What is Shy Drager syndrome?
Shy Drager syndrome refers to a progressive neuromuscular disorder that affects the nervous system, in particular, the body’s involuntary (autonomic) functions, including blood pressure, breathing, bladder function and motor control. It falls on the multiple system atrophy spectrum of disease.
Incidence & etiology:
Estimated incidence is 0.6–0.7 per 100,000 person-years (i.e 0.6 cases per 100,000 persons per year) and a geographical pattern can be observed in the worldwide distribution of the two subtypes. MSA-P is the most common subtype in Western countries, while a predominance of MSA-C cases is observed in Japan. The onset is usually in the sixth decade of life and prognosis is poor with a mean survival of 6 - 10 years from the disease onset. The prevalence rates of the disorder show 4-5 cases per 100,000 persons.
The exact cause of the disease and its subtypes is unknown. However, there are several hypotheses that have been heavily researched and proposed. The vast majority of proposed disease mechanisms encompass the accumulation of intracellular alpha-synuclein. More recently, mitochondrial dysfunction and inflammation have been suggested in its pathogenesis. Alpha-synuclein has been shown to accumulate intracellularly in other nervous system disorders, such as Parkinson's, but alpha-synuclein build-up seems to occur in oligodendrocytes in MSA primarily.
Few ongoing studies suggest that the excess alpha-synuclein is either a result of genetic overexpression in oligodendrocytes of affected patients or a result of increased uptake from the surrounding extracellular environment.
Patients with MSA demonstrate mutations in the COQ2 gene, which encodes for the production of Coenzyme Q10 (CoQ10). CoQ10 is a component of the respiratory chain in mitochondria involved in ATP production.
Brain tissue gathered from autopsies of patients with MSA show a significant decrease in CoQ10, but this was only seen in the cerebellum, suggesting that CoQ10 deficiency may predominate the cerebellar form of MSA. Finally, the role of inflammation has largely been elucidated in brain tissue, demonstrating increased microglial activation.
Alpha- synuclein
Most of the studies assessing the pathogenesis of MSA have focused on the mechanisms underlying α-syn intracellular accumulation. Alpha-syn, which plays a crucial role also in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), is a key protein in MSA neuropathology. The finding of α-syn accumulation not only in neurons, but also in oligodendrocytes, is an important feature of this disease. Furthermore, GCIs, whose presence is required for a diagnosis of “definite MSA” are the main pathological hallmark.
Alpha-syn is a 14 kDa (Kilodalton; an atomic mass unit) protein, composed of 140 amino acids, which is physiologically expressed in the human brain. Its physiological conformation is not completely clear, being still a matter of debate whether its native conformation is a folded tetramer of 58–60 kDa or an unfolded/disordered monomer which assumes an extended conformation in native gels.
The precise function of α-syn is still obscure, although several studies have pointed out a putative role in regulating synaptic vesicles and neurotransmitter release. Furthermore, more complex forms of the protein, in particular oligomers and fibrils, and post-translational modifications (e.g., phosphorylation, nitration and ubiquitination) have been associated with synucleinopathies.
As opposed to neurons, healthy mature oligodendrocytes have not been described to express α-syn and the presence of α-syn in oligodendrocyte precursors is still debated because some laboratories have detected a basal level of α-syn expression in non-primate mammals and humans, while others have not.
Therefore, the finding of α-syn aggregates in oligodendroglia is even more remarkable. Several hypotheses have been proposed to explain the aberrant localization of α-syn in MSA.
Alpha- syn overexpression.
The first hypothesis is that a reactivation of α-syn gene (SNCA) transcription occurs in the disease. The rationale of this conjecture is that an increased transcription would be followed by increased translation and increased protein amount. The putative role of excessive gene expression leading to protein intracellular accumulation is supported by the description of GCIs in oligodendrocytes of brains of PD patients carrying SNCA gene triplication. However, in these specific cases, a protein transfer from over-producing neurons is a possible hypothesis.
All the studies assessing SNCA expression in brains of MSA patients have not found significant differences between MSA and controls or have even detected a downregulation in patients. However, these studies have been performed on RNA extracted from brain samples containing both neurons and glia. Only few studies have investigated the selective expression of SNCA in oligodendrocytes of patients and healthy subjects, with conflicting results.
In-situ-hybridization analyses on autopsy brain samples have detected a negligible level of SNCA mRNA in oligodendrocytes of both patients and controls, thus excluding the possibility that increased SNCA transcription may be implicated as cause of the disease. However, two more recent studies, based on oligodendrocyte isolation and qPCR analysis, have described a basal gene expression level also in oligodendrocytes, with a trend of increase in MSA patients.
The hypothesis of an aberrant SNCA expression in MSA oligodendroglia is intriguing, but the conflicting available data does not allow one to draw definite conclusions about this issue. So far, most of the studies do not support a direct involvement of α-syn gene expression in MSA pathogenesis and the studies suggesting this hypothesis do not provide significant results. However, it must be acknowledged that the isolation of oligodendrocytes from patient’s brains is technically difficult and that the lack of statistical significance may be due to the limited number of subjects used in these studies. Therefore, although SNCA overexpression is unlikely to be the sole mechanism leading to the disease onset, it will be crucial to repeat these experiments in wider cohorts of patients and controls, both in brain-isolated and iPSC-derived oligodendrocytes. It will also be important to investigate the role of pre- and post-transcriptional SNCA regulatory mechanisms, including CpG island methylation, transcription factors, lncRNAs and miRNAs.
