Causes for Parkinson’s Disease

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Causes:
PD is a degenerative disorder of the central nervous system. Most of the PD cases are idiopathic (no cause).

A small proportion of cases can be attributed to known genetic factors.

Other factors such as environmental toxins, herbicides, pesticides and fungicides have been associated with the risk of developing PD no cause in proven.

Genetic Factors:
PD is non genetic disorder.

15% of individuals with PD have a first degree relative who has the disease.

At least 5% of people are now known to have forms of the disease that occur because of a mutation of one of severe specific genes.

Plantations in specific genes have been shown to cause PD.

These genes code for alpha-synuclein(SNCA) parkin(PRKN), Leucine-rich repeat kinase 2 (LRRK 2 or dardar in), PTEN- induced putative kinase 1 (PINK 1) DI-1 and ATPI3A2. In most cases, people with these mutations will develop PD. With the exception of LRRK2, they account for only a small minority of cases of PD. The most extensively studied PD related genes are SNCA and LRRK2 and Glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD- Mutatoins in GBA are known to cause Gauchers disease.

Genome-wise association studies which search for PD mutated alleles with low penetrance in sporadic cases have now yielded many positive results.

SNCP Gene:
The role of the SNCA Gene is important in PD because the alpha synuclein protein is the main component of Lewy bodies.

SNCA is expressed throughout the mammalian brain, and enriched in presynaptic nerve terminals. Missense Mutations of the gene (in which a single nucleoid is changed) and duplications and triplications of the locus containing it have been found in different groups with familial PD.

Missense mutations in SNCA are rare.

Multiplications of the SNCA locus account for around 2% of familial cases. Multiplications of the SNCA have been found in asymptomatic carriers, which indicate that penetrance is incomplete or age dependent.

Level of alpha synuclein expression correlates with disease onset and progression with SNCA gene triplication advancing earlier and faster than duplication.

LRRK 2 Gene:
LRRK2 gene (PARK 8) encodes for a protein called dardarin.

The name dardarin was taken from a basque word for tremors because this gene was first identified in families from England and the North Spain.

A significant number of autosomal dominant Parkinsons Disease cases are associated with mutations in the LRRK2 gene.
Mutation in LRRK2 are the most common known cause of familial and sporadic PD, accounting for approximately 5% of the individuals with a family history of the disease.

There are many different mutations described in exists for a small number.

Mutations in the PINK 1, PRKN and DJ1 may cause mitochondrial dysfunction an element of both idiopathic and genetic PD.

Of related interest are mutations in the progranulin gene that have been found to cause corticobasal degeneration seen in dementia.

This could be relevant in PD cases associated with dementia.

GBA Genes:
Mutations in GBA are known to cause Gauchers disease.

Genome wide association studies, that search for mutated alleles with low penetrance in sporadic cases have now yielded many positive results mendelian genetics are not strictly observed in GBA mutations found in inherited Parkinsonism

Incidentally both gain of functions and loss of functions GBA mutations are proposed to contribute to Parksinsonism through effects such as increased alpha synulcein level.

PD is thought to result from a complex interaction between multiple genetic and environmental factors, though rare managerial forms of the disease do exist.

Mutations in 6 genes (SNCA, LRRK2, PRKN, DJ1, Pink1 and ATP13A2) have been shown to cause familial Parksinonsism.
In common variation in 3 genes (MAPT, LRRK1 and SNCA) and loss of function mutations in GBA have been well validated.

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Sign & Symptoms for Parkinson’s Disease

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Parkinsons Disease affects movement, producing motor symptoms, non-motor symptoms, which include autonomic dysfunction, neuro-psychiatric problems (mood, cognition, behavior or thought alterations) and sensory and sleep difficulties are also common.

Motor Symptoms:
There are four motor symptoms which are considered cardinal in Parkinson’s disease.

These four symptoms are
Tremor
Rigidity
Slowness of movement
Postural instability

Tremor:
This symptom is most apparent and well-known in 30% of patient with PD don’t have tremors at disease onset. Most develop it as the disease progresses. It is usually a rest tremor. Maximal when the limb is at rest and disappearing with voluntary movement and sleep.
It affects to a greater extent the most Distal pact of the limb and at the onset typically appears in only a single arm or leg, becoming bilateral later. Frequency of PD tremor is between 4-6 hertz cycles per second. Pill rolling tremor the tendency of the index finger of the and to get into contact with the thumb and perform together a circular movement.

Rigidity:
It is stiffness and resistance to limb movement caused by increased Muscle Tone, excessive and continuous contraction of muscles. Rigidity is uniform (Lead-pipe rigidity) or ratchet (Cogwheel rigidity). The combination f tremor and increased tone is considered to be at the origin of cogwheel rigidity. It may be associated with joint pains, frequent. In the beginning it is asymmetrical rigidity, neck is affected shoulder muscles prior to the muscles of the face and extremities. Rigidity affects the whole body and reduces the ability to move.

