The Jacquetta Curse of the Tudors: Infant mortality, monarchical mental disorder, Kell antigen positivity, and McLeod syndrome

With his turbulent love life, his constant pursuit of a male heir, and his drastic religious shifts, King Henry VIII of England’s life sounds more like a reality show than history. He was a man of contradictions, pursuing a woman he loved for nearly a decade only to behead her less than four years after their marriage. He fiercely defended Catholicism and was hailed as a defender of the faith, but later broke ties with Rome and declared himself supreme head of the Church of England. Worst of all, the king who was hailed as a “hero” and a “lover of justice and goodness” at the beginning of his reign turned into a tyrant known as the “British Nero” in his later years. Previous hypotheses have included diabetes, syphilis, and hypothyroidism. However, none of these are sufficient to explain why Henry failed to produce a male heir despite multiple matches. Modern historians and doctors have speculated that Henry VIII had Kell positive blood (Kell antigen) and then had McLeod syndrome, possibly inherited from Henry’s great-grandmother, Jacquetta Woodville of Luxembourg. If Henry’s blood type was Kell positive, then this would explain his partner’s strange reproductive pattern, as well as the psychotic changes caused by McLeod syndrome. Because the mutation of the syndrome significantly reduces the expression of McLeod protein, effectively inactivating the Kell antigen. A Kell positive male will cause serious problems for his reproductive partner after his first pregnancy, because the Kell negative mother’s body will produce Kell alloimmunity, which means that her body will attack the Kell positive fetus as a “foreign object”, resulting in the death of the fetus or newborn. This can happen when the same woman and the king have multiple pregnancies. At least three of the king’s children survived infancy, they were the first children born to different mothers, and therefore were completely unaffected by Kell alloimmunity. Even if the first baby received the Kell gene from Henry, the mother’s body would not attack it. However, any fetus conceived after the first baby who inherited the Kell gene from Henry would be killed by the mother’s antibodies. If Henry also had MacLeod syndrome (a genetic disease unique to Kell blood type), then this could finally explain why Henry changed in both size and personality before the age of 40, from a strong, athletic, generous man to a terrifying paranoid man with a significant weight gain and a leg disease that made him almost immobile. In ancient times, people had a limited understanding of science and believed that “the end of science is metaphysics.” For some things that science could not explain at the time, it does not mean that it will never be explained. Now humans with advanced modern medicine can explain things that science could not explain in the past. In the future, therapies will also be able to cure many diseases that were terminal in the past. Patients with mental disorders will no longer be terminal in the future, and will no longer be “village keepers” for life. Parents with mental illness patients at home can hope to “live longer and see”, but before that, we patients need to first diagnose what disease is causing all these obstacles for ourselves.

一、 Kell Antigen System

1. Kell Antigen System

The ABO and Rh blood group systems are extremely familiar to people, but there are other blood group systems that are less familiar to many people, such as the Kell Antigen System.

There are three allele forms of ABO blood type: A, B, and O. The ABO blood types are A, B, AB, and O. The determination of human blood type is determined by genes inherited from parents. There are eight blood types due to the presence of the Rh factor. The Rh factor is a protein located on the surface of red blood cells; if a person inherits this protein, the blood type tends to be positive. If not, the blood type will be negative. ABO must be compatible when transfusing blood. Blood transfusions depend on the type of antibodies in the plasma and the antigens on the surface of red blood cells. If the blood types are incompatible, agglutination will occur and may be fatal. Antigens are foreign molecules that induce immune responses in the body.

The Kell Antigen System is a human blood system, a group of antigens located on the surface of red blood cells, which plays an important role in blood type determination and also targets autoimmune diseases that invade red blood cells. An autoimmune disease is a disease in which the body’s immune cells attack normal self-cells instead of abnormal foreign cells. The medical definition of Kell is a group of red blood cell antigens that play a role in transfusion reactions. The Kell protein consists of a polypeptide chain of 732 amino acids. The Kell antigen system has another name, the Kell-Cellano system. The Kell antigen is not limited to red blood cells, as it is also expressed in trace amounts in other parts of the body, such as the heart and skeletal muscles, lymphatic organs, and the nervous system. The Kell protein is linked to a protein called XK within the blood cell membrane by a disulfide bond.

