Thursday, January 25, 2007

Were the Vikings immune to HIV? Heredity 2006; 96: 280-281. Gaggiotti OE

Heredity 2006; 96: 280–281.

Evolutionary population genetics: Were the Vikings immune to HIV?

Gaggiotti OE

Laboratoire d'Ecologie Alpine, UMR CNRS 5553, Université Joseph Fourier, BP 53, 38041 Grenoble, France

Our hope is that understanding the genetic bases of disease resistance will help us to eradicate various diseases and, in particular, infectious diseases such as AIDS. However, this is not enough. We also need to understand its evolutionary history to identify the mechanisms and factors that have favoured the spread of these beneficial disease resistant alleles. This is no simple task; it requires large databases that include both genetic and nongenetic data (eg geographic coordinates of the samples) and complex statistical methods. In a recent paper, Novembre et al (2005) present an excellent example of an approach that provides valuable information about the spread of a mutation, CCR 32, that confers resistance to HIV-I infection. In particular, they provide compelling evidence indicating that the allele has spread rapidly via long-distance dispersal and intense selection. The restricted geographic distribution of this allele is likely due to the limited time to disperse rather than local selection pressures.

Disease follows humans wherever they go but sometimes a chance event, an error in DNA replication, help us to fight it back. The CCR5 32 mutation is one of the many variants of the chemokine receptor gene, CCR5. This gene produces a molecule that serves as a major cell surface co-receptor for the HIV-1 virus. Individuals homozygous for the 32 allele do not produce a functional protein (Carrington et al, 1999) and are therefore almost completely immune to infection. Heterozygous individuals have reduced susceptibility to infection and delayed onset of AIDS (Carrington et al, 1999).

This mutation was originally identified in Caucasians and is mainly found across Europe and western Asia with frequencies that vary geographically but which average 10%. Its origin predates the emergence of HIV as a human pathogen but its current frequency and estimated age (between 700 and 2900 years but maybe older) suggest that it has been under strong selection throughout its history. Several studies suggest smallpox as the possible selective agent.

The observed allele frequency surface of 32 is noisy and multimodal, with a broad area of high frequency in the Baltic region and additional peaks in the northern coast of France and the extreme west and Volga-Ural region of Russia. This ragged frequency surface is compatible with multiple hypotheses concerning the geographical origin of the mutation and the factors that controlled its spread. In particular, it has been proposed that the high frequency in the Baltic region imply a Viking origin (Lucotte and Mercier, 1998). So in this interesting study, Novembre et al (2005) set out to model the effects of selection and dispersal on the geographic distribution of the allele.

They use as starting point a classic model for the spread of an advantageous mutation, the wave-of-advance model, first introduced by Sir Ronald Fisher (1937), one of the forefathers of evolutionary biology. Using a diffusion model that incorporated the joint effect of selection and dispersal, Fisher showed that, after a gene was established in a population, there would be a wave of advance for which the velocity of the wave is proportional to the selective advantage of the allele. Novembre et al (2005) use a two-dimensional version of this model that was slightly modified in order to incorporate geographical gradients in selection. With this approach they simulated the allele frequency distribution of 32 under various scenarios that considered different initial geographic positions for the mutation and various selection intensities and dispersal distances.

The first interesting result obtained by the authors is that, although allele frequency surfaces generated by this model can be unimodal and smooth, the sampling of genes from such a surface can generate noisy and multimodal surfaces similar to those observed for the 32 mutation. Thus, it is not necessary to invoke unusual local conditions or specific migration events to explain regions of high frequency. Using a maximum likelihood approach the authors evaluated the fit of the model under the various scenarios they considered. The maximum likelihood estimates coincided with scenarios involving strong selection and long-distance dispersal. Selection gradients did not need to be extreme but were steeper in the north–south direction than in the east–west direction. The most likely origin of the mutation is in Spain or northern Germany, contradicting the Viking hypothesis. The only scenarios where a Scandinavian origin was favoured involved spatially uniform selection but their likelihoods were lower than those of scenarios including selection gradients.

The fact that all this detailed information could be obtained using a slight modification of a classical model proposed by R Fisher a very long time ago is a reminder of the richness of the population genetics theory that was developed very early on by the field's founders. Indeed, much of their work is surprisingly modern. More complex models incorporating specific historical events could be envisioned and will certainly follow thanks to the help of modern statistical tools and increased computer power. However, the underlying genetic model will almost certainly be drawn from the 'ancient' population genetics theory that we should always revisit.

Although very innovative, this study rests on a rather stringent prerequisite, the existence of a well studied mutation whose implication in disease resistance has been well established. For the moment few such mutations have been well characterised, but the method could also be used to study adaptive traits other than disease resistance. In any case, this is a very welcome first step that will eventually be followed by more sophisticated methods to study the geographic spread of adaptive traits involving many genes. Some of the existing methods to detect loci under selection (eg Beaumont and Nichols 1996; Vitalis et al, 2001; Beaumont and Balding, 2004) could be combined with approaches that allow the integration of genetic and nongenetic data (eg Gaggiotti et al, 2002). This promises to be a difficult task but it could lead to a better understanding of the way in which complex traits spread across species ranges.

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Fisher R (1937). Ann Eugen 7: 355–369.
Gaggiotti OE, Jones F, Lee WM, Amos W, Harwood J, Nichols RA (2002). Nature 416: 424–427.
Lucotte G, Mercier G (1998). J Aquir Imune Defic Syndr Hum Retrovirol 19: 174–177.
Novembre J, Galvani AP, Slatkin M (2005). PLoS Biol 3: e339.
Vitalis R, Dawson K, Boursot P (2001). Genetics 158: 1811–1823.
Zamoum T, Simon J-C, Crochard D, Ballanger Y, Lapchin L, Vanlerberghe-Masutti F, Guillemaud T (2005). Does insecticide resistance alone account for the low genetic variability of asexually reproducing populations of the peach-potato aphid Myzus persicae? Heredity 94: 630–639 (01 June 2005) Original Article.
Hoekstra HE, Krenz JG, Nachman MW (2005). Local adaptation in the rock pocket mouse (Chaetodipus intermedius): natural selection and phylogenetic history of populations. Heredity 94: 217–228 (01 February 2005) Original Article.

Blame the Vikingss - Multiple Sclerosis in Ireland

Blame the Vikings?

MS has been linked to a Celtic Gene. John Brophy argues that the genetic component could have come from further north
Everyone connected with MS knows that there is a strong genetic component in the disease, which seems to be triggered by a catalyst.

There is plenty of anecdotal evidence that either a sudden shock or long term stress can have this effect, but it must be stressed that scientific tests to date have not shown there is any link between shock and MS.

The genetic question is equally complicated. Some hereditary factors are very well understood. Red hair, for instance happens when a person inherits a gene from both mother and father, and the combination of recessive (hidden) genes results in the hidden factor becoming apparent. The laws governing how this happens have been known since the time of Gregor Mendel.

There are many ailments and diseases which are also hereditary. Researchers have now identified which gene is responsible for cystic fibrosis, and couples planning a family where there is a history of the dis-ease can receive genetic counselling.

But with MS, the question is more puzzling. Over the last few years, all the genes of the human body have been mapped, but in many cases, their function is not yet understood, nor how they relate to one another.

