eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Parkinson Disease in Young Adults

Author: Stephen T Gancher, MD, Adjunct Associate Professor, Department of Neurology, Oregon Health Sciences University
Contributor Information and Disclosures

Updated: Aug 11, 2008

Introduction

Background

Parkinson disease is a slowly progressive, degenerative neurological illness, which most commonly affects middle-aged and elderly individuals. Although easily recognizable when the disease is established, mild or incipient Parkinson disease may be difficult to recognize, particularly in young individuals, and may be overlooked for several months or years.

Young-adult Parkinson disease, which is defined as symptom onset before age 40 years, is comparatively rare. However, an older patient reporting symptom onset in middle age is less rare; as many as 12% of patients in some tertiary referral clinic populations date their symptom onset before age 40 years. Idiopathic Parkinson disease that begins before age 21 years is extremely rare.

Assuming other conditions have been excluded, 2 pathologically distinct conditions should be considered: juvenile parkinsonism and dopa-responsive dystonia. Juvenile parkinsonism is most commonly due to mutations in the parkin gene. It was first described in Japan but has been found in other countries. Symptoms typically begin as rigidity and tremor, but dystonia is also very common. Dopa-responsive dystonia usually starts as a gait disorder resulting from lower extremity dystonia, but it can also be accompanied by bradykinesia. Symptoms may exhibit substantial diurnal variation and usually respond dramatically to low doses of levodopa. The clinical spectrum of these disorders is increasingly wide, and distinction between these different conditions on a clinical basis or by age of onset is not infallible.

Patients with young-onset Parkinson disease have symptoms that are similar to those of older patients but have a higher incidence of dystonia, particularly in the lower extremities. Because dystonia as an isolated symptom of other diseases is unusual, early Parkinson disease should be suspected in middle-aged individuals with an isolated dystonia in the upper or lower extremity.

For more information, see Medscape's Parkinson's Disease Resource Center.

Pathophysiology

Pathologically, Parkinson disease is associated with loss of dopaminergic neurons in the substantia nigra and dopamine deficiency in the striatum. This results in abnormally increased activity of the subthalamic nucleus and internal segment of the globus pallidus, which cause the motor manifestations of the disease. In Parkinson disease, other nondopaminergic neurons also are affected, resulting in a milder deficiency of the other monoamine neurotransmitters, including serotonin and norepinephrine. In concert with dopamine deficiency, depletion of these other neurotransmitters results in psychological and behavioral symptoms, including depression, asthenia, memory and concentration difficulties, and sleep disturbances. Involvement of the intermediolateral cells in the thoracic spinal cord, autonomic ganglia, and autonomic neurons in the wall of the abdominal viscera also occurs in Parkinson disease and results in dysautonomia.

Juvenile parkinsonism may include patients with several different pathologies and is clinically heterogeneous, both in symptoms and in response to levodopa. As discussed under Causes, juvenile parkinsonism is classically an autosomal recessive inherited condition and is associated in some families with a mutation in the gene coding for the protein parkin. Many patients with young-onset Parkinson disease who have typical symptoms and signs of Parkinson disease are found to have a mutation in only one copy of this gene, though, suggesting that this condition may be a dominantly inherited one in some individuals. In contrast to Parkinson disease and juvenile parkinsonism, dopa-responsive dystonia is not a degenerative illness, nor is it associated with loss of dopaminergic neurons, but instead is due to mutations in enzymes involved in the activation of tyrosine hydroxylase, the rate-limiting enzyme involved in dopamine synthesis.

Frequency

United States

The overall prevalence of Parkinson disease is estimated at 0.2% but rises with increasing age, affecting as many as 0.5-2% of individuals older than 70 years. The prevalence has been estimated as 25-50 cases per 100,000 population in individuals younger than 50 years, affecting as many as 100,000 patients in the United States, and approximately 5 cases per 100,000 individuals younger than 40 years.

Mortality/Morbidity

• Prior to the discovery of levodopa, Parkinson disease was associated with a significant mortality rate and shortened life span; the average life expectancy of patients was approximately 10 years after diagnosis. In the latter stages, patients with advanced Parkinson disease were restricted to a wheelchair or bed and died of complications of immobilization, such as aspiration pneumonia, urosepsis, or infected decubiti. Since the development of levodopa and other drugs, the life spans of patients are normal, or nearly so.
• However, a number of signs and symptoms that were rare prior to the discovery of levodopa now are common. These include dementia, adverse mental effects of drug treatment such as hallucinations and psychosis, severe dysarthria, dysphagia, aspiration, and falls and fractures as a result of postural instability and freezing.
• Younger individuals with Parkinson disease have different problems. Troublesome motor fluctuations and dyskinesias are especially common and may occur within several years of the initial symptoms. Severe dysautonomia, freezing, and dementia are less common than in elderly patients but may develop after many years of disease. Painful dystonia during periods of recurrent parkinsonism ("off" dystonia) is a particularly distressing and common motor symptom. In some patients, a nonfluctuating and fixed dystonia may develop and require bracing or surgical correction.

