly as an expression of early synaptic dysfunction, although the exact relationship between aggregation, cellular dysfunction and cell death is not yet known.

In addition to changes in the amino acid sequence, however, duplications and triplications also lead to an increase in the protein’s tendency to form oligomers and fibrillary aggregates, so that the regulation of SNCA expression and translation plays an important, at least modulating role.

It is believed that genetics cause about 10 to 15 percent of all Parkinson’s and people with family members with Parkinson’s are at a greater risk of developing the disease. Early onset is usually associated with multiple copies of the genes linked to the disease. The most common mutations in genes that are associated with Parkinson’s include LRRK2, GBA, and SNCA. 

LRRK2: Mutations in the LRRK2 gene have been shown to alter neurons. Genetic changes in this gene can be found in up to 2% of all people with Parkinson’s. There are at least 20 different mutations that could occur in this gene, some are more common, like G2019S which occurs more frequency in North African families. 

GBA: This gene codes for a protein involved in removing cellular waste from cells. Between 5 to 10% of people with Parkinson’s have a mutation in this gene. However, the chances that those who carry this mutation will develop Parkinson’s in the future is fairly low. Only a handful of mutations on the GBA gene have been linked to increased risk for Parkinson’s. 

SNCA: This gene is linked with Parkinson’s in that it produces the protein alpha-synuclein. The brains of those with Parkinson’s contain clumps of this protein, called Lewy bodies. It is believed that mutations in the SNCA gene can cause an excess amount of this protein in their brains, which then forms the Lewy bodies and becomes toxic.

The Parkinson’s Foundation study, PD GENEration: Mapping the Future of Parkinson’s Disease, is the first national study to offer at home genetic testing and counseling at no cost for those with a confirmed Parkinson’s diagnosis. Patients can also submit results from other genetic testing sites like Nebula Genomics, which offers 30X Whole Genome Sequencing. 

Genetic testing for Parkinson’s Disease typically looks for mutations in the genes: GBA, PARK7, SNCA, LRRK2, parkin and PINK1.

Environmental Factors

In addition to genetic factors, several environmental risk factors may lead to an increased risk of developing Parkinson’s, although scientific studies to confirm these associations have been largely inconsistent. These factors include:

  • Head injury
  • Exposure to metals
  • Exposure to solvents and polychlorinated biphenyls (PCBs)

On the other hand, a strong link has been shown between PD and exposure to pesticides and herbicides. One such herbicide is paraquat, a commercial herbicide used in the U.S. that is banned in 32 countries, including the European Union and China. 

Diagnosis (Part 5 of Is Parkinson’s genetic?)

There is no specific test to diagnose Parkinson’s and thus diagnosis is based solely on medical history, symptoms, and neurological examination. It may be difficult to diagnose Parkinson’s in its early stages, when symptoms are minimal. While an initial diagnosis may be made by any medical provider, confirmation is usually made by a trained neurologist. Two of the four main symptoms must be present over a period of time:

  • Shaking or tremor
  • Slowness of movement, called bradykinesia
  • Stiffness or rigidity of the arms, legs or trunk
  • Trouble with balance and possible falls, also called postural instability

Most tests such as blood tests and imaging tests may be performed to rule out other conditions that may be causing the symptoms. 

Treatment (Part 6 of Is Parkinson’s genetic?)

According to Mayo Clinic, treatment is based on individual symptoms. Methods to treat Parkinson’s include a single or combination of medication, surgery, and lifestyle modifications, like physical therapy and exercise. It’s important to note that medications are used to manage the symptoms, not cure the disease.

Medications

Most medications increase, substitute, or protect dopamine in the brain.

Carbidopa-levodopa: The most common medication is L-dopa (levodopa), a precursor of dopamine. This precursor, unlike dopamine itself, is able to cross the blood-brain barrier and be converted to dopamine in the brain. Levodopa is combined with carbidopa (Lodosyn), which protects levodopa from early conversion to dopamine

Newer forms of levodopa include Inbrija (inhaled form) and Duopa (infusion form).

Dopamine agonists: After several years of taking L-dopa, involuntary movements can occur. For this reason, treatment with a longer-acting dopamine agonist is usually recommended at the beginning of Parkinson’s disease, especially in younger patients. Instead of turning into dopamine, dopamine agonists are different drugs that mimic the action of dopamine and stimulate the dopamine receptors. 

Although they aren’t as effective as levodopa, they last longer

Dopamine agonists include pramipexole (Mirapex), ropinirole (Requip) and rotigotine (Neupro, given as a patch). Apomorphine (Apokyn) is a short-acting injectable dopamine agonist used for quick relief.

MAO B inhibitors: This medication helps prevent the breakdown of dopamine by inhibiting an enzyme that metabolizes brain dopamine.

COMT inhibitors: This medication mildly prolongs the effect of levodopa by blocking the enzyme that breaks down dopamine. When taken together with levodopa, they increase the availability of levodopa by 40 to 90 percent and prolong its plasma half-life. Medications in this category include entacapone and tolcapone.

Other medications: Other medications that are used more rarely are anticholinergics and amantadine. Anticholinergics used to be described to help control tremors. However, side effects including impaired memory, confusion, hallucinations, constipation, dry mouth and impaired urination have led to them not being prescribed as often any more. Amantadine may provide short term relief but also results in some serious side effects like a purple mottling of the skin, ankle swelling, and hallucinations. 

Parkinson's medication
The action of Parkinson’s medication. Wikipedia. CCAttribution-Share Alike 3.0 Unported

Surgery

Deep brain stimulation is a surgical procedure that may help relieve some of the symptoms of Parkinson’s disease. Surgeons implant electrodes into a specific part of your brain. The electrodes are connected to a generator implanted in your chest. Electrical pulses sent to your brain are used to reduce disease symptoms.

Like any surgery, deep brain stimulation involves risks, including infections, strokes or brain hemorrhage. And adjustments to the system may be necessary if a patient does not respond well to the stimulation. 

Deep brain stimulation is most often offered to people with advanced Parkinson’s disease who have unstable medication responses. It is most helpful for controlling the tremors. Deep brain stimulation can stabilize medication fluctuations, reduce or halt involuntary movements (dyskinesia), reduce tremor, reduce rigidity, and improve slowing of movement.

For additional information, clinical trial information, and treatment options, visit the Parkinson Foundation.

If you liked this article, you should check out our other posts in the Nebula Research Library!