2. Kell blood type The Kell blood antigen system is very complex and consists of a variety of highly immunogenic antigens. The KEL gene is a protein-coding gene that encodes many Kell antigens on the surface of red blood cells, and the classification of human blood is based on these antigens. The uniqueness of the Kell antigen system types is that they have allelic polymorphism. This means that it has many alleles that are not identical, which may reach 25 alleles. Alleles are different forms of genes. There are two important alleles that produce two different antigens that differ in only one amino acid. These antigens are uppercase K (formerly Kell) and lowercase k (formerly Cellano). K and k are codominant, but this does not mean that K is dominant and k is recessive. In most populations, the frequency of K antigen is lower than that of k antigen.

3. Kell positive blood type

Kell positive blood type only accounts for 10% of the total population, and they differ from Kell negative blood type by only one amino acid.

4. Kell negative blood type Kell negative blood type is very common, and about 90% of the population (including men and women) belongs to this blood type. People with Kell negative blood type do not have Kell antibodies.

5. The role of Kell blood type in reproductive compatibility Kell blood type plays an important role in reproductive compatibility. The type of Kell antigen determines the cause of hemolytic disease of the newborn (HDN). This is not common and occurs when the mother carries Kell-negative antigens and the father carries Kell-positive antigens; a Kell-positive father may pass on either Kell-negative or Kell-positive genes to his child. If the child inherits the Kell-negative allele, the pregnancy will be normal. However, if the child inherits the Kell-positive allele, the mother’s immune cells will treat the Kell-negative allele as a foreign body, attacking and destroying the red blood cells of the developing embryo. If the first child is Kell-negative, the pregnancy may be normal and will not have this complication, but the Kell-positive antigen can enter the mother’s blood during pregnancy, leading to the production of Kell antibodies, which will attack subsequent pregnancies with Kell-negative fetuses. This will cause severe fetal anemia because maternal anti-Kells will target red blood cells and inhibit their production.

6. Diseases associated with the Kell antigen system It has been reported that some autoimmune hemolytic anemia diseases are associated with inhibition of the Kell antigen system. In this case, the Kell antigen system is very weak and the red blood cells may be weakly positive or negative, or even Ko (null). When autoimmunity returns to normal, the strength of Kell antigens will also return to normal.

Kell antigens may weaken due to the presence of alloantibodies in the serum (alloantibodies are produced against alloantibodies that enter the body through pregnancy or blood transfusion) or the presence of immunoglobulin G autoantibodies against Kell blood group or enzymatic degradation of certain microorganisms. All of the above reasons are aspects of autoimmune hemolytic anemia, which destroys red blood cells.

Hemolytic disease of the newborn (HDN) can be caused by anti-K. HDN caused by anti-Kell antibodies is extremely severe because Kell antigens are present on the surface of red blood cells and anti-K rapidly enhances the immunity of fetal liver macrophages against these erythroid progenitors (immature progenitors that are precursors to red blood cells) instead of mature red blood cells, thereby inhibiting the synthesis of red blood cells. This results in severe anemia and possible fetal death. Since red blood cell precursors lack hemoglobin, measuring bilirubin (produced by hemoglobin degradation) in the presence of anti-K cells does not accurately indicate the severity of anemia, unlike anti-Rh-related hemolytic anemia, where bilirubin levels are important for measuring the severity of the disease, so Kell cell blood compatibility testing is recommended to avoid complications.

7. Relationship between McLeod syndrome and Kell antigen system On the surface of red blood cells, XK protein is linked to Kell glycoprotein; XK protein is a protein present in the membrane and has a transport function. McLeod syndrome occurs due to lack of XK and reduced Kell antigenicity. Kell antigen is poorly expressed, and the red blood cell morphology is abnormally star-shaped with spike-like protrusions, called acanthocytosis.

Symptoms of McLeod syndrome usually appear around the age of 30 and include muscle atrophy or muscle tissue deterioration, as well as neurological diseases such as loss of reflexes. People with McLeod syndrome may experience cognitive impairment and other psychiatric disorders, such as depression and obsessive-compulsive disorder, heartbeat problems, and personality changes, as happened to King Henry VIII. These symptoms may worsen with age. Symptoms usually affect the nervous system, heart, and blood vessels. Pathological changes include neuronal loss, atrophy, and gliosis, mainly in the caudate nucleus and globus pallidus, but may also occur in the thalamus, substantia nigra, and putamen, while sparing the cerebellum and cortex. These changes may be shown by an increase in T2 signal on magnetic resonance imaging (MRI).