We are left with questions like, for instance, why the incidence of MS is about twice as high in Donegal as in most other parts of Ireland.

But equally, there could be a Viking gene. In Canada, where there is a high MS rate, it is well known that people of Scottish ancestry are more susceptible, and this has given rise to theories about a Celtic Gene.

The Vikings arrived in Ireland in the year 835 AD. No amount of diplomacy can hide the fact that they were very bloodthirsty and barbaric characters, who often murdered babies and had a gruesome range of tortures. Just check on the doings of characters like Ivar the Boneless if you doubt this.

In Ireland they founded big settle-ments on the east coast, including Dublin, Wicklow, Arklow, Wexford and Waterford. Even in surnames like Doyle, Dubh-ghall, the dark foreigner, their memory is preserved.

In England, they captured the northern half of the country, called the Danelaw, and ran a protection racket on the other half, taking up to 8,000 ounces of silver in one year as tax from the Saxons.

They were stopped for a short while by Alfred the Great, but their cousins, who had settled in Normandy, arrived back in England in 1066, conquered everyone, including their Viking cousins, and have effectively ruled the country ever since and shrewdly marrying new money to keep themselves on top.

In Ireland, they arrived in 1169, but within a couple of centuries had become “more Irish than the Irish themselves” so that today, it is likely that everyone in Ireland has Vikings who came here werefrom Norway and Denmark.

The Swedish Vikings, though, concentrated on going down the river valleys of central Europe, where they enslaved the local populace and sold them to eastern traders. They had a huge influence: by the year 1,000 they had become the imperial guard in Byzantium, and even to this day there are places like the Lebanon where some people have fair hair and blue eyes.

In these places, too, there seem to be pockets of high incidence of MS though more work needs to be done to see if there is a link.

The Normans made their way by sea into the Mediterranean, where they founded the Kingdom of the Two Sicilies, with its capital in Naples, and the Vikings had earlier set up in parts of Spain.

One other intriguing factor came from a conversation I had about the recent MS conference in Oslo. Some people there were talking to people from the ethnic minority of the Saami or Laplanders. Obviously, they share the same environment and diet as the rest of the population, but the claim was made that they never get MS unless they intermarry with the Nordic population.

This provides some food for thought.

It could be pointed out there are isolated cases of MS in places where the Vikings are not recorded as having reached – but since it’s pretty certain they reached North America and most of the Mediterranean, there’s no knowing how far they, or the crusading Normans, might have reached.

One other clue worth pursuing could come from folklore. The Norse sagas are among the largest bodies of folklore and mythology recorded. We in Ireland know very little about them, but it could be worth checking to see if they contain stories of anyone with MS symptoms. If so, that would show that the Vikings knew about the disease – though the absence would say nothing.

Heart disease pinned on Vikings

Vikings may be the reason why more people suffer from heart disease in the North East of England, researchers claim.
The world’s largest-ever study of family heart disease suggests Vikings interbred for three centuries. Nordic invaders are said to have passed on genetic disorders which can cause heart disease, concludes the study, sponsored by the British Heart Foundation and the Medical Research Council. Alistair Hall, of the University of Leeds and joint leader of the £2.5 million Family Heart Study, said: “We know that cardio-vascular disease, particularly coronary artery com-plaints, is big in Northern Europe.

“In this country, heart disease is higher in the North than in the South. There are certain clusterings, and these happen to coincide with certain patterns of invasion. There is no better explanation yet, and it appears to make sense.”

According to the findings of the survey, those whose families stayed in the North East are more likely to be more at risk to heart disease, says The Independent on Sunday.

The scientists say more positive genetic invasions elsewhere, particularly those of the Romans and Normans, created a stronger, hetero-geneous gene pool.

Sunday, January 21, 2007

Proc (Bayl Univ Med Cent) 2001 October; 14 (4): 378-384.

The Vikings and Dupuytren's Disease

Adrian E. Flatt

Copyright © 2001, Baylor University Medical Center

George Truett James Orthopaedics Institute, Baylor University Medical Center, Dallas, Texas.

Dupuytren’s disease (DD) is an ancient affliction of unknown origin. It is defined by Dorland as shortening, thickening, and fibrosis of the palmar fascia producing a flexion deformity of a finger. Tradition has it that the disease originated with the Vikings, who spread it throughout Northern Europe and beyond as they traveled and intermarried. After being present for hundreds of years, DD was named in the 19th century after a famous French surgeon, who was not the first to describe it. This article reviews the history of DD and describes its incidence, clinical manifestations, and treatment.

In the year 865, “a great heathen army” of Vikings landed on England’s east coast; an earlier raid on the monastery of Lindisfarne prompted a cleric of the times to say, “Never before has such terror appeared in Britain as we have now suffered from a pagan race.” By the 10th century, 3 of England’s 4 kingdoms were dominated by the Vikings, who gradually converted to Christianity and settled in the conquered territories (1).
The Viking age of exploration, trading, and colonization lasted nearly 300 years. They raided as far as Newfoundland to the west, the Mediterranean and its many ports to the south, and the Caspian Sea—by way of the rivers of Eastern Europe, such as the Volga and Dneiper—to the east.
The areas bordering the North Sea were significantly colonized, with Scotland, Ireland, England, France, Holland, and Belgium being principally involved. Vikings were present in Scotland for nearly 500 years. They left behind many Scandinavian family and place names that replaced the original Gaelic. They also left behind DD, which has persisted in some areas to this day; in Scotland, for example, since the 15th century the flexed fingers of adult male bagpipers have been known as “the curse of the MacCrimmons.” In England, the Vikings who settled in the area of East Anglia became farmers, and to this day surnames derived from Scandinavian roots are common. My family name referred to those who settled on the flat lands of East Anglia. Like the Vikings, Flatt children were born with ash-blond hair, and many were blue eyed. This held true until ships of the Spanish Armada wrecked off the English coast in 1598. Survivors swam ashore and joined the local farmers; as a result, subsequent Flatt children were blond at birth but had jet-black hair by their teenaged years—as did I. The Flatts must have had strong genes, since neither my father nor I have had DD despite our Viking roots.

In his 1963 book, the Australian hand surgeon John Hueston wrote, “Dupuytren’s contracture is virtually confined to people of European descent” (2). Its highest incidence is recorded in Iceland. As expected, the incidence is also high in Scandinavia: In a Norwegian study of 15,950 citizens, DD was present in 10.5% of men and in 3.2% of women (3). In a large 1962 review of published figures, P. F. Early arrayed the countries of European stock in order of incidence of DD: Denmark, Australia, New Zealand, Canada, United Kingdom, Germany, and the United States. He also commented that the incidence in Australia, Canada, England, and Wales was similar since their populations are of basically English stock, which may itself represent a diluted strain of Danish (Viking) stock (4). The incidence in Sweden is matched in Edinburg. Two different studies by James and Ling in Scotland showed such a high family incidence that DD was described as inherited through a single autosomal-dominant gene of variable penetrance (5, 6).
In a study in the French port of Toulon, 60% of the general population had brown eyes and 40% had blue eyes, but 80% of inhabitants with DD had blue eyes. The latter individuals were traced to the families of Breton and Norman sailors in the city’s history (7).
DD is relatively uncommon in Spain, Greece, and Italy, except for Greece and Italy’s northern Adriatic Coast, which was penetrated by a northern genetic invasion during the Austro- Hungarian Empire.
In 1985, Robert McFarlane of Canada published a preliminary report of the activities of the committee on DD of the International Federation of Societies for Surgery of the Hand. In 812 patients, the family origin was Northern European in 68%, Southern European in 3%, black African and American Indian in 0.2%, Chinese in 2%, and Japanese in 16%. Northern European ancestry can hardly apply to Japan, where DD appears to be a different condition, in that 95% of cases occur in men and only 6% of cases occur in families with a history of DD—compared with 26% in other countries. I understand that an update of this massive study will be published shortly (8).
More recently, Hueston has modified his earlier views. He now states that an autosomal-dominant trait “explains a little of the etiology of DD,” but that much work remains to explain “the clear-cut preference for races of Northern European origin” (9). Quoting his own experience of “often seeing 40 cases of DD each week in consultation in Melbourne,” he comments: “DD may now be claimed by enthusiasts to have penetrated all five major races of the world. But what is the significance of these reports of infinitesimal incidence in such enormously populous races? Some interpret this wide occurrence as denying a European genetic origin. However, these reports of an exotic case or two in populations of hundreds of millions can scarcely be taken seriously” (9).