Race

Parkinson disease affects all races.

• The prevalence is described as highest in Caucasians living in Europe and North America, intermediate in Asians living in Japan, and lowest in blacks living in Africa; however, to what extent these differences are due to race, geographic variation, or inaccuracies in sampling is not clear.
• A single, door-to-door study of Parkinson disease in a rural county in Mississippi found no difference in prevalence in whites and blacks; however, many authorities still suspect that race is a factor in the risk of developing Parkinson disease.
• Juvenile parkinsonism due to the parkin mutation is described as accounting for more cases of juvenile parkinsonism in Japan than in other countries. However, more recent studies in other countries have also shown a large fraction of young adults (under age 40) as having the parkin mutation.

Age

• Parkinson disease is more common with advancing age. It affects as many as 0.5% of individuals aged 60-69 years and as many as 1-2.5% of individuals older than 80 years.
• It is unusual in individuals younger than 50 years, with prevalence rates ranging from 0-46 cases per 100,000 population, averaging 27 case per 100,000 population among studies. It is still rarer in individuals younger than 40 years, with most studies reporting fewer than 5 cases per 100,000 population. In some referral populations, however, as many as 10% of patients with Parkinson disease report disease onset before 40 years.
• Approximately 10,000-15,000 individuals 40 years and younger in the United States have Parkinson disease. This is nearly half of the estimated total number of individuals of all ages in the United States with amyotrophic lateral sclerosis (ALS).

Clinical

History

• Diagnosis of Parkinson disease in young patients is similar to that in elderly patients and is based on finding a combination of tremor, rigidity, bradykinesia, and postural instability. The symptoms may, however, be vague and difficult to pinpoint or to date accurately and may include fatigue, malaise, myalgias, mild incoordination, depression, and other less well-defined complaints. The initial symptoms typically start insidiously and emerge slowly over weeks or months. This slow progressive pattern is characteristic of the disorder. In fact, other patterns, such as a stable, waxing and waning course over many months, or the abrupt appearance of various signs or symptoms, are unusual and should raise concerns about the diagnosis.
• Juvenile parkinsonism (onset before age 20 y) and dopa-responsive dystonia usually begin with dystonia affecting the lower extremities. However, these 2 conditions overlap considerably, and exceptions have been identified by genetic testing. Patients with sporadic Parkinson disease with typical symptoms and onset in middle age have rarely been found to have a mutation in the same gene, parkin, that results in juvenile parkinsonism. Patients with the clinical picture of dopa-responsive dystonia also have demonstrated this mutation.
• Tremor
  • Tremor is the most common initial symptom, occurring in approximately 70% of patients. It usually is described by patients as shakiness or nervousness. It may vary considerably, emerging only with stress, anxiety, or fatigue, or it may occur only when supporting weight with the affected limb, such as experiencing arm tremor when getting out of a low chair.
  • Most commonly, tremor affects the upper extremity. It generally begins in the fingers or thumb, but also can start in the forearm or wrist. A very common pattern is for the tremor to begin in the upper extremity, spreading to the ipsilateral lower extremity or the contralateral upper extremity before becoming more generalized. Although Parkinson disease is a rare cause of tremor affecting the head or neck, chin or lip tremors are seen occasionally, usually ipsilateral to the extremity tremor. Most classically, the tremor of Parkinson disease disappears with action or usage of the limb, but this is not seen in all patients.
• Bradykinesia
  • Symptoms of bradykinesia are more varied than those of tremor. These may include a feeling of weakness, without true weakness found on physical examination; loss of dexterity, sometimes described by patients as the "message not getting to the limb"; fatigability; or aching when performing repeated actions.
  • Facial bradykinesia is characterized by depression or fatigue. The speech may become softer, less distinct, or more monotonous. In more advanced cases, speech is slurred, poorly articulated, and difficult to understand. Drooling is an uncommon initial symptom in isolation but is reported commonly in patients with mild disease.
  • Truncal bradykinesia results in slowness or difficulty in rising from a chair, turning in bed, or walking. If walking is affected, patients may limp, take smaller steps, or be transiently unable to move. This "freezing" is seen commonly in patients with more advanced disease; it is more prominent in doorways or narrow areas, and can result in patients getting trapped behind furniture or being unable to cross a door threshold easily.
  • In the upper extremities, bradykinesia can cause small effortful handwriting (ie, micrographia) and difficulty using the hand for fine dexterous activities such as using a key or kitchen utensils. In the lower extremity, unilateral bradykinesia commonly causes limping, which occasionally can be an initial symptom.
• Rigidity
  • Though a common physical sign of Parkinson disease, rigidity is a less common symptom in patients with early onset of the disease.
  • Some patients may describe stiffness in the limbs but this may reflect bradykinesia more than rigidity.
  • Occasionally, individuals may describe a feeling of ratchety stiffness when moving a limb, which may be a manifestation of cogwheel rigidity.
• Other initial symptoms include regional pain, variously described as coldness, tingling, cramping, or aching; depression or anhedonia; slowness in thinking and speaking; a general feeling of weakness, malaise, or lassitude; and a number of dysautonomic symptoms, including constipation.
• In young patients, dystonia is a common initial symptom, producing cramping or aching and a tendency of the extremity (usually the foot) to turn in or the great toe to dorsiflex. Common dystonic symptoms include curling, inversion, or plantar flexion of the foot, and adduction of the arm and elbow, causing the hand to rest in front of the abdomen or chest. These dystonic postures can wax and wane, occurring with fatigue or exertion.