McLeod syndrome (MLS for short): McLeod phenotype is a recessive mutation in the Kell blood group system. The McLeod gene encodes the XK protein located on the X chromosome. XK protein deficiency is an X-linked disease. Mutations cause McLeod syndrome with or without neuroacanthocytosis. The gene on the X chromosome that causes McLeod syndrome is physically close to the gene that causes chronic granulomatous disease. Therefore, an individual with a relatively small deletion may have both disorders. Female carriers may present with a milder form of McLeod syndrome.

The age of onset of neurologic symptoms ranges from 18 to 61 years: most patients present before age 40, and nearly all clinical observations suggest a slowly progressive course of the disease; the reported interval between onset and death ranges from 7 to 51 years; the mean age of death is 53 years (range, age 31 to 69 years). The mean duration from diagnosis to death is 21 years. Cardiac problems, particularly tachycardia, appear to be the leading cause of premature death in patients with MLS; other causes of death include pneumonia, seizures, suicide, and sepsis.

About one-third of patients present with chorea: restlessness and small involuntary movements of the ankles and fingers may occur early in the disease. Later, choreiform movements of the limbs may develop in up to 95% of patients. Involuntary facial tic-like movements are also common, but orofacial dystonia is not typical.

Psychiatric disorders: Up to 80% of patients may develop psychiatric disorders gradually. Anxiety, depression, and “emotional lability” are common, and some patients have obsessive-compulsive or psychotic symptoms. Psychometric testing may reveal memory and executive function problems.

Ankle reflex loss is seen in almost all patients: generalized reflex loss is also common. Patients rarely report sensory symptoms. Slowly progressive muscle weakness and atrophy are common, but only about half of patients eventually develop clinically significant weakness.

Two-thirds of patients have evidence of cardiac disease: cardiomyopathy and arrhythmias (atrial fibrillation and atrial flutter) have been reported.

Epilepsy: Epileptic seizures are seen in about half of patients.

二、Henry VIII’s marriage and fertility history

1. Henry VIII’s six marriages

It can be summarized in one sentence: divorce, beheading, death, divorce, beheading, life.

As can be seen from the six marriages of Henry VIII in the above figure, he only had one legitimate male heir, Edward VI, who only lived to the age of 15.

Because of Kell positive antibodies, the first children of many of Henry’s partners were often healthy and not affected by this curse. It is believed that Henry caused at least 11 pregnancies with his multiple wives and mistresses, and possibly more than 13. Records show that only four of them gave birth to healthy babies: Queen Mary I, the fifth child born to Henry and his first wife Catherine of Aragon; Henry FitzRoy, the first child of Henry and his mistress Elizabeth Blount; Queen Elizabeth I, the first child of Henry and his second wife Anne Boleyn; and Edward VI, the first child of Henry and his third wife Jane Seymour.

Only four children survived infancy in 11 pregnancies, three of which were firstborns. The survival of Henry FitzRoy, Elizabeth and Edward is consistent with Kell positive reproductive patterns, and doctors were helpless in Henry VIII’s time. If these children had neonatal hemolytic anemia at the time, they would not have lived long at all. In today’s world of advanced modern medicine, these babies have a higher survival rate. Doctors can usually give babies a blood transfusion shortly after or even before they are born. Fortunately, Kells positive is uncommon. More than 90% of people are Kells negative.

Henry’s first wife, Catherine, had a sister named Juana, the Spanish “mad woman”. Henry and Catherine’s fifth pregnancy gave birth to the only surviving heir, Queen Mary I, “Bloody Mary”. Because both parents had an abnormal family history, Mary may have suffered from various diseases (anxiety, insomnia and neuralgia) and had no heirs. After Mary’s death, Elizabeth I, the daughter of Anne Boleyn, succeeded to the throne. This queen never married and had no heirs. After her death, James of the Stuart family inherited the throne, and the Tudor dynasty withdrew from the British royal rule. The previous issue introduced the James family genetic disease porphyria (werewolf vampire myth) of the Stuart family: a mental abnormality-type genetic metabolic disorder caused by inbreeding of the European royal family

2. Henry VIII’s Kell-positive reproductive pattern

Catherine: Henry was nearly 18 years old when he married 23-year-old Catherine of Aragon. Their first daughter was a girl, but died. Their second child was a boy who lived only 52 days. After marriage, they confirmed four more pregnancies, but three of the children were either stillborn or died shortly after birth. Their only surviving fifth child was Mary, who was eventually crowned the fourth monarch of the Tudor dynasty.

