Synucleinopathies: Types, Clinical Features, and Diagnosis

Introduction

Synucleinopathies are a group of disorders caused by abnormal clumping of α-synuclein proteins in the nervous system. Depending on where these clumps form, different conditions arise. Examples of such conditions are pure autonomic failure, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), and Parkinson's disease. These disorders result in autonomic failure. This occurs due to the degeneration and dysfunction of neurons. The spread of misfolded α-synuclein proteins causes all these changes. Synucleinopathies symptoms can include issues with blood pressure regulation, urinary and sexual function, digestion, and temperature control. Rapid eye movement sleep behavior disorder is a common early sign of these conditions.

What Is Synuclein and Its Members?

Synucleins are a family of soluble proteins with unclear functions. They share common features, including an acidic carboxyl terminus and several imperfect repeat motifs in the amino terminus. The following are the members of the synuclein family:

• Alpha-Synuclein (α-Synuclein): This first member discovered was purified in 1988 from Torpedo electroplaque and rat brain. It is also known as the non-amyloid component (NAC) of plaque precursor protein because the NAC peptide, isolated from amyloid-rich senile plaques in Alzheimer’s disease (AD) brains, is identical to residues 61 to 95 of αS. The αS gene is located on chromosome 4q21.3-q22.

• Beta-Synuclein (β-Synuclein): β-synuclein (βS) is highly similar to αS and was first isolated from the bovine brain, initially named phosphoneuroprotein-14. The gene for βS is mapped to chromosome 5q35. Both αS and βS are predominantly found in the presynaptic terminals of neurons, suggesting their involvement in synaptic function.

• Gamma-Synuclein (γ-Synuclein): γ-synuclein (γS) was originally isolated from breast cancer tissue and is called breast cancer gene-specific product 1. In addition to breast tissue, γS is present in the brain and spinal cord, with the highest abundance in the peripheral nervous system. Unlike αS and βS, γS is mainly located in the cytoplasm and mapped to chromosome 10q23.

• Synoretin: The most recent member is primarily expressed in the retina with low-level expression in the brain. The gene for synoretin has yet to be mapped.

While alphaS has been extensively linked to neurodegenerative synucleinopathies, there has been no significant evidence implicating beta S and gamma S in neurological diseases until recently.

What Are the Types of Synucleinopathies?

Conditions such as pure autonomic failure, multiple system atrophy (neurodegenerative disorder affecting movement, autonomic function) (MSA), dementia (a decline in cognitive function) with Lewy bodies (DLB), and Parkinson's disease that comes under synucleinopathies are mentioned below in detail.

1. Pure Autonomic Failure - In 1925, Bradbury and Eggleston first reported cases of pure autonomic failure. It is observed in patients exhibiting severe orthostatic hypotension and syncope. Bradbury-Eggleston syndrome, or idiopathic orthostatic hypotension, was its previous name. Pure autonomic failure is an adult-onset, sporadic, gradually progressive disorder. The sign of orthostatic hypotension with a propensity for syncope is clinically significant. It may occur in conjunction with or precede bowel dysfunction, heat intolerance, or genitourinary dysfunction.

Clinical features include -

• Orthostatic Hypotension: It may be symptomatic or asymptomatic. Common symptoms include lightheadedness, dizziness, vision changes, weakness, fatigue, and cognitive symptoms.

• Supine Hypertension: It occurs in approximately half of all patients with pure autonomic failure, and systolic blood pressures often exceed 200 mm Hg.

• Other Symptoms:

  • Symptoms of bladder disturbances range from urgency and frequency to urinary retention and incontinence, sometimes requiring catheterization.

  • Erectile dysfunction (inability to achieve or maintain an erection) is commonly reported in men.

  • Constipation can be an early and severe symptom.

  • About half of all patients report abnormal sweating.

2. Multiple System Atrophy: With motor signs of predominant Parkinsonism (MSA-P) or predominant cerebellar ataxia (MSA-C), autonomic failure is a hallmark of MSA, a progressive neurodegenerative disorder. The disorders formerly known as striatonigral degeneration, olivopontocerebellar degeneration, and Shy-Drager syndrome are included in the term multiple system atrophy, coined in 1969 by Graham and Oppenheimer.

Clinical features include -

Most patients initially present with motor symptoms.

• Parkinsonism: Characterized by bradykinesia (slowness of movement), rigidity, and a jerky postural tremor. The classic ‘pill-rolling’ resting tremor seen in Parkinson's disease is rare in MSA-P.

• Cerebellar Features (MSA-C): Includes ataxic limb movements, wide-based gait, and nystagmus (involuntary, repetitive eye movements). These features may predominate initially but tend to overlap with Parkinsonism as the disease progresses.

