The Mad King of England: Neuroscience behind the Royal Malady

Ian Fox | 17 MAR 2021

Disease and Pathology
Genetics
Mental Health
History

George III was King of Great Britain and Ireland from 1760 to 1820. He ascended the throne of Britain when he was only 23 years old and he reigned for just over 40 years – making him one of Britain’s longest ruling monarchs. His reign was marked by great national unrest, including the loss of the American War of Independence and then – only a few years later – the constant threat of invasion by Napoleonic France. Under his leadership, Britain navigated through the storm of war, eventually triumphing over France in 1815, and this brought about a 100-year long peace in Europe – known as ‘Pax Britannia’.

Now, I know what you are thinking – what does this have to do with neuroscience and the brain? Well, despite George III’s great political achievements, he is most commonly remembered in history as the ‘Mad King of England’ (Rohl, Warren, & Hunt, 1998). Although he was one of Britain’s longest reigning monarchs, George III was recorded to be relatively weak, both physically and mentally, especially during the latter half of his life. He suffered from a series of ailments, including ‘flying gout’, colic, insomnia, delirium, and acute mania (Rohl et al., 1998). Interestingly, he was also afflicted with hallucinations and delusions, often believing that two of his children – who had died in childhood – were still alive. It was also reported that he would talk rapidly and incoherently, apparently chattering endlessly for over 70 hours before he died, but this is disputed (Brooke, 1972). Altogether, he suffered from four, possibly five, manic attacks, the last of which occurred between 1810-1820 and eventually claimed his life.

It is clear then that the King was gripped by a terrible illness that overwhelmed his mind. But what exactly caused George III to go ‘mad’? This question has interested many historians and scientists for centuries, but to this day no one has solved the case of George III and ‘the Royal Malady’. For many years, the official diagnosis of the King was ‘madness’, a term widely used by 18th century medical professionals to describe any patient suffering from any form of mental disturbance causing a drastic change in character and personality (Rohl et al., 1998). Psychiatrists in the 19th century would eventually change this diagnosis to ‘mania’ which, as you can imagine, is still not very helpful, since mania can be implied of any mental disorder which causes rapid mood changes (Ray, 1855).

Whenever God of his infinite goodness shall call me out of this world, the tongue of malice may not paint my intentions in those colours she admires, nor the sycophant extol me beyond what I deserve.

King George III

It is clear then that the King was gripped by a terrible illness that overwhelmed his mind. But what exactly caused George III to go ‘mad’? This question has interested many historians and scientists for centuries, but to this day no one has solved the case of George III and ‘the Royal Malady’. For many years, the official diagnosis of the King was ‘madness’, a term widely used by 18th century medical professionals to describe any patient suffering from any form of mental disturbance causing a drastic change in character and personality (Rohl et al., 1998). Psychiatrists in the 19th century would eventually change this diagnosis to ‘mania’ which, as you can imagine, is still not very helpful, since mania can be implied of any mental disorder which causes rapid mood changes (Ray, 1855).

It would not be until 1966 that the case of George III and the Royal Malady would suddenly be reopened when two British psychiatrists, Ida Macalpine and Richard Hunter, proposed an intriguing and controversial hypothesis. They suggested that George III suffered from an acute and rare genetic disorder, known as ‘porphyria’ (Macalpine & Hunter, 1966). Porphyria itself is not considered a disorder of the brain in the classical sense such as Alzheimer’s disease and Parkinson’s disease. Instead, porphyria is actually a blood disorder that, in some instances, can cause detrimental effects on the brain. Macalpine and Hunter insisted their theory was correct via a retrospective diagnosis based on the fact that the King suffered from sporadic attacks with unusual symptoms that can also be found in modern day porphyria patients. For instance, the King would experience periods of severe and rapid mood changes, such as going from a state of depression to intense manic episodes. These derangements would also coincide with other health problems, such as gall stones, ‘bilious attacks’, chest infections, and mostly importantly – the dark discolouration of his urine, which is a hallmark feature of porphyria (Macalpine & Hunter, 1966). Like porphyria patients, the King would often recover from these attacks; his mental health would improve, and the colour of his urine would return to normal. Since his first major attack in 1788, he would not relapse until 1795 – almost 7 years later. However, from then on, the relapse periods would become shorter and the symptoms would worsen; the King’s psychotic episodes would become more intense and he even gradually lost his sight (Macalpine & Hunter, 1966).

As previously stated, porphyria is a genetic disorder and therefore it is often inherited. With this in mind and to further support their claim that George III suffered from porphyria, Macalpine and Hunter traced signs of the disease in some of the King’s ascendants, notably Mary Queen of Scots. Additionally, they also traced porphyria in some of George III’s descendants, including possibly Queen Victoria and two members of the current royal family, however their identities remain anonymous (Rohl, Warren, & Hunt, 1998). Ida Macalpine and Richard Hunter were simultaneously praised and despised upon their publication of this new theory. Many claimed it was a meaningful breakthrough, whilst others contested their diagnosis, suggesting that their interpretation was misleading and in some cases, fraudulent (Peters, 2011). Nevertheless, there is no doubt that the publication of Macalpine and Hunter’s theory sparked a huge public interest into porphyria, as demonstrated by the publication of the best-selling books ‘George III and The Mad Business’ and ‘The Purple Secret’. However, not much is actually known about porphyria, especially at the neuroscientific level. How, for example, does porphyria affect the brain and how does it cause ‘madness’?