Although the fact that Henry and Catherine of Aragon’s first child did not survive is somewhat atypical, some cases of Kell sensitization may even affect the first pregnancy. If Mary inherited the recessive Kell gene from her father Henry, then her mother Catherine’s fifth pregnancy would meet the hypothesis of Kell sensitization, giving birth to a healthy baby.

Anne Boleyn: Anne Boleyn’s pregnancy was a classic example of Kell alloimmunization, she gave birth to a healthy first child, then miscarried three more sons in the late stages.

Jane Seymour: Had only one child before she died, but that healthy first child also matched a Kell alloimmunized father.

Given the above, Henry’s reproductive problems can be explained by the fact that he was heterozygous for Kell antigens, possessing both the K and non-immunogenic Ko or k alleles, while his reproductive partners possessed the more common k allele. The rarity of the immunogenic K antigen better explains why so many of Henry’s matches with different women failed. If Henry VIII could have found a Kell positive wife like himself, about 9% of Europeans have Kell positive blood type, so if he did find her, he might have had many children. The future may finally have a definitive answer, and researchers are asking the current British monarch for permission to exhume the remains of her distant relative and perform DNA tests on his hair and bones.

3. Henry VIII and symptoms related to McLeod syndrome

The phenotype of McLeod syndrome (MLS) is a recessive mutation of the Kell blood group system. The McLeod gene encodes the XK protein located on the X chromosome. XK protein deficiency is an X-linked disease. XK protein is present on the surface of red blood cells and covalently bound to the Kell protein. Without this protein, Kell antigens are weakly expressed on the cell surface and are therefore unlikely to be recognized by the surveillance immune system. Therefore, it can be considered necessary for the presentation of Kell antigens. McLeod pathological features include psychosis, behavioral changes, dementia, epilepsy, movement disorders, peripheral neuropathy, muscular dystrophy, cardiomyopathy, and hemolytic anemia with acanthocytosis. In middle age, Henry developed chronic leg ulcers, which further fueled the long-standing speculation that he had type II diabetes. The ulcers could also be caused by osteomyelitis, a chronic bone infection that can make walking extremely painful. In the last few years of his life, Henry’s mobility had deteriorated to the point where he needed to be carried in a chair with a cane. The report noted that this lack of mobility was consistent with known cases of McLeod’s syndrome, with one patient beginning to notice weakness in his right leg at age 37 and atrophy of both legs by age 47.

The records do not indicate whether Henry exhibited other physical symptoms of McLeod’s syndrome, such as persistent muscle contractions (twitches, spasms, or cramps) or abnormal increases in muscle activity, such as twitches or hyperactivity. McLeod’s syndrome can also be associated with chronic granulomatous disease (CGD), but Henry was primarily documented as having only one chronic lesion, rather than the usual many chronic bacterial and fungal lesions of CGD. The multiple ulcers would provide additional support for the diagnosis of CGD and MLS. Unfortunately, based on medical knowledge at the time, it was difficult to find that a severely obese man with one or more leg ulcers had cardiomyopathy or mild anemia. However, he did suffer from mobility problems. Interestingly, other literature reports a case of an MLS patient who had mild dementia and aggressive behavior. Other literature describes a case of a patient with cognitive impairment, slurred speech, confusion leading to unemployment, excessive nudity, and physical abuse of his wife. While some of these descriptions fit some of Henry’s clinical features, the only MLS features Henry undoubtedly exhibited were cognitive impairment and the development of violent psychosis in his later years. The dramatic changes in his personality provide stronger evidence that Henry had MacLeod syndrome: in the dozen years before his death, his mental and emotional instability increased to the point that some called his behavior psychotic.

MacLeod syndrome is similar to Huntington’s disease, which affects muscle coordination and causes cognitive impairment. McLeod syndrome usually begins to appear between the ages of 30 and 40, often resulting in myocardial damage, muscle disease, psychiatric abnormalities, and motor nerve damage.