Physical

The principal manifestations of Parkinson disease are tremor, rigidity, bradykinesia, and changes in gait and posture.

• Tremor is, most typically, a resting tremor that is reduced or eliminated with limb movement. It is seen commonly in the upper extremities during walking and can be seen more obviously by asking the patient to perform rapid movements with the contralateral limb (eg, rapidly clenching and unclenching a fist). A minority of patients may have an action or sustention tremor, best seen by holding the arm outstretched.
• Rigidity
  • Rigidity may be either "lead-pipe" or cogwheeling; it may be present in the limbs and is frequently asymmetric. The degree of rigidity varies widely and does not correlate well with tremor or bradykinesia. It commonly is abolished or reduced by levodopa or dopamine agonists and is frequently minimally present or absent in patients on long-term drug treatment. It is best recognized by passively moving a limb in 2 or more planes, such as simultaneously flexing and extending the elbow while supinating and pronating the forearm.
  • Rigidity also can be detected by passively moving one limb while the patient simultaneously moves the contralateral limb, such as drawing an imaginary circle in the air. However, a mild increase in tone is observed normally with this maneuver in healthy individuals; mild rigidity, in the absence of other signs, should be interpreted with caution.
• Bradykinesia
  • Bradykinesia is seen as a paucity or slowness of movement. In the limbs, this results in a reduction in the amplitude and speed of movement. It is best recognized by having the patient tap the index finger against the thumb, supinate and pronate the forearm in the air, clench and unclench a fist, or tap the heel or the toes against the ground. When more severe, it may be difficult for a patient to initiate and maintain a movement, producing functional weakness; however, on direct motor testing and with encouragement, little or no weakness is observed.
  • Handwriting changes, particularly micrographia, are a frequent manifestation, and are a sensitive sign of incipient Parkinson disease in many patients; mild micrographia is sometimes noticeable by comparing old and recent signatures on credit cards. Bradykinesia also can result in changes in facial expression, causing reduced blinking and smiling. Myerson sign (blinking when the glabella is tapped repeatedly) is observed commonly but is nonspecific.
  • Speech and swallowing may be affected. The speech may be slightly softer, muffled, and less distinct. In more severe disease, the speech is rapid, monotonous, and slurred. Palilalia, repeating the initial syllable of a word similar to stuttering, also can occur in patients with more advanced disease and can be a side effect of medications. Sialorrhea and dysphagia are common problems in patients with more advanced disease.
• Changes in gait, posture, and balance are frequent manifestations of Parkinson disease. Initial gait changes may include limping and reduced or absent arm swing. As the disease worsens, patients may have en bloc turning (ie, lack of truncal rotation when turning), festination (ie, a short-stepped, propulsive gait, as if falling forward), or freezing (ie, transient inability to move the legs, commonly seen in doorways or in narrow quarters). Freezing also can be noticeable as a subtle hesitancy in initiating walking after standing or after turning directions.
• The posture may become more flexed, sometimes to extreme levels. Postural stability is affected, producing retropulsion. This is sometimes obvious without provocation and can be recognized by standing behind the patient and pulling the upper trunk backwards at the shoulders. Scoliosis, usually away from the more affected side, is seen occasionally.
• Dystonia is recognized most commonly in the lower extremities, causing an equinovarus posturing in the foot and ankle and curling of the toes. In the upper extremities, the arm is held adducted against the chest and flexed at the wrist; when severe, the hand may be held in a fist and the palm may become macerated or thickened.
• Few other neurological manifestations are noted in patients with Parkinson disease; pyramidal signs, ophthalmoplegia, anisocoria, cerebellar ataxia, or severe dysautonomia at symptom onset is atypical and usually suggests an alternative diagnosis. Reflex asymmetries may be observed occasionally, typically causing a mild degree of hyperreflexia ipsilateral to the more affected side. Spontaneous dorsiflexion of the great toe (the "striatal" toe) also is seen.
• Although cognition and mood are affected in many patients with Parkinson disease, findings of the office mental status examination are normal in most patients. Signs of higher cortical dysfunction, such as neglect, agnosia, dysphasia, apraxia, or severe memory disturbances, are not observed in patients with idiopathic Parkinson disease, with the exception of patients in whom Lewy body dementia develops late in the disease course; it is very rare in younger patients.