As stated before, porphyria is a blood disorder, but more specifically it is a disease that affects how blood is made. Porphyria itself is not a single disorder but refers to a group of eight disorders, each of which is characterised by the unique effect it has on how blood is produced (Meyer, Schuurmans, & Lindberg, 1998). Blood, obviously, is very important and without it our tissues and cells would not be able to receive oxygen. Oxygen is transported in the blood through a molecule called heme which also gives blood its characteristic red pigment. Heme is made through the heme biosynthetic pathway – a multistep process – in which several intermediate molecules (heme precursors) are treated by specific enzymes and are eventually converted into heme. The proper function of these enzymes is imperative to the production of heme – if one enzyme is faulty, then the heme precursors cannot be properly processed. Porphyria is caused when one of these enzymes becomes faulty either through genetic changes (i.e. mutations), or sometimes through the use of specific drugs (Elder, Gray, & Nicholson, 1972). The heme precursors then begin to accumulate in the body and eventually become toxic, causing problems such as motor neuropathy (difficulty moving), gastrointestinal distress, skin lesions, and of course – neuropsychiatric problems (Meyer et al., 1998). It is important to note that not all of the porphyrias cause neuropsychiatric problems, but the ones that do are called the ‘neuroporphyrias’ (Lin et al., 2008).

So, what exactly are the neuropsychiatric symptoms of the neuroporphyrias, and what are the causes behind them? As mentioned previously, porphyria is not traditionally seen as a neurological disorder. This, in addition to the large variation in neuropsychiatric symptoms between patients, means that the brain-based symptoms of the disorder have not been well characterised. For instance, Kuo et al (2011) was one of the first to clearly define several neurological manifestations in patients with acute intermittent porphyria (AIP). Out of 12 patients, 8 had ‘conscious disturbances’, 4 had seizures, and 7 had motor paresis (inability to move arms or legs) (Kuo et al., 2011). Other researchers have also reported aggression, psychosis, and hallucinations, as well as a high comorbidity with other disorders such as depression and schizophrenia (Suh et al., 2019). Nerve atrophy (i.e. the degeneration of brain tissue overtime) has also been reported in AIP patients, especially in brain areas that control vision and where visual information is processed, known as the parieto-occipital lobes (Suh et al., 2019).

Some AIP patients also display a condition called posterior reversible encephalopathy syndrome (PRES) (Zhao, Wei, Wang, Chen, & Shang, 2014). PRES also affects the parieto-occipital lobes by degenerating the white matter in the region. The white matter is important for nerves in the brain to relay signals at a much faster speed; in other words, it acts as an insulator for nerve signalling. MRI scans from AIP patients with PRES show a white ‘bleeding’ in the parieto-occipital lobes, signifying the loss of white matter, which causes patients to have headaches, seizures, and visual abnormalities (Suh et al., 2019; Zhao et al., 2014). Blindness is not unusual with cases of porphyria, and so it was with the case of George III – could PRES explain why the King lost his sight, and does this further support the ‘porphyria hypothesis’? White matter atrophy has also been observed in the nerves that control the movement of the arms and legs, which may also explain why many porphyria patients experience motor paresis.

It is quite clear then that porphyria is more than just a blood disorder and it can have a detrimental impact on the functioning of the brain. But how exactly do the heme precursors exert their toxic effect on the brain? What are the underlying mechanisms behind the neuroporphyrias? The answer to these questions has remained elusive to neuroscientists for many decades, and to this day the exact mechanisms are poorly understood. One of the leading theories is that one of the heme precursors behind porphyria, called aminolevulinic acid (or ‘ALA’) looks and acts very similarly to a type of neurotransmitter called γ-aminobutyric acid (or ‘GABA’). GABA is vital for regulating nerve signalling activity and it has been theorised that ALA might interfere with normal GABA function (Windebank & Bonkovsky, 2005). This means that ALA may impair how nerves send their signals around the brain which could result in headaches, seizures, and possibly psychiatric problems like hallucinations and delusions.

Experiments have also been done on cells that have been grown in petri dishes. From these experiments, researchers have found that elevated ALA levels cause other harmful chemicals to build-up and damage the cells (Kazamel, Desnick, & Quigley, 2020). They also reported that ALA damages the DNA of the cells, and also that the cells showed decreased energy production – very harmful indeed! Researchers have also tried to model porphyria in mice, with some success. They have shown that when they genetically engineer the ALA enzyme and reduce its functionality, the mice show similar motor symptoms as porphyria patients, as well as damage to the brain (Kazamel et al., 2020). Although we still do not understand much about the mechanisms of porphyria, perhaps with this animal model researchers can begin to describe the exact neuroscientific underpinnings of the disorder.

There are still many questions that neuroscientists are asking about porphyria. For example, why is the white matter targeted? Why does porphyria seem to affect the posterior regions of the brain that control visual processing? And above all, why are some patients more affected than others? Although the porphyria theory about George III is still, well – a theory, and many researchers believe that George III instead suffered from bipolar disorder (Peters, 2011), there is no doubt that ever since the publication of Macalpine and Hunter’s paper, interest in porphyria has only gone up. From the perspective of a neuroscientist, porphyria becomes more and more interesting the more we unveil about it, and perhaps soon we will acquire a full picture of the disorder that may (or may not!) have driven one of Britain’s greatest Kings to madness.

Editors: Matt Higgs and Uroosa Chughtai

References:

Published by Brain Domain

Leave a comment