4. Henry VIII, McLeod syndrome, and Kell antigens

If Henry has MLS, he will have inactivated Kell antigens. His children will only inherit random segregation of his genotype and therefore will not necessarily be protected from alloimmunization against the immunogenic K allele, a process that involves both the mother and the fetus. Specifically, Henry’s boys will not inherit his presumed X-linked McLeod mutation, so if the boy inherits Henry’s immunogenic K allele and the mother is Kell negative, alloimmunization may still occur.

In contrast, although Henry’s daughters would have inherited his McLeod mutation as well as a normal X chromosome from their mother, some of them might still have experienced negative immunogenic selection if they also co-inherited the immunogenic K antigen. Normally, X inactivation occurs randomly, so some red blood cells (RBCs) display the MLS hematological phenotype while others do not. Thus, those RBCs that fail to express the MLS phenotype (i.e., silence the MLS mutation allele) are able to display the immunogenic K allele.

These analyses could explain why Henry also lacked viable female offspring. However, during normal development, random inactivations can become severe and be biased by chance. Thus, inactivation of the wild-type McLeod protein predominates. Therefore, these women also develop MLS, and maternal immunity may be down-activated, allowing them to survive the fetal period. In other women, the situation may be reversed, carrying mutant McLeod inactivation on the X chromosome, and subsequently developing HND. This is not a hypothetical concept. Complete suppression of the wild-type gene may result in women who manifest X-linked disease.

For example, there are reports of a case of X-linked hemophilia B in a woman with an X chromosome defect. There are also reports of a mother of an MLS patient with acanthocytosis, and another report of a woman with a new point mutation in the McLeod gene that resulted in a marked skewed X chromosome inactivation, especially in the blood and brain.

Therefore, women with abnormal inactivation during fetal development may develop MLS, and they may or may not develop Kell-related HDFN. These women may develop neurological symptoms of MLS later in life. One could question whether Henry VIII’s daughter, Mary I (aka Bloody Mary), was a poster child for this condition.

The historical record does not support a diagnosis of MLS for Henry VIII or other English monarchs. Although the phenotypic likelihood of Henry VIII suffering from MLS is controversial at best.

It is well known that English and other European monarchs suffered from mental illness over the past millennium. King Charles VI of France (1368–1422), his grandson King Henry VI of England (1421–1471), and King George III of England all suffered from insanity requiring regencies. Some authorities believe that George III suffered from porphyria and believe that his ancestors Margaret Tudor (Henry VIII’s sister), Mary Queen of Scots, and King James VI of Scotland also suffered from the disease.

Since Catherine de Vallois (daughter of King Charles VI of France) was the wife of Henry V, and subsequently the mother of Henry VI, the grandmother of Henry VII, the great-grandmother of Henry VIII, and a direct ancestor of George III, it is tempting to speculate that she carried and shared a partially penetrant genetic predisposition to mental illness. Therefore, Henry VIII may have inherited the same genetic predisposition to mental illness and hereditary insanity from her.

Furthermore, the intermittent occurrence of this phenomenon in later members of the British royal family suggests that Henry VII passed this partially penetrant trait to his descendants. Consistent with this, other members of the British royal family over the past thousand years have exhibited traits that can reasonably be described as eccentricities. However, given that MLS is X-linked, a cursory look suggests that it is unlikely to be the culprit for the genetic predisposition to mental illness carried by Catherine de Vallois. This is because King Henry VIII must have inherited his only X chromosome from his mother, Elizabeth of York. It is unlikely that she also carried the X-linked mutation that causes MLS. Furthermore, this view is supported by investigations into her father, Edward IV, and her maternal grandfather, Richard Woodville, who lived to the ages of 41 and 64 with no signs of mental illness, both of whom were past the typical age of onset of MLS (between 30 and 40 years old). Therefore, given the neurological features described in Henry VIII’s ancestors, there is no evidence for X-linked inheritance of MLS.

Given the above, if Catherine de Vallois did have a genetic predisposition to mental illness, it is more likely that this predisposition was autosomal. However, this does not negate the possibility that Henry VIII’s McLaughlin mutation was spontaneous, i.e., it arose “de novo”. Unfortunately, there is no widely accepted common diagnosis for these four kings, no DNA studies available, or even a generally accepted diagnosis for any of them.