Greek and Roman literature contain no record of anything resembling DD. The Icelandic sagas of the 12th and 13th centuries describe a number of “miracle cures” recently discussed by Whaley and Elliot (10). Four cases are considered in detail, two of which could well have been DD. Whaley and Elliot found no evidence of DD in early Anglo-Saxon and Gaelic medical literature. In addition, the more extensive medical literature of medieval Europe before 1614 shows no evidence of the condition (11).
On December 5, 1831, Baron Guillaume Dupuytren delivered a lecture on permanent retractions of the flexed fingers which was published under the title “Leçon sur la rétraction permanente des doigts.” To this day, the condition bears his name, despite the fact that history shows that Felix Platter in 1680, Henry Cline, Jr., of St. Thomas’ Hospital in 1808, and Sir Astley Cooper in 1818 had already described a similar condition, with Cline specifically noting the involvement of the palmar fascia. Cooper and Dupuytren knew each other and communicated on several occasions before Dupuytren’s famous lecture in December 1831.

Born in 1777, Guillaume Dupuytren was generally acknowledged as the greatest French surgeon of the 19th century; the English journal, The Lancet, named him in his lifetime “the most erudite and accomplished surgeon in Europe.” An ambitious man, he came from relatively humble origins and in his later years was created baron by Louis XVIII. He would now be called a draft dodger since his colleagues on the faculty of medicine in Paris arranged his deferment from the draft for Napoleon’s armies. In a fiercely competitive system, he rose in 20 years from a prosector of anatomy to chief surgeon of the Hôtel de Dieu in Paris (Figure 1).
Oliver Wendell Holmes described Dupuytren as “a square solid man with a high domed head, oracular in his utterance, indifferent to those around him, sometimes, it is said, very rough with them.” Critical of all those about him, he had few friends among his medical colleagues. Considerable adverse comments are recorded by his contemporaries: he was called “the greatest of surgeons, the meanest of men”; it was noted, “With absolute faith in his own abilities he made work his religion”; and his colleague stated, “If I could have avoided speaking of M. Dupuytren, it would have been a great relief to me, for I find myself in a very great embarrassment. I am almost sure to have all parties dissatisfied” (12).
Dupuytren’s name has been applied as an eponym to at least 12 diseases, fractures, operations, and instruments. He hated to write, and all his “literature” was recorded and published by his students in the local medical journals as “Leçons orales de clinique chirurgicale de Dupuytren.” For his time, he had a scientific and inquiring mind and was a caring physician who visited his patients every day. On ward rounds, he dressed distinctively in a green coat, white vest, blue trousers, and a small green cloth cap, which he had designed himself. The picture of this domineering, all-confident surgeon was marred by his almost constant “nervous habit of gnawing the nails of his left thumb and index finger” (13). His assistants were in awe of him. He has been described as “plying his whip unceasingly on the backs of his jaded horses,” a description that could apply to some clinical rounds in this 21st century. Dupuytren developed pleurisy at the age of 68 and died while his colleagues debated whether to drain the empyema, no doubt influenced by Dupuytren’s opinion that “it is better to die of the disease than of the operation”(14).

DD usually presents with a palmar nodule on the line of the ring or small finger (Figure 2). One hand, not necessarily the dominant, is affected first and later the other may show the characteristic nodule and finger contracture. The metacarpophalangeal joint is usually involved first and later the proximal interphalangeal joint.
DD is usually painless at onset and insidious in its progress. However, I am constantly amazed at how patients will tolerate significant degrees of contracture and appear for advice only when they start to poke themselves in the eye when washing their face. Erik Moberg of Sweden contends that men are frequently sent for treatment by their wives, who are bothered by the clawlike manipulation with the hand.
A multitude of causes have been suggested for DD, but only heredity has general acceptance. Despite positive family histories, however, about 30% of cases are sporadic.
DD is relatively rare, occurring in 1% to 2% of the population. The disease is more common in men; the incidence in women is approximately 15% of those requiring surgical care but becomes higher in those who require nonsurgical treatment. There is a progressive rise in incidence with age. DD usually occurs in the fifth, sixth, and seventh decades; the peak age in men is 40 to 59, and in women, 40 to 69. The expression of the disease gene is almost complete in men over the age of 75 but is of much lower penetrance in women, unless it arises from both parents. In those with family histories of DD, the onset occurs earlier and leads to more marked contractures.

In a group of patients, DD presents more aggressively. Hueston has named this more aggressive form Dupuytren’s diathesis. (Diathesis is the variable penetration of an autosomaldominant gene.) In these patients, there is an early onset of disease, a positive family history, bilaterality, and involvement of areas other than the hand. When data from 736 international patients were reviewed, researchers found that when all factors contributing to the diathesis were present, the rate of recurrence or extension was 78%, whereas when all factors were absent, the rate was only 17% (Figure 3).
Dupuytren’s diathesis is present in every member of a family but may show varying degrees in different members. However, each family member is “born to get it.” This constitutional tendency for the onset of DD in the hands is closely related to tissue depositions elsewhere.
The “strength” of the diathesis varies. When low, there are no clinical signs of DD. When high, early recurrence may require radical secondary surgery. Clinical grading of this diathesis is an inexact science and requires great experience in diagnosis and treatment selection on the part of the surgeon.
Hueston records seeing a case of proven Dupuytren’s contracture in a 12-year-old boy. A similar-aged boy was sent to me for leg amputation because of a mass on the sole of his foot. Based on a biopsy, sarcoma had been diagnosed. (Pathologists who are not told of a physical examination or a family history often are forced to suggest fibrosarcoma because of the cellular activity seen in the slide.) The boy’s hands showed no real involvement, but his father and grandfather both showed marked bilateral involvement. I did not amputate his leg, and the boy was alive and well a number of years later.

A great variety of conditions have been associated with DD. Some are tenuous relationships; others are more marked. It is generally conceded that individuals with diabetes, epilepsy, chronic alcoholism, and pulmonary tuberculosis have an increased incidence and earlier onset of DD. However, Fisk has pointed out that no variety of disease, injury, activity, or occupation could induce DD in someone who was not genetically so determined (15).
Among other medical conditions that have been said to be associated with DD are arthritis, diabetes mellitus, myocardial disease, reflex sympathetic dystrophy, hepatic disease, alcoholism, barbiturate ingestion, peptic ulcers, fibromatosis, compulsive personality, carpal tunnel syndrome, trigger fingers, HIV, and smoking (16). DD is essentially a condition of middle and later ages, and its association with many common and chronic diseases is probably more coincidental than causative.

