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25 Years Ago, the First Report of a Mutation Associated With Parkinson’s Disease

25 Years Ago, the First Report of a Mutation Associated With Parkinson’s Disease

Image: Mahmoud-Ahmed/pixabay

  • A quarter century has passed since the first report of a genetic mutation associated with Parkinson’s disease, in a gene responsible for making the alpha-synuclein protein.
  • There are no blood tests or imaging options to diagnose Parkinson’s disease, and because of the large variability of symptoms, it is often called a “snowflake disease”.
  • Once it is diagnosed, simple changes in one’s routines can make big differences – as we saw recently in the instance of Father Stan Swamy.

On July 5, 2021, Father Stan Swamy, an 84-year-old Jesuit priest, died at the Holy Family Hospital, Mumbai. Per the Bombay high court’s directions, Stan Swamy had been moved from prison – he had been arrested in October 2020 – to the hospital on May 28, 2021. The court later extended his hospital stay due to his deteriorating health. The fact that Swamy was suffering from Parkinson’s disease has since been public knowledge, if it wasn’t already before.

Neurological disorders like Parkinson’s have become a leading cause of disability around the world. Exactly a quarter century has passed since the first report of a genetic mutation associated with Parkinson’s disease: in the gene SNCA, responsible for making the protein alpha-synuclein. Over the years, scientists have associated more than 30 mutations in this gene with Parkinson’s disease.

Mutations in other genes have also been subsequently identified to be associated with Parkinson’s disease. However, most of them have been identified in Caucasian cohorts, and efforts are underway today to collect similar information from other populations. While there are approved chemical treatments, as well as surgical interventions, there is no cure for Parkinson’s disease.

But none of these interventions will be of use unless we as a society increase awareness and eliminate the stigma surrounding Parkinson’s disease, and in fact all diseases.

It is a well-established medical fact that as Parkinson’s disease becomes more severe, the ability to swallow is significantly compromised. If proper interventions are not provided for the patient’s dysphagia (swallowing difficulty), the condition can lead to malnutrition, dehydration and aspiration (when food or liquid ‘goes down the wrong pipe’). Aspiration can lead to aspiration pneumonia – the leading cause of death among people with Parkinson’s.

Several reviews and meta-analyses, including one published in 2017, have discussed the global age distribution in the occurrence of the disease. One poorly appreciated fact is that about 10% of individuals affected by the disease are diagnosed in the prime of their lives.

Figure 1: From the 2017 paper – Poewe, W. et al. Parkinson disease. Nat. Rev. Dis. Primers 3, 17013 (2017)

The American professional boxer Muhammad Ali was diagnosed with Parkinson’s syndrome at 42 years, in 1984, at a time when experts widely believed it typically occurred later in life. Michael J. Fox, star of the Back to the Future film franchise, was diagnosed with Parkinson’s disease, around the age of 30.

Clinically, Parkinson’s syndrome is different from Parkinson’s disease: the former is characterised by physical manifestations of Parkinson’s disease, such as tremors, rigidity, unstable posture and slow movements. Although there is still debate on what may have caused Ali’s Parkinson’s, the fact remains that his and Fox’s symptoms surfaced at a young age. The average age of diagnosis of Parkinson’s is 62 years.

It’s complicated

To the casual observer, Parkinson’s syndrome and Parkinson’s disease are the same. But Parkinson’s syndrome is not primarily a consequence of neurodegeneration – while Parkinson’s disease is. Parkinson’s syndrome might lead to neurodegeneration, when the individual will be diagnosed with Parkinson’s disease.

Parkinson’s disease is a consequence of dysregulated biochemical pathways that lead to neuroinflammation and eventually to cell death. The substantia nigra, a region of the brain, is home to cells that produce the neurotransmitter dopamine. But because of specific mutations in one or multiple genes, these cells slowly die, resulting in lower amounts of dopamine in the body, and thus impaired and deteriorating neuronal and motor function.

Individuals with Parkinson’s disease are typically prescribed increasing amounts of a form of dopamine to compensate for the loss of these nerve cells.

A 3D rendering of the substantia nigra (highlighted in red). Image: FrozenMan/Wikimedia Commons, CC BY-SA 4.0

We tend to align neurodegenerative diseases with aging because it is difficult to dissociate the concept of ‘degeneration’ from age. Degeneration implies decay and decline; and decay and decline in a biological system is typically correlated with age. But as we have seen in the cases of Ali and Fox, Parkinson’s can occur well before the average age of 62. As a general rule, then, when Parkinson’s is diagnosed in individuals younger than 50, it is called young onset Parkinson’s disease (YOPD).

The biochemical changes that occur are the same in both YOPD and PD, just the time of onset is different.

Parkinson’s disease is more frequently reported among older individuals, so when symptoms occur in younger individuals, they are often overlooked or attributed to other causes. Currently, at least 10 million people worldwide live with Parkinson’s diseases. About a million of them are in the US; India has between 500,000 to 1 million people with Parkinson’s disease.

According to some estimates, as many as 10% of people with Parkinson’s disease are diagnosed before the age of 50 and some as young as 25. One of the authors here – Girija Muralidhar – was diagnosed with YOPD at the age of 45.

As has happened with a number of YOPD patients, it took some time before a correct diagnosis was available. This is because of the lack of patient awareness of YOPD and a tendency among physicians to consider other reasons for the symptoms of Parkinson’s disease, which at an early age are not pronounced. For example, in Girija’s case, a rotator cuff tear and frozen shoulder masked a characteristic symptom of PD: a stiff arm that was difficult to move. (In unaffected individuals, a normal feature of walking is a complementary motion of the arms.)

Not a needle in a haystack

Muhammad Ali and Michael J. Fox before testifying at a Senate Committee hearing on the importance of funding to combat Parkinson’s disease, 2002. Photo: US Congress

There are no blood tests or imaging options to diagnose Parkinson’s disease, and because of the large variability of symptoms from one person to another, Parkinson’s is often called a “snowflake disease”. Some genetic mutations have been linked to it, but only a fraction of cases appear to have genetic causes, making routine genetic screening also hit-or-miss.

YOPD has a higher likelihood of being the result of genetic factors, although a combination of genetic and environmental factors hasn’t been ruled out either. Getting an exhaustive medical history is perhaps more important for Parkinson’s disease than for most other diseases. Individuals with YOPD may have no initial motor symptoms and instead have early non-motor symptoms like depression and anxiety, further exacerbating the difficulty in diagnosing the disease.

If we knew precisely what we are looking for, it would be like looking for a needle in a haystack. Unfortunately, we don’t yet know what this needle looks like.

Once it is diagnosed, simple changes in routines can profoundly improve the lives of all persons with Parkinson’s disease, regardless of age. Some of these include reducing physical barriers in homes and making these spaces more accessible for patients, and providing assistive devices and utensils to address dysphagia – not unlike a simple sipper and straw that was eventually provided to Stan Swamy.

Such modest adaptations can make the difference between life and death. While scientists continue to define and look for the critical needle, we as a society can promote awareness of and support for Parkinson’s disease.

Deepti Pradhan is a scientist, science communicator, and a cancer patient and survivor advocate. She is currently associate director of Prospect Research at Yale University. She tweets at @TildeCafe_. Girija Muralidhar is a retired immunologist. An active patient advocate for Parkinson’s disease, she was previously member of People with Parkinson’s Advisory Council.

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