A Tribute to the Mastermind, Stephen Hawking: Neuromuscular Disorders

Introduction:

One wonders how many people know “Stephen Hawking”! Is he well known as “Oprah Winfrey”, the late “Prince”, or “Michael Jordan. The last year movie of “The theory of everything” casted by the brilliant actor, Eddie Redmayne and earned him an Oscar, has perhaps introduced more people to the mastermind “Stephen Hawking” whom this article is dedicated.      

Stephen Hawking, one of a few living genius of our time, is an English theoretical physicist and cosmologist, and the director of Research at the Centre for Theoretical Cosmology at the University of Cambridge. His scientific works include collaboration with Roger Penrose on gravitational singularity theorems in the framework of general relativity, and the theoretical prediction that black holes emit radiation, often called Hawking radiation. Hawking was the first to set forth a theory of cosmology explained by a union of the general theory of relativity and quantum mechanics, so called “The theory of everything”. Hawking has a rare early-onset, slow-progressing form of Amyotrophic Lateral Sclerosis (ALS), commonly known as motor neurone disease, that has gradually paralysed him over the decades. He now communicates using a single cheek muscle attached to a speech-generating device. Hawking has not limited his knowledge to the scientific arena for the experts, but has popularized it by writing easy read books such as “The brief history of time” for the public. (1-8)

Neuromuscular Disorders:

Neuromuscular disorders encompass a large group of disorders, including ALS, that befell on Stephen Hawking slowly from his final year at Oxford until his formal diagnosis at age 21. These disorders that lead one way or another, to the impairment of the function of different muscles of the body, are caused by either the pathology in the neurons controlling such muscles, or the pathology at the junction of the neurons to the muscles. If just the neurons in the central nervous system are involved, such as in stroke or CVA (cerebrovascular accident), or Parkinson’s disease, they are classified as “upper motor neuron” disorders. If only the neuromuscular junctions are involved, such as spinal muscular atrophies, they are classified as “lower motor neuron” disorders. Some of these disorders such as ALS (Amyotrophic Lateral Sclerosis) are mixed of upper and lower motor neuron disorders. (9-10)

The Lesson we never learned: Polio!

Polio or poliomyelitis, an infectious paralytic disease inflicting humans’ children for thousands of years, is an obvious example of a neuromuscular disorder, caused by a virus, Poliovirus. After thousands of years, the virus was only identified about a hundred years ago, in 1908 and only about 60 years ago a vaccine against it was developed. (11-2) The poliovirus that has paralyzed and killed millions of children over history, and nowadays has been tamed by the vaccine (only 416 in 2013 worldwide down from 350,000 in 1988) is an enterovirus. This RNA virus enters the body of the child through mouth and while it may look like a sore throat or pharyngitis, it colonizes in gastrointestinal tract, by hijacking the host cell’s own machinery to replicate. By spreading through the lymph nodes such as tonsils, the virus later on reaches the blood stream and finally in about 1% of the cases invades the motor neurons and leads to muscle weakness and paralysis and in some cases to death. (13-4)

Despite the long history of poliovirus invasion to our beings and its extensive damage to our children, we never learned the lesson to figure out the causes behind other neuromuscular disorders to prevent our own paralyses in different forms! Next I will explore other relatively obvious known such disorders caused by microbial invasions, that have faded in our oblivion!

 The Story of Shingles:

Varicella zoster virus (VZV) causing Shingles, is a neurotropic herpesvirus that infects nearly all humans. Primary infection usually causes chickenpox (varicella), after which virus becomes latent in cranial nerve ganglia, dorsal root ganglia and autonomic ganglia along the entire neuraxis. This virus is a very good example of a microbial invasion that does not leave our bodies after the first attack and entry, but remains there in “latent” form until one day, years later to reactivate, attack and causes different damage. Although the usual zoster of shingles spreads along one to three dermatomes, and causing some pains and discomfort, in some cases, it could cause more damages, such as post-herpetic neuralgia and myelopathy, causing muscle weakness, paresis and numbness if not much paralysis. These neuromuscular complications could occur weeks to even years after the resolution of the shingles rashes and mostly in older population and immune-compromised subjects, specially when comorbid with other infections, such as AIDS. (15)

 Guillain–Barré syndrome:

Guillain–Barré syndrome is a rapid-onset muscle weakness progressing over half a day to two weeks. During the acute phase, the disorder can be life-threatening, affecting the breathing muscles, autonomic system and even cardiac muscles. This disorder that has been named after two French neurologists, Georges Guillain and Jean Alexandre Barré, and is currently known as an Immuno-polyneuropathy, starts with infections in most patients before the acute onset of paralysis. These infections mostly in the form of gastroenteritis and respiratory tract infection, have been attributed to some bacteria and viruses such as Campylobacter jejuni, Cytomegalovirus, Epstein-Barr virus, Varicella zoster virus, Mycoplasma pneumonia, dengue fever, zika virus, hepatitis E virus, and even influenza virus. (16-20)

 HIV-related neuromuscular disorders:

The human immunodeficiency virus (HIV) causes diverse disorders of the brain, spinal cord and peripheral nerves, and neuromuscular disorders such as nemaline myopathy and bibrachial amyotrophic diplegia, a form of motor neuron disease. There is also suspicion that HIV infection could be a risk factor for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. However, manifestations of ALS in HIV infected subjects could be treated effectively with Highly Active Antiretroviral Therapy (HAART). (21) In 1985, the fourth year of the emerging AIDS epidemic, Hoffman et al. (22) described a 26 year old man infected with HIV with both upper and lower motor neuron signs. Many feared there would be an epidemic of viral ALS. However, that fear was never realized. By mid-2002, there had been reports of 19 HIV patients with motor neuron disorders, but a major difference between HIV-associated ALS and primary ALS is its rapid progression of the first, in contrast to the slow progression of the latter. (23)

 Myastenia Gravis:

Myasthenia gravis (MG) is a neuromuscular disorder, leading to fluctuating muscle weakness and fatigue. In the most common cases, muscle weakness is caused by circulating antibodies blocking acetylcholine receptors and the post-synaptic neuromuscular junction, inhibiting its excitatory function. Myasthenia gravis is well known as an autoimmune disorder, where the antibody in myasthenia gravis attacks normal human protein, targeting a protein called an acetylcholine receptor, or a related protein called a muscle-specific kinase. Human leukocyte antigens have been associated with MG susceptibility and relatives of MG patients have a higher percentage of other immune disorders. The thymus gland that form part of the body’s immune system, is enlarged in these patients. (24) While the trigger to this autoimmune mechanism of the disease is not yet known, microbial invasions in the latent format, like in other autoimmune disorders posted on this site, could be such triggers.

Amyotrophic Lateral Sclerosis (ALS):

Amyotrophic lateral sclerosis (ALS) is a progressive, invariably fatal neurologic disorder resulting from upper and lower motor neuron degeneration, which typically develops during the sixth or seventh decade of life, unlike the uncommon case of Stephen Hawing that occurred in his early 20’s. The disease may occur with increased frequency within certain families, often in association with specific genomic mutations, while some sporadic cases have been linked to environmental factors such as toxins and infections. (25) As discussed above ALS-like syndromes or secondary ALS could occur in other infections and immune-compromised subjects such as HIV infected patients. These syndromes are fast progressing and more fatal, probably due to the acute impact of the infection, while the primary ALS seems to be related to the latent impact of microbial invasion, i.e. appearing clinically years after the first microbial attack. The suspicion of the role of microbial invasion in the causation of ALS dates back to as early as 1970, when Temin & Mizutani (26) published their article in the science journal “Nature”, relating retroviruses in the pathogenesis of ALS.

 A defining characteristic of all retroviruses is that they possess an enzyme, reverse transcriptase (RT) that has the ability to convert RNA into complementary DNA. Therefore, detection of RT has been used as a generic retroviral screening method that requires no previous knowledge of viral genome nucleotide sequence. Viola et al (27) in 1975 found RT activity in cytoplasmic particulate fraction from two ALS patients’ brains. Soon a growing interest in finding the retroviral origin of RT in patients with ALS, rose and in the 1980s, with the discovery of human T cell leukemia virus-1 (HTLV-1) and HIV, ALS-like syndromes were reported. It is estimated that HTLV-1 infects 15 to 20 million individuals throughout the world. The HTLV-1 antibody prevalence rate varies from 0.2 to 10% among adults, increasing with age, and in some places eventually reaching 20 to 50% of the female population aged 60 and above (28). The two major diseases associated with HTLV-1, adult T-cell leukemia/lymphoma (ATL) and HTLV-1 associated myelopathy/tropical spastic paraparesis in endemic areas. The latter neuromuscular disorder is a slowly progressive disorder with 50% of patients becoming wheelchair bound after 10 years, resembling much as ALS, involving both upper and lower motor neurons. Since the discovery of this paralytic or ALS-like disorder, in mid-1980s, it has been shown that some of the primary ALS cases in fact have been HTLV-1 seropositive. The clinical differentiation between ALS and this ALS-like disorder is the presence of atypical symptoms of sensory and autonomic, and the longer survival of 10.6 years on average, in contrast to the shorter survival rate of a few years in the primary ALS, and also the positive response to steroids in some cases. (29-31)