McLaury syndrome is associated only with phenotypic inactivation of the Kell antigen system; therefore, unless skewed X chromosome inactivation occurs, MLS and unsuccessful pregnancy in the female partners of Kell-positive males can coexist in one individual. Without DNA analysis, there is no way to further substantiate the possibility that Henry had both problems that led to his mental degeneration into a murderous tyrant.

三、The legend of the curse of Jacquetta in the Tudor dynasty

Several male maternal relatives of Henry VIII followed the Kell-positive reproductive pattern. Henry VIII’s Kell-positive gene may have been inherited from Jacquetta, the great-grandmother of the King of Luxembourg. Jacquetta’s male descendants generally had reproductive failure, while female descendants generally had high fertility, indicating that the Kell phenotype was inherited in the family.

Jacquetta Woodville was born into an aristocratic family and later married into the royal family. She is the ancestor of every British monarch since then. She was the daughter of Pierre de Luxembourg (Count of Saint-Pol) and Margaret de Baux (cousin of Sigismund of Luxembourg, current Holy Roman Emperor and King of Bohemia and Hungary), and later married John of Lancaster, 1st Duke of Bedford (third son of King Henry IV of England and Mary de Bohun), and then married Lord Richard Woodville. She had no children from her first marriage, but she had at least 13 children with Richard Woodville, including daughter Elizabeth, who married King Edward IV.

Figure: Historical portrait and stills of Jacquetta Woodville

It is rumored that Jacquetta Woodville’s ancestor Siegfried of Luxembourg (c. 922–998) was a descendant of the water goddess Melusina. In the book The White Queen, it is implied that Margaret Beaufort, the mother of Henry VII and the grandmother of Henry VIII, may be responsible for the death of Elizabeth Woodville’s sons Edward and Richard. The two princes were imprisoned in the Tower of London. Elizabeth Woodville (Edward IV’s queen and Jacquetta’s daughter) and her daughter Elizabeth cursed the murderer of her two young sons, requiring the murderer’s son and all future grandchildren to die, so that the bloodline could not continue. Later, Elizabeth Woodville’s daughter Elizabeth became the queen of Henry VII (Elizabeth of York), and the curse was backfired on Jacquetta’s descendants.

Elizabeth of York and Henry VII had seven children, the eldest son Arthur, Margaret, Henry, Elizabeth, Mary, Edmund, and Catherine. At first, the eldest son Arthur married Catherine of Aragon, but died of illness soon after. Then his younger brother Henry married his brother’s widow Catherine and inherited the throne as Henry VIII. As mentioned above, Margaret Tudor was Henry VIII’s sister. It was also based on her ancestry that the Stuart family eventually inherited the thrones of England, Ireland and Scotland: Mental abnormalities caused by inbreeding of European royal families

Therefore, modern medicine believes that Jacquetta may not have cursed Henry VII through witchcraft, but through the genes of the Kell locus.

1. The source of Jacquetta’s Kell antigen

Jacquetta is the source of the Kell antigen, and her daughters will carry the allele, so half of Edward IV’s boys or half of Henry VIII’s brothers may have alloimmunization and fertility problems. None of Edward IV’s boys reached childbearing age and got married. George Plantagenet died in infancy, leaving two children as “Princes in the Tower”.

Looking back at Henry VIII’s paternal family tree, Henry VII had seven children who lived to the ages of sixteen days (Catherine), sixteen months (Edmund), three years (Elizabeth), fifteen years (eldest son Arthur), thirty-seven years (Mary), fifty-one years (Margaret), and fifty-five years (Henry VIII). Isoimmunization is a highly unlikely cause of death in a six-month-old child. However, Catherine Tudor’s death at eight days old is consistent with HND. However, given the high postpartum mortality rates at the time and that her mother, Elizabeth of York, died in childbirth, this suggests another problem and makes it unlikely that Henry VII was the source of the Kell antigens. Therefore, Jacquetta is undoubtedly the most likely source of Kell antigens.

2. Jacquetta’s children

Given the above analysis, the study of Jacquetta’s children is obviously relevant to determine whether she is a carrier of Kell positive genes. Although K/K homozygotes are rare, Jacquetta is more likely to be a K/k heterozygote, so her offspring have a 50% chance of inheriting the immunogenic K allele.

Eldest son: Lewis Woodville was born in 1438. He died in 1451 at the age of 12 and had no children.

Second son: Anthony Woodville was born in 1442 and played a leading role in the events of the time. He was an outstanding jouster on horseback and participated in the Battle of Towton and the Battle of Barnet. Although married twice, he remained childless.