• Tremor: Irregular postural and action tremors are common, with minipolymyoclonus evident on neurophysiologic examination.

• Pyramidal Tract Dysfunction: Manifests as hyperreflexia (overactive or exaggerated reflexes), spasticity, and extensor plantar responses.

• Other Symptoms -

  • Prominent dystonia may affect the neck, trunk, or extremities.

  • Motor impairment often leads to falls, and about half of all patients require gait aids within three years of symptom onset. Speech may be hypokinetic, ataxic, spastic, or mixed, progressing to anarthria and dysphagia as the disease advances.

  • Orthostatic hypotension may be accompanied by supine hypertension. Symptoms range from asymptomatic severe drops in blood pressure to recurrent syncope.

  • Early and severe sexual dysfunction are also reported. It manifests as erectile dysfunction in males and genital hyposensitivity in females.

  • Neurogenic bladder symptoms include frequency, urgency, incontinence, and incomplete emptying.

  • Symptoms include heat intolerance due to anhidrosis or excessive sweating due to compensatory hyperhidrosis.

  • Diurnal or nocturnal inspiratory laryngeal stridor occurs in about half of all patients and is often associated with sleep apnea.

  • Periodic limb movements and excessive daytime sleepiness are common.

3. Dementia With Lewy Bodies

In 1996, the term ‘dementia with Lewy bodies’ was introduced to describe the syndrome where dementia either precedes or occurs within one year of the onset of Parkinson's disease.

Clinical features include -

• Fluctuating cognition.

• Recurrent visual hallucinations.

• REM sleep behavior disorder.

• At least one parkinsonism feature (bradykinesia, resting tremor, or rigidity).

• Autonomic dysfunction.

• Neuroleptic sensitivity.

• Postural instability with repeated falls.

• Neuropsychiatric manifestations

• Constipation is common.

• Genitourinary symptoms occur in approximately one-third of patients.

4. Parkinson Disease -

James Parkinson first described a syndrome in 1817 as being marked by slow movement (bradykinesia), shaking when at rest (resting tremor), stiffness (rigidity), and difficulties with posture and walking. Parkinson's disease is the most common synucleinopathy.

Clinical features include-

Approximately 90 percent of Parkinson's disease patients develop at least one non-motor symptom. Common and can be the initial symptom, including:

• Constipation is seen as a complaint. It occurs due to reduced colonic motility that leads to less frequent defecation.

• Gastrointestinal Issues include gastric retention causing nausea, early satiety, and abdominal distention.

• Swallowing difficulties may be present. Due to reduced swallowing frequency, sialorrhea (excessive saliva) is common in later stages.

• Orthostatic hypotension affects up to 50 percent of Parkinson's patients.

• Urinary dysfunction is generally milder than in multiple system atrophy (MSA).

• Erectile dysfunction is also reported, and vaginal dryness, decreased libido, and difficulty reaching orgasm are reported in women.

How Can Synucleinopathies Be Diagnosed?

Synucleinopathies diagnosis requires several procedures, including genetic testing, neuroimaging, and clinical evaluation. Detection of various synucleinopathies is done with the help of specific symptoms and clinical diagnostic criteria. Brain atrophy and dopamine transporter deficiencies can be distinguished by distinctive patterns in imaging tests like MRIs (magnetic resonance imaging) and PET (positron emission tomography) scans. A cerebrospinal fluid (CSF) analysis may occasionally show higher than normal levels of alpha-synuclein or associated biomarkers. Tests for autonomic function, urologic evaluations, and urodynamic studies are also used for diagnosis.

How Are Synucleinopathies Treated?

A comprehensive strategy treats both motor and non-motor symptoms in synucleinopathies. Common treatment approaches are listed below:

• Levodopa and dopamine agonists are important pharmacological treatments for motor symptoms like bradykinesia and tremor.

• Fludrocortisone or Midodrine are useful medications for autonomic dysfunctions like orthostatic hypotension.

• Non-pharmacological interventions are important, such as speech therapy for communication problems and physical therapy to improve mobility.

• Advanced treatments like deep brain stimulation may be considered for those with severe motor complications.

Conclusion

Autonomic failure is a common problem in all these synucleinopathies, like pure autonomic failure, MSA, DLB, and Parkinson's disease. The extent of autonomic nervous system involvement differs among these disorders. MSA mainly affects the central nervous system, while Lewy body disorders affect the peripheral nervous system. MSA usually shows the most severe autonomic dysfunction, followed by moderate involvement in DLB and milder symptoms in Parkinson's disease. Pure autonomic failure patients experience severe autonomic symptoms. Specific clinical and laboratory findings may suggest its progression to other synucleinopathies.