In DD, fibromatosis can occur in areas other than the palm and fingers. The most common site is as knuckle pads, followed by the sole of the foot. Peyronie’s disease (penile deposits) is not common but is, in fact, associated with DD. Histological and biochemical studies show these tissues to be identical to those in the palm and digits.

Knuckle pads
When looking at the dorsum of one’s proximal interphalangeal finger joints, the skin is seen to be wrinkled in full joint extension. The pattern of wrinkles varies in each individual but will disappear on full flexion of the joint. Normally the skin over the joint is not tethered. In some patients, the skin over the joints thickens into nodules, which often are tethered to deeper structures (Figure 4). These nodules are usually free of pain and rarely noticed by the patient. Occasional burning pain has been reported, and they are tender when knocked.
These nodules are said to be present in >80% of patients with DD; observation over time shows that they may develop, regress, or show little change. Knuckle changes can be present even before the palmar disease causes finger contractures. They are considered a warning sign that the patient may be prone to developing the typical palmar signs. McIndoe was so certain of this predisposition that he stated, “The clinician who observes a patient to have knuckle pads may be quite sure that the patient either has a Dupuytren’s contracture or that one will develop in the future” (17). This is particularly likely in patients subject to Dupuytren’s diathesis.

Plantar nodules
Involvement of the sole of the foot frequently presents on the medial border of the sole near the highest point of the arch (Figure 5). The lump is painless; it is fixed within the plantar aponeurosis while the overlying skin is freely movable. Contracture of the toes does not occur. Hueston reported that in 224 patients, 20% had plantar nodules, but when the nodule was associated with recurrence or extension of the disease, the incidence rose to 75%. The biopsy is predominantly cellular and frequently misdiagnosed as fibrosarcoma. These plantar nodules occur most commonly in patients with epilepsy.

In Sweden, Skoog examined the hands of 207 patients with epilepsy and found that 42% had palmar involvement, 26% had knuckle pads, and 8% had plantar involvement (18). He suggested that the use of barbiturates was associated with the occurrence of DD. But Thieme compared 351 patients with epilepsy who had DD with 408 controls and found that in those with a history of barbiturate intake the number of patients with or without DD was identical. Even in patients who had taken barbiturates for >5 years, there was no significant difference between the 2 groups (19).

The association between diabetes and DD is well known, but the DD contractures are usually mild and curiously affect the long and ring fingers most frequently; the small finger is rarely affected. Some physicians believe that early contractures should be considered a warning sign of diabetes development. The association is almost always with non–insulin-dependent diabetes, but cases associated with insulin-dependent diabetes have been reported (20). Some suggest that the pattern of inheritance predisposes patients to both DD and diabetes mellitus. The true incidence of DD in proven diabetes probably approaches 40%, but it has been variously quoted as varying between 1.6% and 32%.

In the United Kingdom, the prevalence of DD is about 5.5%, but in 50 patients with HIV, it was found to be 36%. According to one theory, DD may be caused by oxidation by free radicals, and it is known that an increase in the production of free radicals occurs in HIV (21).

Trauma and occupational stresses
One of the etiological factors always proposed in DD is trauma to the hand—particularly repeated blows to the palm. An isolated injury to the palm may cause a reaction hard to distinguish from DD, but the injury itself is not the prime cause; more often than not, the injury draws attention to the palmar lesion or a contracture of a finger that had previously been ignored.
Occupational stresses have long been associated with DD. Dupuytren’s second DD patient was a coachman with involvement of the ring and small fingers of his whip hand. These fingers, used in the power grip, are most frequently involved in all patients, and yet many of them have sedentary occupations. Several papers reported a high incidence of DD in brewery workers, but later views associated the contractures with the known association of alcoholism with DD. Hueston personally studied the hands of 551 clerical workers and 1154 laborers who included 530 brewery workers and found no difference in the incidence of DD among these groups (22).
In 1912, a government committee in Great Britain found no conclusive connection between trauma, occupations, and Dupuytren’s contracture. This view is supported by many recent studies in other countries, particularly Australia and Scotland. In some Eastern European countries, DD is still classified as an industrial disease, but it appears that the reasons for acceptance or rejection of a claim in the various jurisdictions vary from case to case and are not necessarily based on current knowledge (23).
In the USA in general, administrative law judges, carriers, and claimants’ attorneys consistently do not relate DD to work activities or injury. However, the law says that when “symptoms” arise at work in the presence of an “underlying but unrelated condition,” then these symptoms become entirely proportionally compensable with respect to medical care and work law. English common law says employment of an individual with a predisposition to any condition does not absolve the employer of the responsibility for the effects of the condition if these are brought on during the course of that individual’s employment.

Many nonsurgical treatments of DD have been tried—radiation, dimethyl sulfoxide, vitamin E cream, ultrasound, physical therapy, steroids, interferon, and antigout medicines—but to no avail. In addition, several attempts have been made to chemically dissolve the affected tissue. In 1907, Langemark tried using fibrinolysin; in 1931, Hesse used pepsin; and in 1965, Bassot used trypsin mixed with hyaluronidase. In many cases, the condition rapidly recurred, leading to general disappointment with this type of therapy. Hueston reports that intralesional injections of triamcinolone acetate controlled a Dupuytren’s nodule in his own palm (24).
In 1981, Brickley-Parsons et al showed that the fundamental cause of the finger contractures in DD is “an active cellular process that progressively draws the distal extremities of the affected tissue closer together at the same time that the original tissue is being replaced. The result of these two processes is simply a shorter, smaller piece of tissue fabric containing collagen molecules, fibrils, and fibers of normal length and organization.” The development of DD is always along anatomically identifiable connective tissue structures. This logical explanation of the mechanism, but not the cause, of the contractures gave further stimulus to the search for nonsurgical methods of contracture release (25).
In July 2000, Badalamente and Hurst reported on enzyme injection as a treatment for DD. They injected clostridial collagenase into the lesions of 29 patients. In 34 metacarpophalangeal joints, 28 corrected to 0°, and 2 corrected to 50° of normal extension with full range of motion. In 9 proximal interphalangeal joints, 4 corrected to normal and 2 to within 15° of normal. There were 2 failures. Side effects have been minimal. They concluded that the injections appeared to have merit, and further studies are planned (26).