Third son: John Woodville was born in 1445 and married Catherine Neville, Duchess of Norfolk, a marriage of political expediency, perhaps to increase the power of the Woodville family. Catherine was at least 65 years old and he was only 19 or 20, but she outlived him, as John was executed in 1469. They undoubtedly had no children.

Fourth son: Lionel Woodville was born in 1447 and entered the church, becoming Bishop of Salisbury. There is no evidence that he married or had children, except for rumors that he was the father of Stephen Gardiner (later Bishop of Winchester). Lionel is recorded as the first person to receive an honorary degree from the University of Oxford.

Fifth son: Richard Woodville never married and had no children. Richard kept a low profile and tried to avoid taking sides in the Wars of the Roses. There are unconfirmed rumors that he secretly married and had a son, who he raised under different names to avoid the violent murder of many of his relatives.

Sixth son: Edward Woodville, born in 1455, appears to have never married and had no known children.

Seventh son: Thomas Woodville married Ann Holland, but history does not record him having any offspring.

Thus, of the seven sons, four apparently had no children, and the other three had no documented offspring. Only Anthony and Thomas had documented marriages, but no children; Lewis died young; John married a postmenopausal woman; Lionel, Richard, and Edward never married.

This neither confirms nor disproves Kell’s positive blood type, but it supports the above inference that if the disease was a causal factor, Jacquetta was the most likely source of the disease. Therefore, Jacquetta’s genes were likely the curse that prevented Henry VIII from producing a healthy male heir.

IV. Inherited metabolic disorders IEMS

1. Inherited metabolic disorders IEMS

IEM diseases can occur at any age, from the fetal period to the elderly, and are often divided into early-onset and late-onset diseases at the age of 1. Late-onset patients generally have higher enzyme activity than early-onset patients, so the degree of late-onset disease will be milder than that of early-onset patients. However, at present, the prognosis of some late-onset patients is not as good as that of early-onset patients, because some early-onset patients can be screened out at birth heel blood, or early acute attacks can be diagnosed under the diagnosis of professional pediatric metabolic doctors in first-tier cities. Early diagnosis and disease management or surgical intervention (liver transplantation) can mostly lead to normal development. However, late-onset patients have good metabolic capacity at birth, and many heel blood screenings cannot detect abnormal metabolites. They often have acute attacks in late childhood or adulthood. There are many twists and turns in clinical diagnosis, which makes it impossible to diagnose and cannot be diagnosed in the first time. As a result, some late-onset patients may be disabled or even die in the acute phase.

The clinical manifestations of the nervous system in late-onset IEM disease are highly heterogeneous, mainly manifested as epilepsy, cognitive impairment, mental and behavioral abnormalities, acute/chronic myelopathy, movement disorders, peripheral neuropathy and myopathy. Moreover, most of these patients have normal growth and development before the first onset of the disease, so they are easily misdiagnosed as acquired diseases, such as encephalitis, myelitis or other degenerative diseases.

If some IEM diseases are not diagnosed in time and are treated incorrectly, the patient’s disease process will be aggravated, leading to disability and death. For example, patients with urea cycle disorders (UCD) are treated as encephalitis with symptoms such as coma, delirium, epilepsy, and vomiting in the acute stage, and corticosteroids and large-dose intravenous immunoglobulin are used as incorrect treatment methods, resulting in brain edema and brain damage in patients.

For more information about IEMs, a genetic metabolic disorder, please refer to previous articles: Diagnostic methods for IEMs, a genetic metabolic disorder: genetic metabolomics testing

2. Benefits of IEMS diagnosis

Many family members of patients said, “These genetic metabolic disorders are rare diseases. Even if they are diagnosed, there is no medicine to treat them. What’s the point of spending so much money to diagnose them?” We believe that diagnosis has the following benefits

It can evaluate the disease status of family patients: for example, if the elder brother is diagnosed with a certain disease, then according to the genetic pattern, it can be analyzed whether the younger brother and grandparents are patients (mild symptoms) or carriers. Then, according to the diagnosis, disease management and fertility risk assessment of family members can be carried out.

