The Genetic Cause Of Parkinson's Disease

Parkinson’s disease is a progressive chronic disease that affects the nervous system. The disease begins with small changes that might go unnoticed, such as a tiny tremor. However over time, the disease will progress to the point that the affected person is completely unable to control movement in any normal way. Currently, almost one million people in the United States are affected by this disorder (Parkinson’s Disease Foundation). However the cause is yet to be discovered and there is presently no cure for this devastating disease.

2. pathogenesis
Overall pathogenesis The underlying pathological cause in Parkinson’s disease is injury or death to the dopamine producing cells located in the substantia nigra pars compacta to the caudate
nucleus and putamen located in the basal ganglia (Samii et al.). The clinical symptoms of Parkinson’s disease are evident when 80% of striatal dopamine and 50% of the nigral neurons are lost (Samii et al.). Additionally Lewy bodies are present in the remaining neurons. Lewy bodies contain proteins that are resistant to their degradation and continued to persist in the cortex, amygdala, locus ceruleus, vagal nucleus and the peripheral autonomic nervous system (Samii et al.).
Causes- unknown except genetic, explain genetic cause The underlying cause that leads to the destruction of the dompamine producing cells and the formation of Lewy bodies is in most cases of Parkinson’s Disease unknown with the exception of several risk factors associated with the onset of the disease. However, there are a small number of individuals with Parkinson’s disease who have known gene mutations, affecting genes that play a role in dopamine cell function, that causes the disease directly. Parkinson’s Disease will have an early onset for patients with a genetic cause, as affected by mutations in genes for parkin, PINK1, LRRK2, DJ-1 and glucocerebrosidase (Parkinson’s Disease Foundation).
Risk factors-aging

Risk factors- genetic predisposition Although most Parkinson’s cases are not inherited, having a first degree relative with the disorder increases the risk of developing PD by four to nine percent, with fifteen percent of people with Parkinson’s report having a relative with the disease (Parkinson’s Disease Foundation).
However, environmental exposures can also account for a familial pattern in these patients (Samii et al.). While this genetic predisposition is not fully understood, the identification of particular gene mutations that lead to the select cases with genetic cause is an important area of research for the disease as the genetic forms can be studied in great detail in scientific setting, and may ultimately provide a greater understanding for the common forms of the disease (Parkinson’s Disease
Foundation).
Risk factors environmental exposure