 The source of increased RT activity detected in more than half the ALS cases has not been found yet. Many have speculated that the responsible virus is likely to be a human endogenous retrovirus (HERV). HERV are retroviral-like sequences that make up 8.2% of the human genome (32). A large number of pathologies especially autoimmune disorders and malignancies, some posted on this site have been linked to HERVs (33). First evidence of HERV involvement in ALS came in 2004 when Hadlock et al.(32) showed increased immune response to HML-2 gag protein in serum samples from ALS patients with IgG reactivity in 57% compared to 11% in control, and IgM reactivity of 11% in ALS compared to no reactivity in controls. Evidence for a direct role of HERV-K expression in ALS was found in 2011, when Douville et al. (34) showed increased HERV-K expression directly in brain tissue from ALS cases. Brain tissue from patients with ALS exhibited increased HERV-K pol RNA expression, particularly from loci 7q34 and 7q36.1, compared to brain tissues from systemic disease, accidental death, and Parkinson’s disease. Given that ALS is primarily a disease of motor neurons, expression of HERV-K pol in ALS was stratified by brain regions, namely: prefrontal, sensory, motor, and occipital. The result was substantially higher expression in prefrontal cortex and sensory cortex compared to motor cortex from patients with ALS. Regional differences in HERV expression were not seen in the control patient groups, suggesting that the patients with ALS had a unique pattern of HERV expression in the brain.

 Conclusion:

Stephen Hawking is not the only celebrity to be inflicted with ALS, but long before him, was the great baseball player of 1930’s, Lou Gehrig, that the disease actually took on his name, being known as “Lou Gehrig’s disease” as well. Lou Gehrig’s illness while started in a later age of 35 than early 20’s of Hawking (both unusually later onset for typical ALS), he succumbed to death in less than three years. While I do not know much about the childhood of Stephen Hawking, if he had contracted any infectious disease or being surrounded by a germ-contaminated environment, Lou Gehrig lost two sisters from Whooping cough at early ages and one brother in infancy. When diagnosed in June of 1939 at the Mayo Clinic, he wrote to his wife, Eleanor “There isn’t any cure… there are very few of these cases. It is probably caused by some germ…Never heard of transmitting it to mates… There is a 50–50 chance of keeping me as I am. I may need a cane in 10 or 15 years. Playing is out of the question…” (35) He either heard from somewhere that the illness could be caused by some germ (s) or had a good guess, that to this day it is still in scientific debate. Although a recent article by McKee et al. (36) in 2010 provoked the question that ALS in athletes such as Lou Gehrig could be caused by head concussions and of traumatic origin, the incidence of the disease in such athletes are very rare and is unproven.

 What is known and detailed in this article is that ALS and other neuromuscular or motor neuron disorders, despite their variations, regarding the age of onset, rate of progression, primary or secondary, occur either in direct link with an infection with an acute onset and rapid progression, or an indirect or latent infection with slow progression. The primary or classic ALS that still awaits further exploration and confirmation of antibodies seropositivity as recited from some research here, occurs in old age that is more immune-compromised and infectious prone. If any case of neuromuscular disorders including ALS being recognized not as primary or idiopathic or even genetic, as the familial type seems to have caused by genetic mutations that are primarily caused by microbial invasions as posted elsewhere on this site. But all these disorders if labeled as “secondary” to a cause such as infections, then more research efforts will be made towards the discovery of the offending agent (s) and ultimately the treatment and hopefully their preventions. In a such a day that could be not too far, we will not lose greats such as Lou Gehrig and Stephen Hawking to death and disability!

Dr.Mostafa Showraki, MD, FRCPC                                                                  Lecturer, School of Medicine, University of Toronto,Author: “ADHD:Revisited” Book/ “adhdrevisited.com”/”medicinerevisited.com”

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