Dupuytren completed his first operation for contractures on June 12, 1831. General anesthesia was not introduced until 1835, so this operation and many subsequent procedures were done with assistants “immobilizing” the operative area. Some patients drank 1 to 2 bottles of wine preoperatively. History does not record how effective this was. Dupuytren’s operative technique was reported as follows:
The hand of the patient being firmly fixed, he [Dupuytren] commenced by making a transverse incision, ten lines in length [12 lines = 1"], opposite the metacarpo-phalangeal articulation of the ringfinger, the bistoury divided first the skin, then the palmar aponeurosis with a crackling noise audible to the ear. The incision completed, the ring-finger straightened, and was as easily extended as in the natural state. Wishing to spare the patient the pain of a fresh incision, Dupuytren endeavoured to extend the section of the aponeurosis by gliding the knife transversely, and deeply, under the skin towards the ulnar border of the hand to accomplish the disengagement of the little finger, but in vain; he was only able to partially extend the incision of the aponeurosis. Consequently, he determined to make a fresh transverse incision opposite the articulation of the first and second phalanges of the little finger, and thus detached its extremity from the palm of the hand, but the rest of the finger remained flexed towards this part. He then divided the skin from the aponeurosis by a fresh incision, opposite the articulation of the corresponding metacarpo-phalangeal joint. This produced a slight relaxation, but its effects were incomplete. At length a third, and last, incision was made transversely, opposite the middle of the first phalangeal joint, and the little finger was at once able to be extended with the greatest ease. This result distinctly showed that the last incision had divided the point of insertion of the aponeurotic digitation. Very little blood was lost by these incisions, and was stopped by dry charpie; the ring and little fingers were placed in extension by the aid of an appropriate instrument fixed on the back of the hand.
The postoperative course was normal for the times. On the third day, suppuration was commencing. The next day, suppuration was completely established; nevertheless, by the 20th day, cicatrization was complete.
Following this first operation, a great variety of procedures have been tried and have eventually distilled down to a relatively few useful operations. Earlier operations consisted of fasciotomies, in which the cords were cut via small skin incisions. (In 1808, Henry Cline advocated “cutting through the aponeurosis with a common knife.”) This procedure was gradually replaced by fasciectomy, in which the contracting bands were excised to varying extents. The results of these 2 procedures were not long lasting, and more extensive excisions were advocated, culminating in the 1940s with the MacIndoe operation of radical excision of the palmar aponeurosis and its extensions. This was done through a lengthy transverse incision on the line of the distal palmar crease, with the palmar skin being raised as a full thickness skin graft. I was taught to do this early in my training but abandoned it fairly rapidly in favor of the Willie Sutton approach of going where the disease was present. Nowadays, the common approach is through longitudinal incisions to obtain a good view of all diseased tissue, with the line of incision being converted into Z plasties on closure.
Each digit can be solely involved, or varying combinations can occur (Figure 6). Involvement of the thumb or little finger is technically very challenging because of the fascial plane’s involvement in the thumb web space and involvement of the abductor digiti minimi area of the little finger. In late disease, the digital joints’ involvement in this finger can be so severe that the fingernail will grow into the palm, and amputation is the only reasonable treatment (Figure 7).
Patients with the diathesis or with multiple areas of palmar involvement are often best treated by excision of the adherent skin and underlying tissues and by covering the area with a fullthickness skin graft obtained from the inner aspect of the arm (Figure 8). This grafting does not always take completely over the irregular contours of the palm, and this failure has led to the use of the open palm method. In this, the wounds are partially sutured under no tension, and a sterile dressing is applied to the raw areas. For a reason not well understood, palmar skin is “for giving,” and the raw area heals well with full epithelial coverage in about a month or 6 weeks. (This healing property is not present in the skin of the dorsum of the hand.)
Whatever procedure is used, postoperative care should be entrusted to a trained hand therapist whose services are invaluable, particularly in women. For some unknown reason, the disease appears in women in a later age group, their proximal interphalangeal joints are prone to postoperative stiffness, and sympathetic dystrophy occurs more frequently in them than in men.
The decision to operate should be based on the surgeon’s experience, an intimate knowledge of the normal and abnormal neurovascular anatomy in the area, and the need for increased function. Operating in the absence of digital contracture is rarely, if ever, justified. For example, palmar nodules occasionally cause discomfort, but this does not warrant surgical excision (Figure 2). The rate of contracture is important; in younger people or those with the diathesis, it occurs more rapidly than in older patients. Two consultations 3 to 6 months apart will establish the rate of contracture, and patients will better understand the need for surgery.
While surgery can improve the contractures, it will have no beneficial effect on progression of the disease. Recurrence is often said to appear in the operative area, but in fact it is extension of the disease into areas previously unaffected that causes the “recurrence.” This has caused the use of radical clearance procedures not always justified by the state of disease or the age of the patient. I have never met a patient who was not grateful for the reassurance that he or she did not have cancer, though few admit the thought had occurred to them.

1. Vesilind PJ. In search of Vikings. National Geographic. 2000;197:7–9.

2. Hueston, JT. Dupuytren's Contracture. London: Churchill Livingstone; 1963. p. 13.

3. Mikkelsen, OA. Epidemiology of a Norwegian population. In: McFarlane RM, McGrouther DA, Flint MH. , editors. Dupuytren's Disease: Biology and Treatment. New York: Churchill Livingstone; 1990. p. 191.

4. Hueston JT: 2.

5. James, JIP. The genetic pattern of Dupuytren's disease and idiopathic epilepsy. In: Hueston JT, Tubiana R. , editors. Dupuytren's Disease. London: Churchill Livingstone; 1985. pp. 94–99.

6. Ling RSM. Genetic factor in Dupuytren's disease. J Bone Joint Surg. 1963;45B:709–718.

7. Bronet, JP. Etude de 1000 dossiers de maladie de Dupuytren. In: Tubiana R, Hueston JT. , editors. La Maladie de Dupuytren. 3rd ed. Paris: L'Expansion Scientifique Francaise; 1986. p. 98.

8. McFarlane, RM. Some observations on the epidemiology of Dupuytren's disease. In: Hueston JT, Tubiana R. , editors. Dupuytren's Disease. London: Churchill Livingstone; 1985. pp. 122–126.

9. Hueston, JT. Dupuytren's disease. In: Tubiana R. , editor. The Hand. Vol. 5. Philadelphia: WB Saunders; 1999. pp. 421–427.

10. Whaley DC, Elliot D. Dupuytren's disease: a legacy of the north? J Hand Surg [Br]. 1993;18:363–367.

11. Elliot, D. The early history of contracture of the palmar. In: McFarlane RM, McGrouther DA, Flint MH. , editors. Dupuytren's Disease: Biology and Treatment. New York: Churchill Livingstone; 1990. p. 1.

12. Peltier LF. Guillaume Dupuytren and Dupuytren's fracture. Surgery. 1958;43:868–874.

13. Mann RJ. Of Guillaume Dupuytren, who feared nothing but mediocrity. Mayo Clin Proc. 1977;52:819–822.

14. Tubiana, R. History. In: Tubiana R, Leclercq C, Hurst LC, Badalamente MA, Mackin EJ. , editors. Dupuytren's Disease. London: Martin Dunitz; 2000. pp. 1–11.

15. Fisk, G. The relationship of manual labor and specific injury to Dupuytren's disease. In: Hueston JT, Tubiana R. , editors. Dupuytren's Disease. London: Churchill Livingstone; 1985. pp. 104–105.

16. Gordon S. Dupuytren's contracture: the significance of various factors in its etiology. Ann Surg. 1954;140:683–686.

17. Hueston JT: 55.

18. Skoog T. Dupuytren's contracture with special reference to etiology and improved surgical treatment, its occurrence in epileptics. Acta Chir Scandinav. 1948;96(suppl 139):1.

19. Thieme W. Quoted in James JIP. The relationship of Dupuytren's contracture and epilepsy. The Hand. 1969;1:47.

20. Welsh, KJ.; Spencer, JD. Immunology and genetics. In: McFarlane RM, McGrouther DA, Flint MH. , editors. Dupuytren's Disease: Biology and Treatment. New York: Churchill Livingstone; 1990. p. 100.