3. clinical features The core clinical features of Parkinson’s Disease are: resting tremor, bradykinesia, rigidity, and postural instability (Parkinson’s Disease Foundation). However not all Parkinson’s patients present all of these symptoms. Because the only definite diagnosis of Parkinson’s disease would require autopsy, physicians rely on these clinical features of the disease to make the diagnosis and to differentiate it from other parkinsonian disorders (Jankovic 368).
One of the first indications of the presence of the disease is often a resting tremor. About 70 percent of patients experience a slight tremor during the early stages of the disease (Parkinson’s Disease Foundation). This resting tremor causes the affect body part to shake uncontrollably when the patient’s muscles are relaxed and ceases when the patient begins an action. Often the tremor will begin on one side of the body but as the disease progresses it often spreads to the other side of the body (Parkinson’s Disease Foundation). Tremors are almost always most prominent in the distal part of an extremeity however than can also involve the lips, chin, and jaw but rarely involve the neck/head or voice (Jankovic 369). However, while resting tremors are a hallmark feature of the disease, many patients with Parkinson’s Disease have postural tremors that are even more disabling (Jankovic 370). These Parkinson’s related postural tremors or “re-emergent tremors” appear after the patient lies down horizontally. These are considered to be a variant of the rest tremor because they occur at the same frequency and are responsive to dopaminergic therapy (Jankovic 370).
Bradykinesia, which describes a slowness of movement, is the most characteristic clinical feature of Parkinson’s Disease. As a symptom, it is present in many disorders that affect the basal ganglia. However the impairments at the basal ganglia that result in bradykinesia encompass more than just a slowness of movement, it describes difficulties with planning, initiating, and executing movements, performing sequential and simultaneous tasks, loss of spontaneous movements and gestures, drooling due to impaired swallowing, monotonic and hypophonic dysarthria, loss of facial expression, decreased blinking, and reduced arm swing while walking (Jankovic 369). Furthermore, it is common for patients with bradykinesia to walk with slow shuffling steps. The reduction in movement caused by bradykinesia can affect a patient’s speech, which can become quieter and less distinct as the disease progresses (Parkinson’s Disease Foundation). Although is it without solid confirmation, it is hypothesized that, “bradykinesia is the result of a disruption in normal motor cortex activity mediated by reduced dopaminergic function…. Anatomically, the deficit appears to be localized in the putamen and globus pallidus, resulting in a reduction in the muscle force produced at the initiation of movement. Analysis of electromyographic recordings showed that patients with bradykinesia are unable to energize the appropriate muscles to provide enough force to initiate and maintain large fast muscles” (Jankovic). Bradykinesia ultimately makes it very difficult for patients to move around and accomplish daily tasks.
In normal muscle tone, muscles are relaxed when they are inactive and tighten and contract during activation. However in Parkinson’s disease patients, muscles lack this normal tone and remain rigid. Rigidity is defined as “increased resistance during passive mobilization of an extremity, independent of direction and velocity of movement” (Baradaran). Thus the muscle tone is always stiff and doesn’t relax. This contributes to a decreased range of motion but can also be so severe that is can cause discomfort and pain (Parkinson’s Disease Foundation). While this symptom is a core feature in the diagnosis of Parkinson’s Disease, the mechanism which creates rigidity is poorly understood. It has no direct relationship to dopamine deficiency thus it doesn’t fit the model of basal ganglia pathophysiology (Baradaran). Additionally, the amount of rigidity a patient experiences is altered during various states of drowsiness or relaxation. While the mechanism that causes rigidity is not completely understood, some potential mechanisms have been hypothesized. One such theory is that PD patients have increased excitability in stretch reflex pathways (Baradaran). In other words, when a muscle is stretched, this change in muscle length signal to a hyperactive transcortical loop that responds by over resisting the stretch, creating rigidity. Another theory is that spinal reflex pathways are misfiring. It is believed that the caused of rigidity varies from patient to patient and is likely caused by several pathophysiological mechanisms (Baradaran).
The fourth primary motor symptom of Parkinson’s Disease is postural instability. Postural instability is an abnormal difficulty in maintaining an upright position. A patient with postural instability has lost some of the necessary reflexes needed to maintain an upright posture (Parkinson’s Disease Foundation). This can cause patients to lose their balance and fall down very easily. Patient’s frequently display retropulsion, “the tendency to sway backwards when rising from a chair, standing or turning” (Parkinson’s Disease Foundation). Postural instability is usually absent in the earlier stages of the disease thus it is sometimes not classified as a primary clinical feature of the disorder (Samii et al.). However, in later stages of the disease it is very common and can be potentially very dangerous as it can often lead to bone fractures and further injuries to the patient.
The secondary motor symptoms for Parkinson’s Disease are not used for a diagnosis or measure of disease progression as there are many and the presentation of the symptoms vary greatly from patient to patient. These secondary motor symptoms include freezing, microphagia, mask-like expression, unwanted accelerations, stooped posture, dystonia, impaired fine motor dexterity and motor coordination, impaired gross motor coordination, poverty of movement, akathisia, speech problems, difficulty swallowing, sexual dysfunction, cramping and drooling (Parkinson’s Disease Foundation). In general, these primary and secondary motor symptoms make it difficult or in more severe cases, impossible for patients to accomplish tasks required for daily life (eating, dressing, bathroom etc) and are potentially dangerous due to the increased risk of falls (Mayo Clinic Staff). Parkinson’s Disease is a devastating disorder that impacts every moment of every day for it’s patients.
In addition to motor symptoms, most people with Parkinson’s experience many nonmotor symptoms.
Although many of these symptoms may be unobvious to others, they can potentially be more debilitating than motor impairments. There are several non motor symptoms that often appear years before motor symptoms in Parkinson’s patients. These early symptoms include: loss of sense of smell, constipation, REM behavior disorder, mood disorders and orthostatic hypotension (Parkinson’s Disease Foundation). However, because diagnosis is made using the criteria of motor symptoms, these symptoms can go undiagnosed until motor symptoms present. Additional nonmotor symptoms include: sleep disturbance, bladder problems, sexual problems, excessive saliva, weight loss or gain, vision problems, dental problems, cognitive difficulties, visuospatial difficulties, executive dysfunction, depression and anxiety. (Parkinson’s Disease
Foundation).