Hypokinesia (Slowness of movement):
It is associated with difficulties along the whole course of the movement process, from planning to initiation and finally execution of a movement. Performance of sequential and simultaneous movements is hindered. Bradykinesia is a very disabling symptom in the early stages of the disease. Initial complaints are problems when performing daily tests which require fine motor control like writing, sewing or getting dressed.

Clinical evaluation is based in similar tasks such as alternating movements between both hands or both feet.
Bradykinesia is not equal for all movement or times. It is modified by the action activity or emotional state of the subject, to the point that some people are barely able to walk yet can still ride a bicycle. Generally people with PD have less difficulty when some sort of external cue is provided.

Postural Instability:
It is seen in the last stage of disease, leading to impaired balance and frequent falls, then to bone fractures. Up to 40% may experience falls and around 10% may have falls weekly, with number of falls being related to severity.

Festinating (rapid shuffling steps and forward flexed pasture when walking, speech, swallowing disturbances, including voice disorder may be seen. Mask like face expression or small handwriting may seen.

Classification of Parkinson’s Disease

Parkinson's Disease

Parkinson’s Disease

Classification:

Parkinsonism word is used for a motor syndrome. The main symptoms are tremor at rest, stiffness, slowing of movement and postural instability.
Parkinsonian syndromes can be divided into four subtypes according to their origin:
1. Primary/Idiopathic
2. Secondary/Acquired
3. Hereditary P
4. Parkinson Plus Syndrome/ Multiple System Degeration

Primary Parkinsonism:
It means Parkinsonism with no external identifiable cause. In recent years several genes that are directly related to some causes of Parkinson’s Disease have been discovered.

The term Familial Parkinson’s Disease and Sporadic Parkinson’s Disease can be used to differentiate genetic from truly idiopathic forms of disease.

Usually classified as a movement disorder PD also gives rise to many non-motor types of symptoms like sensory deficits, cognitive difficulties or sleep problems.

Parkinson’s Plus Disease are primary Parkinsonism’s which present additional features. They include Multiple System Arophy, progressive supranuclear palsy, corticobasal degeneration and dementia with Lewy Bodies.

In terms of pathophysiological part, PD is considered a Synucleiopathy due to abnormal accumulation of alpha synuclein protein in the brain in the form of Lewy Bodies, as opposed to other disease such as Alzheimer’s Disease, where the brain accumulates Tan Protein in the form of Neurofibrollary Tangles.

The most typical symptoms of the Alzheimer’s Disease, dementia, occurs in advanced stages of PD, while it is common to find neurofibrillary tungles in brains affected by PD.

Dementia with Lewy Bodies (DLB) is another synucleiop that has similarities with PD, and especially with the subsets of PD cases with dementia.

Parkinson’s Disease

Parkinson's Disease

Parkinson’s Disease

Parkinson’s Disease (PD), Idiopathic Primary Parkinsonism, Hypokinetic rigid syndrome (HRS), or paralysis agitans is a degenerative disorder of the Central Nervous System mainly affecting the Motor System.

The cause of this cell death is poorly understood in the early course of the disease. The most obvious symptoms are Movement Related; these include shaking, rigidity, slowness of movements and difficulty with walking and gait. Thinking and behavioral problems may arise, with dementia in the advanced stages of the disease; Depression is the most common Psychiatric Symptom. The sensory symptoms include Sleep and Emotional problems.

Parkinson’s disease is more common in older people after the age of 50.

When it is seen in young adults it is called young onset PD (YOPD). The main motor symptoms are called Parkinsonism or a Parkinsonian Syndrome. Disease may be primary or secondary; Primary Parkinson’s Disease is referred to as Idiopathic (Having no known cause). Some atypical causes have a genetic origin, while secondary Parkinsonism is due to known causes like toxins. Many risks and protective factors have been investigated. The clearest evidence is for an increased risk of PD in people exposed to Pesticides and reduced risk in Tobacco Smoking.

The pathology of the disease is characterized by the accumulation of a protein into Lewy Bodies in the neurons and from insufficient formation and activity of the Dopamine in certain parts of the midbrain, where the Lewy bodies are located, is often related to the expression and degree of the symptoms of an individual. Diagnosis of the typical cause is mainly based on symptoms, with tests such as Neuroimaging being used for confirmation.

Treatments are effective at improving the early motor symptoms of the disease. Treatment is typically with medications L-DOPA and Dopamine Agonists.

As the disease progresses and Dopaminergic Neutons continue to be lost, these drugs eventually become ineffective at treating the symptoms and the same time produce a complication marked by involuntary writhing movement.

The primary symptoms of Parkinson’s Disease are all related to voluntary and involuntary motor symptoms.
Tremors: Trembling in fingers, hands arms, feet, legs, jaw, or head.
Rigidity: stiffness of the limbs and trunk, which may increase during movement.
Bradykinesia: slowness of voluntary movement.