For example, if the eldest daughter of this family in the previous article can be diagnosed earlier and receive standardized treatment for the disease, she may not die. At the same time, if the younger brother Jiajia is diagnosed earlier, it is very likely that the consequences of this acute crisis can be avoided. At the same time, the disease status of the second daughter and the father can be diagnosed, and the risk of the second daughter’s marriage and childbirth can be avoided in the future.

Previous article: A family of three with mental disorders as the first symptom, one of them died and the other was disabled.

Help other patients get diagnosed: Sometimes in the clinic, patients are diagnosed with some new mutations or new disease genes. These points will be added to the gene bank under the evaluation of doctors and researchers, so that more other patients can be diagnosed. Once diagnosed, there will be a circle of patients, so patients will not feel so lonely in the journey of the disease.

Get treatment: With the development of medical care, some genetic metabolic disorders have some standardized treatment methods, such as supplementing coenzyme factors, optimizing metabolism through circulating substrates, and reducing non-metabolizable substances through dietary management. Early diagnosis of such patients and timely standardized treatment can prevent brain nerve damage, and the patient’s intelligence and physical development can develop normally. After diagnosis, good management of the current disease can sometimes prevent the disease from worsening, giving patients a time difference and waiting for gene therapy to cure them in the future.

In the family introduced in the previous article, the eldest sister, the fourth brother and the father had mental disorders. They had been receiving palliative treatment for mental illness (treatment for mental disorders). Therefore, this type of mental disorders will recur. Because there is no diagnosis, there is no correct treatment method to manage the disease. During the repeated acute period, the grassroots hospital treated them as mental illness, so that the siblings later had an acute metabolic period. Some patients with this type of IEM disease who were not diagnosed in time in the clinic died in the acute period without a confirmed cause, such as Jia Jia’s eldest sister in the article.

The disease can be paid attention to by more medical research and development groups: If the probability of diagnosis of patients is small, then the number of people diagnosed with this disease will not be large, and many opportunities will be lost, such as: pharmaceutical companies develop drug treatments, medical teams pay attention to the disease and develop nursing opportunities for the disease.

3. IEMS disease and future radical treatment

The treatment goal of IEMs is to correct metabolic defects. The main treatment principles include dietary therapy to limit the intake of defective enzyme substrates, coenzyme factor therapy, nitrogen excretion agents to promote the excretion of toxic metabolites, cocktail therapy and liver transplantation therapy. A large part of IEMs are preventable and controllable. If detected early and properly intervened, patients can even live healthily without the disease.

Current treatments for inherited metabolic disorders (IEM):

Nutritional management (diet therapy) for inherited metabolic disorders

Coenzymes, nitrogen-removing agents, and mitochondrial cocktail therapy for inherited metabolic disorders Liver diseases caused by inherited metabolic disorders: the evolution of liver transplantation and the future prospects of hepatocyte transplantation Future treatments for inherited metabolic disorders (IEM): Except for some types of IEM diseases that can be cured by liver transplantation, the current treatments for IEM are not therapies that can cure such diseases, and some patients suffer from sequelae of brain damage due to failure to receive timely treatment. Because brain damage is irreversible, current treatments cannot cure brain damage. Future treatments will mainly explore curative therapies: gene therapy, enzyme replacement therapy, stem cell therapy, etc. Among them, gene therapy and enzyme replacement therapy can cure such metabolic disorders in patients, and stem cell therapy and brain-machine interface stimulation can repair human nerves (brain nerves and muscle nerves, etc.). The combined treatment of these future therapies can change the current medical predicament of patients. Most of these therapies are currently in the research and development stage. I believe that they will be clinically applied to patient treatment in the near future. At this stage, patients need to manage their diseases and nutrition and wait for the day of medical progress.

Future curative treatment for inherited metabolic disorders

References for this article:

Jung HH, Danek A, Walker RH, et al. McLeod Neuroacanthocytosis Syndrome. 2004 Dec 3 [Updated 2021 Sep 16]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1354/

Dean L. Blood Groups and Red Cell Antigens [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2005. Chapter 8, The Kell blood group. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2270/

Stride P, Lopes Floro K. Henry VIII, McLeod syndrome and Jacquetta’s curse. J R Coll Physicians Edinb. 2013;43(4):353–60. doi: 10.4997/JRCPE.2013.417. PMID: 24350322. Chinese version of this article:都铎王朝的杰奎塔诅咒：婴儿早夭、君主精神异常的凯尔抗原阳性与麦克劳德综合征McLeod