Alpha- syn uptake from oligodendrocytes.
A second hypothesis about the mechanisms leading to α-syn accumulation in MSA suggests that the protein is not produced directly in oligodendroglia, but that it is taken-up from neurons or from the extracellular environment.
Various studies have demonstrated the ability of neurons to uptake α-syn both in vitro and in vivo and a possible transfer of α-syn from neuron-to-neuron has been demonstrated as well. However, the prominent oligodendroglial pathology in MSA has prompted various laboratories to investigate the possible transfer of α-syn from neurons to oligodendroglia.
Oligodendroglial cell lines have shown the ability to uptake α-syn monomers and increased levels of oligodendroglial α-syn have been observed in a double transgenic mouse overexpressing α-syn under MBP and PDGF promoters, when compared to the MBP-mouse model. An extensive study has investigated the uptake of various forms of α-syn from oligodendroglia in vitro and in vivo.
Oligodendrocytes are able to internalize α-syn monomers, oligomers and, although to a lesser extent, fibrils. The same species of α-syn can also be internalized in vivo, after injection into the mouse cortex. Moreover, grafted oligodendrocytes can uptake α-syn from host rat neurons overexpressing human α-syn.
Symptoms in Parkinsonian type (MSA-P)
This is the most common type of MSA with signs and symptoms that are similar to those of Parkinson's disease, such as the following:
Rigidity in muscles.
Difficulty bending arms and legs.
Slow movement (bradykinesia).
Tremors (rare in MSA compared with classic Parkinson's disease)
Postural instability.
Symptoms in Cerebellar type (MSA-C)
The main signs and symptoms in this type of disorder are problems with muscle coordination (ataxia), but others may include:
Impaired movement and coordination, such as unsteady gait and loss of balance (patients present with repeated history of fall)
Slurred, slow or low-volume speech (dysarthria)
Visual disturbances, such as blurred or double vision(diplopia) and focus problems.
Difficulty swallowing (dysphagia) or chewing.
General sign and symptom
In addition, the primary sign of multiple system atrophy is:
Postural (orthostatic) hypotension, a form of low blood pressure that makes the patient feel dizzy or lightheaded, or even faint, when he/she attempts to stand up from sitting or lying down.
The patient can also develop dangerously high blood pressure levels while lying down (supine hypertension).
Symptoms involving other involuntary (autonomic) body functions.
Urinary and bowel dysfunction
Constipation
Loss of bladder or bowel control (incontinence)
Sweating abnormalities
Reduced production of sweat, tears and saliva
Heat intolerance due to reduced sweating
Impaired body temperature control, often causing cold hands or feet
sleep disorders
Agitated sleep due to "acting out" dreams
Abnormal breathing at night
Sexual dysfunction
Inability to achieve or maintain an erection (impotence)
Loss of libido
Cardiovascular problems
Color changes in hands and feet caused by pooling of blood Cold hands and feet.
Psychiatric problems
Difficulty controlling emotions, such as laughing or crying inappropriately.
Treatment and management of MSA:
As of now, there is no cure for multiple system atrophy. The combination of symptom management and emerging research of novel therapies can give affected patients symptomatic relief and hope.
Symptomatic management is targeted at the predominant features of how MSA or its subtypes manifest. Parkinsonism is treated with a variety of agents, including monoamine oxidase inhibitors and levodopa. For cerebellar ataxia, cholinergic agents have been used. Urinary and fecal incontinence have been treated with Trospium chloride or vasopressin analogs, laxatives, or straight catheterization.
Midodrine and fludrocortisone have been used to treat orthostatic hypotension with physical therapy as a supplement for additional motor symptoms. Novel therapies in the pipeline include agents that block alpha-synuclein accumulation or uptake into oligodendrocytes. Selective serotonin reuptake inhibitors (SSRIs), including sertraline and paroxetine, have recently shown promise.
In vitro studies demonstrate that sertraline blocks the alpha-synuclein uptake and aggregation in oligodendrocytes. In 2006, a clinical trial of the SSRI paroxetine demonstrated a statistically significant improvement in motor function amongst patients with MSA.
Mesenchymal stem cells (MSCs) have also been explored in the treatment of MSA. A 2019 phase I/II clinical trial utilized intrathecal implantation of MSCs in 24 patients with MSA at quantities varying from 10-200 million. Derived from adipose tissue, MSCs use demonstrated a statistically significant decreased rate of disease progression. Studies aiming at modulating inflammation and microglial activation are underway as well.
The myeloperoxidase (MPO) inhibitor Verdiperstat was shown to decrease microglial activation and neuronal rescue in a mouse model of MSA. A phase 3 placebo-controlled human trial on the efficacy of verdiperstat in improving the quality of life for patients with MSA is currently underway.