21. Bower M, Nelson M, Gazzard BG. Dupuytren's contractures in patients infected with HIV. BMJ. 1990;300:164–165.

22. Hueston JT: 15.

23. McFarlane RM. Dupuytren's disease: relation to work and injury. J Hand Surg [Am]. 1991;16:775–779.

24. Hueston, JT. Dupuytren's disease, current views on etiology and pathogenesis. In: Tubiana R. , editor. The Hand. vol. 5. Philadelphia: WB Saunders; 1999. p. 426.

25. Brickley-Parsons D, Glimcher MJ, Smith RJ, Albin R, Adams JP. Biochemical changes in the collagen of the palmar fascia in patients with Dupuytren's disease. J Bone Joint Surg Am. 1981;63:787–797.

26. Badalamente MA, Hurst LC. Enzyme injection as nonsurgical treatment of Dupuytren's disease. J Hand Surg [Am]. 2000;25:629–636.

Figures and Tables

Figure 1
The Baron Guillaume Dupuytren (1777–1835).

Figure 2
An early nodular involvement on the line of the ring finger.

Figure 3
The rate of extension and/or recurrence in Dupuytren’s diathesis. When all factors are present, the extension or recurrence rate is 78%, but when all factors are absent, the rate is only 17%. Reprinted with permission from McFarlane RM. Some observations.

Figure 4
Knuckle pads over the proximal interphalangeal joints of the fingers.

Figure 5
(a) Dupuytren’s involvement of the sole of the foot. (b) The involvement arises within the plantar fascia. It need only be removed if discomfort hinders walking.

Figure 6
Involvement of various digits: (a) index finger, (b) long finger, (c) ring finger, (d) small finger, and (e) multiple digits.

Figure 7
Severe involvement of the small finger on both hands in (a) a woman and (b) a man. The likelihood of providing full range of motion by surgery is remote. In the hardworking farmer pictured in (b), the logical treatment was amputation through the proximal

Figure 8
Dupuytren’s diathesis. (a) Previously, the small finger was partially amputated, but the involvement was particularly severe in the thumb web. (b) Surgical clearance combined with excision of involved skin and full-thickness skin grafting provided


Paget's Disease Egill Skalagrimsson - J R Coll Physicians Edinb Buchanan WW

Did the 10th century viking (c. AD 910-990) Egill Skalagrimsson had Paget's Disease?

WW Buchanan

Emeritus Professor of Medicine, Hamilton, Ontario, Canada.


Multiple Sclerosis in Finland - Helsingin Sanomat - Pentti Tienari

Viking gene suspected factor in multiple sclerosis

The genetic heritage of the Vikings could be a factor in the spread of the degenerative neurological disease multiple sclerosis (MS).
Researchers have noticed high concentrations of MS in Scandinavia and Northeast Scotland, areas with large Viking settlements in the past. In Finland, areas where MS occurs more frequently than elsewhere include Ostrobothnia, the upper reaches of the Eurajoki and Kokemäenjoki rivers, and in the northeast of the southern area of Uusimaa.

Dr. Pentti Tienari of the Clinic of Neurology at the Helsinki University Central Hospital has studied the prevalence of MS in Finland. MS appears to be most frequent in areas where the population is largely of Northern European origin. In North America the disease is most common in Southern Canada and in the parts of Minnesota where large numbers of Finns settled. The disease is rare in Asia and Africa. "The most recent studies in molecular genetics in different universities suggest that the effect of genes on the geographic appearance of the disease is greater in Finland than previously believed", Tienari says. Currently experts feel that MS is not caused by genetic factors alone. Instead its emergence is believed to involve a combination of genetic and environmental factors. Seven genes believed to increase the risk of MS have been identified in Finland. Certain genetic factors have accumulated in the population of South Ostrobothnia, which are found among MS patients in the area. According to Tienari, they suggest that genes with an MS risk factor were brought into the area with a fairly small original population. Over generations, the factors became more firmly established within the limited gene pool with little dilution from outside. Kyrönmaa, a coastal region in Ostrobothnia, has an exceptionally high frequency of MS. Experts believe that large numbers of people moved to the area in the 13th century from the Kokemäenjoki and Eurajoki areas, which also have high concentrations of the disease. Residents of the areas on the two rivers are known to have had close contacts with Vikings about 1,000 years ago. In other parts of Europe, scientists have noticed a correlation between the frequency of MS and a history of a Viking presence.


Vikings and Diseases - Skadi Forum

Viking voyages: the origin of multiple sclerosis? An essay in medical history.

Poser CM.

Department of Neurology, Harvard Medical School, Boston 02215 USA.

Multiple sclerosis is most frequently found in Scandinavia, Iceland, the British Isles and the countries settled by their inhabitants and their descendants, i.e. the United States, Canada, Australia and New Zealand. This suggests that the Vikings may have been instrumental in disseminating genetic susceptibility to the disease in those areas, as well as in other parts of the world. The Vikings raided most European countries and settled in Normandy and in Sicily and southern Italy. They engaged in trade with the Arabs along the river routes to the Caucasus, to the Black and Caspian Seas, and penetrated Persia, India and probably China. They also migrated to the East and established the Russian state. Under the name Varangians, they became part of the Byzantine army and were active in all the military activities of the Byzantine Empire. They participated in the Crusades. Russians, many of Scandinavian origin also constituted a regiment of the Mongol army and roamed throughout that Empire as well. The custom of capturing and keeping or selling women and children, which was widespread in the early Middle Ages, as well as the flourishing slave trade in men, were important factors in this genetic dissemination.

Med Hypotheses. 1997 Dec;49(6):477-86.

Multiple sclerosis: a geographical hypothesis.

Carlyle IP.

Multiple sclerosis remains a rare neurological disease of unknown aetiology, with a unique distribution, both geographically and historically. Rare in equatorial regions, it becomes increasingly common in higher latitudes; historically, it was first clinically recognized in the early nineteenth century. A hypothesis, based on geographical reasoning, is here proposed: that the disease is the result of a specific vitamin deficiency. Different individuals suffer the deficiency in separate and often unique ways. Evidence to support the hypothesis exists in cultural considerations, in the global distribution of the disease, and in its historical prevalence.

More about the Viking hypothesis of origin of the Delta32 mutation in the CCR5 gene conferring resistance to HIV-1 infection.

Lucotte G, Dieterlen F.

Centre de Neurogenetique Moleculaire, 44 rue Monge, 75005, Paris, France

The chemokine receptor CCR5 constitutes the major coreceptor for the HIV-1, because a mutant allele of the CCR5 gene named Delta32 was shown to provide to homozygotes a strong resistance against infection. In the present study the frequency of the Delta32 allele was collected in 36 European populations and in Cyprus, and the highest allele frequencies were found in Nordic countries. We constructed an allele map of Delta32 frequencies in Europe; the map is in accordance to the Vikings hypothesis of the origin of the mutation and his dissemination during the eighth to the tenth centuries.

Dupuytren contracture in North Germany. Epidemiological study of 500 cases

Brenner P, Krause-Bergmann A, Van VH.

Department fur Plastische, Rekonstruktive und Asthetische Chirurgie, Universitat Leuven, Belgien.