Causes

• The etiology of Parkinson disease is largely unknown in most patients. However, evidence does exist for both genetic and environmental causes. In the United States, rural residence, exposure to well water, and prior use of pesticides are environmental factors that have been found to be associated with an increased risk of developing Parkinson disease.
• Genetic factors also may be important in the pathogenesis of the disease. A positive family history is found in approximately 15-20% of patients with idiopathic Parkinson disease, but the mutation or mutations responsible in most cases are not identified.
  • Currently, 5 different genetic mutations have been found to cause autosomal dominantly inherited Parkinson disease. These are generally rare, although one condition, PARK8, has been described in up to 5% of families with Parkinson disease and a dominantly inherited pattern.
  • Three autosomal recessive forms are also known. Of these 3 forms, PARK2 (the parkin mutation), may be responsible for familial Parkinson disease in other inheritance patterns and is the most common form of genetically inherited disease that has been recognized to date.
• Although considered rare, mutations in the gene coding for the protein parkin (termed PARK2) may be more common than previously thought and may account for a large number of patients with young-onset Parkinson disease.
  • This mutation was originally described in patients with juvenile parkinsonism, and it was described as an autosomal recessive condition. However, PARK2 may be an autosomal dominant or semidominant condition, causing disease onset in middle age. In one series of patients with sporadic disease and onset before age 40 years, 18% of patients had a mutation in this gene. Most patients were heterozygous, ie, they had one normal and one abnormal parkin gene.
  • In another study involving families with 2 or more siblings with Parkinson disease, a mutation in this gene was found in 18% of the patients. One third of affected members of these families had mutations in both parkin genes; the other two thirds had one normal parkin gene. This study also found that the patients with 2 abnormal genes had earlier disease onset, suggesting that there may be a "dose effect" in having 1 or 2 mutated parkin genes. The study also indicated that some patients had disease onset at or older than age 60 years, suggesting that a mutation in the parkin gene can cause Parkinson disease that can start at an age typical of sporadic Parkinson disease.
• Dopa-responsive dystonia, discussed in more detail in another article, is due to a one of two different mutations. The more common form, which occurs in an autosomal dominant inheritance pattern, is due to a mutation in a gene coding for the enzyme GTP-cyclohydrolase (GTPCH), which is involved in the synthesis of tetrahydrobiopterin, a cofactor needed for the enzyme tyrosine hydroxylase. A less common autosomal recessive form, due to a partial deficiency in tyrosine hydroxylase, also occurs. As partial penetrance and new mutations have been described in patients with GTPCH-1 deficiency, a family history may not be present. In these disorders, dopamine is depleted in the striatum, but no cell degeneration occurs. Interestingly, a recent study reported that 3 of 10 families thought to have dopa-responsive dystonia actually had a mutation in the parkin gene instead, further illustrating the clinical overlap in these conditions.
• The biochemical basis for cell degeneration is unknown. However, evidence exists that patients with Parkinson disease have a deficiency of the mitochondrial enzyme complex I in the midbrain. In cell culture and animal models, inhibitors of complex I enhance oxidant or excitatory amino acid toxicity to dopaminergic neurons.

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