Dupuytren's disease is the "classical" hand illness of the north: it affects people of Celtic or Viking descent throughout the whole of northern Europe, whereas it is an unknown disease in the Mediterranean region. Dupuytren's contracture appears to be an extremity-related disease. Owing to the unclear etiology and a lack of up-to-date demographic data for northern Germany this study aims--together with the literature--to elucidate the role of associated illnesses in an attempt to discover pathogenic explanations. 566 patients suffering from Dupuytren's disease in the area around Hanover were analysed with respect to epidemiological features and their Tubiana contracture stage. 91.2% were of pure northern German stock, 12.5% had a family predisposition. The male-to-female ratio was 7:1. Men were afflicted on average at the age of 56 years. Intellectuals were scored 3.17, while manual workers scored 4.21. There were pre-existing ipsilateral lesions in 15% of cases. 55.1% had bilateral contracture. Ectopic penile and plantar fibrosis or knuckle pads were found in 6.7% of cases. The distribution of stages I-IV decreased by 2.4% from 59.1% among the 1,808 afflicted finger rays. With a score of 3.7-3.72, drinkers and smokers presented significantly more severe contractures, while the 8.2% of diabetics displayed a milder form. Among the epileptics--all of whom were affected bilaterally--the Tubiana stage of 3.71 exceeded the median manual score of 3.63 for the group as a whole. Thus Dupuytren's disease is a general but not an exclusively extremity-related sickness. The androtropy is pathognomic. Women develop the disease one decade later than men. In old age the male-to-female ratio equalizes. Drinkers, smokers and heavy manual workers present a more severe affliction, while diabetics suffer from a significantly less severe form. Although the ulnar type dominates, the radial type accounts for 14.4% of cases. 1.9 million Germans are chronically ill because of Dupuytren's disease. Despite a trauma history, Dupuytren's disease is not recognized as an occupational disease.

Philos Trans R Soc Lond B Biol Sci. 1999 Jan 29;354(1379):99-108; discussion 108-9.

hemochromatosis: Celtic X Viking origin of the mutation

A European allele map of the C282Y mutation of hemochromatosis: Celtic versus Viking origin of the mutation?

Lucotte G, Dieterlen F.

International Institute of Anthropology, Paris, France.

The aim of this new meta-analysis (to the end of 2002) is to compile the Y allele frequencies of the C282Y mutation of hereditary hemochromatosis (HFE gene) for 63 European populations, representing a total of 10,708 unrelated people concerning control samples. A new allele map of C282Y frequencies in Europe was constructed. The highest European frequencies are observed in the Celtic populations in Ireland, in the United Kingdom, and in France, but elevated frequencies are also observed in Scandinavia.

Clin Genet. 2003 Jul;64(1):36-47.

Evidence that the Cys282Tyr mutation of the HFE gene originated from a population in Southern Scandinavia and spread with the Vikings.

Milman N, Pedersen P.

Department of Medicine B, Rigshospitalet, University of Copenhagen, Copenhagen and Department of Clinical Biochemistry, Naestved Hospital, Naestved, Denmark.

Hereditary hemochromatosis has been recognized as a clinical disorder for more than 100 years. The common form of the disorder is caused by the Cys282Tyr mutation (C282Y) of the HFE gene. Hereditary hemochromatosis affects predominantly people of Northern European origin. The C282Y mutation probably occurred on a single chromosome carrying the ancestral hemochromatosis haplotype, which subsequently was spread by emigration and the founder effect. It has been estimated that the C282Y mutation appeared 60-70 generations ago. It was initially suggested that the ancestral C282Y mutation occurred within the Celtic group of peoples. However, we hypothesize that the distribution of the C282Y mutation in Europe is more consistent with an origin among the Germanic Iron Age population in Southern Scandinavia. From this area, the mutation could later be spread by the migratory activities of the Vikings. The aim of the present study was to evaluate the validity of these two hypotheses. Several arguments are in favor of the 'Viking hypothesis': first, the highest frequencies (5.1-9.7%) of the C282Y mutation are observed in populations in the Northern part of Europe, i.e. Denmark, Norway, Sweden, Faeroe Islands, Iceland, Eastern part of England (Danelaw) and the Dublin area, all Viking homelands and settlements. Second, the highest allele frequencies are reported among populations living along the coastlines. Third, the frequencies of the C282Y mutation decline from Northern to Southern Europe. Intermediate allele frequencies (3.1-4.8%) are seen in the populations in Central Europe, which is the original Celtic homeland. Low allele frequencies (0-3.1%) are recognized in populations in Southern Europe and the Mediterranean.

Immunogenetics. 1997;46(3):222-5.

Absence of the hemochromatosis gene Cys282Tyr mutation in three ethnic groups from Algeria (Mzab), Ethiopia, and Senegal.

Roth M, Giraldo P, Hariti G, Poloni ES, Sanchez-Mazas A, Stefano GF, Dugoujon JM, Coppin H.

CNRS UPR 8291, CHU Purpan, 31300 Toulouse, France.

A Celtic origin for hemochromatosis, a common genetic iron metabolism disorder, has been postulated for a long time. To check whether the two mutations recently identified in the HLA-class I candidate gene for this disease were found only in Caucasians, we examined their frequencies in individuals originating from Algeria, Ethiopia, and Senegal. The presumably disease-causing mutation, responsible for the Cys282Tyr substitution, was not found in any member of these ethnic groups, although it was shown to be highly prevalent in populations of European ancestry. This geographic distribution supports the previously suggested Celtic origin for the disease. In contrast, the mutation responsible for the His63Asp substitution is not restricted to European populations. Although absent in the Senegalese, it was found on about 9% of the chromosomes of the Central Ethiopians and Algerians (Mzab) genotyped for this study. This second mutation, which probably represents a common variant unrelated to hemochromatosis, thus appears to have occurred earlier than that responsible for the Cys282Tyr substitution. More detailed population studies are needed to provide information on the age of these two mutations and eventually show how the hemochromatosis-causing mutation chronologically spread throughout Europe.

Int J Hematol. 2003 Jan;77(1):48-54.

Frequencies of the hereditary hemochromatosis allele in different populations. Comparison of previous phenotypic methods and novel genotypic methods.

Milman N, Pedersen P, Steig T, Melsen GV.

Department of Medicine B, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

AIM: The frequencies of the hereditary hemochromatosis allele were compared for different populations assessed by previous phenotypic methods and the present genotypic methods.
METHODS: From a literature survey, the calculated hemochromatosis allele frequencies from 16 studies using phenotypic biochemical markers (threshold levels for transferrin saturation [range, 46%-70%] and serum ferritin [range, 164-700 microg/L]) were compared with allele frequencies of the Cys282Tyr mutation of the hemochromatosis gene reported in 19 genotypic studies. RESULTS: Calculated phenotypic allele frequencies are high in Scandinavia: Iceland, 6.1% to 7.4%; Norway, 5.8%; central Sweden, 6.3% to 6.9%; Denmark, 6.1%. Frequencies are similarly high in Wales, Canada, Utah, South Africa, and Australia (range, 5.2%-9.8%). Frequencies are low in Finland (1.9%) and northern Italy (4.5%). Genotypic allele frequencies of the Cys282Tyr mutation are likewise high in Scandinavia. Frequencies are high in the United Kingdom and northern France and low in Finland, central Germany, northern Italy, and Greece. The phenotypic-genotypic ratios of the hemochromatosis homozygosity frequencies for the same geographic area were calculated. A ratio of 1.0 indicates that the 2 methods give similar results. In 3 studies, the ratio was above 1.0, the highest ratio of 1.67 being reported from Italy. In most studies the ratio was slightly below 1.0 (0.71-0.97). The lowest ratio was found in Finland (0.33).
CONCLUSION: In most studies there was good agreement between the hemochromatosis allele frequencies determined by phenotypic and genotypic methods. A high ratio (northern Italy) may indicate that phenotypic selection criteria were too loose and/or that causes of iron overload other than the Cys282Tyr mutation are frequent in the region. A low ratio (in Finland) may indicate phenotypic selection criteria that were too stringent and/or a low penetration rate of the mutation.

Neth J Med. 2003 Sep;61(9):291-5.

Two Dutch families with hereditary hyperferritinaemia-cataract syndrome and heterozygosity for an HFE-related haemochromatosis gene mutation.

Simsek S, Nanayakkara PW, Keek JM, Faber LM, Bruin KF, Pals G.

Department of Internal Medicine, University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands.

Hereditary haemochromatosis is an autosomal recessive disorder, leading to progressive iron overload, which is very common among the Caucasian population. In the vast majority of the cases, the hereditary iron overload is caused by mutations in the HFE gene. Most prominently this is the homozygous Cys282Tyr mutation. We report two Dutch families in which both propositi were found to be heterozygous for Cys282Tyr in the work-up of hyperferritinaemia. Frequent phlebotomies had no effect on the ferritin level, but led to microcytic anaemia. Finally, the family history with bilateral cataracts was the clue for the correct diagnosis. Hereditary hyperferritinaemia-cataract syndrome (HHCS) is an autosomal dominant disease characterised by elevated serum ferritin levels and bilateral cataracts in the absence of iron overload. Several point mutations and deletions within the iron-responsive element (IRE) in the 5' noncoding region of the L-ferritin gene have been found in HHCS families. In the first Dutch family a G to C transition at position 32 was found and a G to A mutation at the same location was found in the second Dutch family. In individuals with an isolated hyperferritinaemia (normal transferrin saturation), the presence of early onset (familial) cataract should raise the possibility of HHCS, even when Cys282Tyr heterozygosity is found.

Scand J Gastroenterol. 1999 May;34(5):529-34.

High prevalence of the hemochromatosis-associated Cys282Tyr HFE gene mutation in a healthy Norwegian population in the city of Oslo, and its phenotypic expression.

Distante S, Berg JP, Lande K, Haug E, Bell H.

Dept. of Medicine, Aker University Hospital, Oslo, Norway.

BACKGROUND: Previous studies have shown that 5%-10% of white subjects are heterozygous for the HFE gene C282Y mutation, which is associated with hemochromatosis. The aim of our study was to determine the prevalence of heterozygosity and homozygosity for the C282Y HFE gene mutation and its phenotypic expression in a group of healthy Norwegians.
METHODS: Fasting blood samples were obtained from 505 unrelated hospital employees. Serum iron, transferrin, and serum ferritin were measured. Transferrin saturation was calculated. The presence of HFE gene mutation was determined with a polymerase chain reaction-based analysis.
RESULTS: Two of the 505 subjects (0.4%) were homozygous and 75 (14.9%) were heterozygous for the C282Y mutation. Median serum ferritin among the heterozygotes was 59 microg/l, compared with 47 microg/l among individuals without the C282Y mutation (P = 0.12). Median transferrin saturation among the heterozygotes was 31%, compared with 24% among individuals without C282Y mutation (P <> 200 microg/l. Eight of these (35%) had the C282Y mutation: two homozygotes and six heterozygotes. Transferrin saturation > 50% was observed in 25 individuals (5.0%). Twelve of these (48%) had the C282Y mutation; two were homozygotes and 10 heterozygotes. Only eight individuals (1.6%) had a transferrin saturation > 60%: one homozygote, five heterozygotes, and two individuals without mutation.
CONCLUSIONS: Fifteen per cent of a healthy Norwegian population is heterozygous for the HFE gene mutation C282Y. This is among the highest reported prevalence values among healthy individuals. Half of the subjects with transferrin saturation greater than 50% were carriers of the C282Y mutation.

Prevalence of the Cys282Tyr and His63Asp HFE gene mutations in Spanish patients with hereditary hemochromatosis and in controls.

Sanchez M, Bruguera M, Bosch J, Rodes J, Ballesta F, Oliva R.

Genetics Service, Institut Clinic de Malalties Digestives, IDIBAPS, Hospital Clinic and University of Barcelona, Villarroel, Spain.

BACKGROUND/AIMS: A mutation (Cys282Tyr) of the HFE gene has recently been reported to be present in most of the patients with hereditary hemochromatosis of Northern European ancestry, but in a lower frequency in Italy. No data are so far available on the prevalence of these mutations in Spain. Therefore, we initiated the present study to determine if the reported Cys282Tyr HFE mutation is also the main cause of hereditary hemochromatosis in Spain. In addition, we investigated the presence of the His63Asp HFE mutation in patients and in controls.
METHODS: Thirty-one hereditary hemochromatosis patients and 485 controls were screened for the Cys282Tyr and the His63Asp mutations, using polymerase chain reaction amplification of genomic DNA, followed by digestion with the restriction enzymes Rsa I or Dpn II, respectively, and the separation of the products by electrophoresis.
RESULTS: Twenty-seven out of 31 (87.1%) hereditary hemochromatosis patients were homozygous for the Cys282Tyr mutation. None of the patients was homozygous for the His63Asp mutation, and two patients (6.5%) were compound heterozygous (Cys282Tyr/His63Asp). Only one of 512 (0.2%) controls was homozygous for the Cys282Tyr mutation, and 29 (5.7%) were heterozygous. The Cys282Tyr mutation is present with an allelic frequency of 90.3+/-7.5% in patients with hereditary hemochromatosis and 3.0+/-1.1% in controls. Twenty out of 487 (4.1%) controls were His63Asp homozygous, while 171 (35.1%) were heterozygous. The His63Asp mutation is present with an allelic frequency of 21.7+/-2.7% in controls.
CONCLUSIONS: The high frequency of the Cys282Tyr mutation in hereditary hemochromatosis patients indicates that this mutation is the most common defect associated with hereditary hemochromatosis in Spain. The finding of some patients with the wild genotype at position 282 suggests the existence of other changes in the HFE gene or in other loci involved in the disease. We have found one of the highest allelic frequencies reported for the His63Asp mutation in our controls (21.7+/-2.7%).

J Gastroenterol Hepatol. 2004 Jan;19(1):86-90.

Absence of hemochromatosis associated Cys282Tyr HFE gene mutation and low frequency of hemochromatosis phenotype in nonalcoholic chronic liver disease patients in India

Thakur V, Guptan R, Hashmi A, Sakhuja P, Malhotra V, Sarin S.

Departments of Gastroenterology and Pathology, G.B. Pant Hospital, New Delhi, India.

BACKGROUND AND AIM: Hereditary hemochromatosis (HHC) is an autosomal recessive disorder causing primary iron overload syndrome and chronic liver disease (CLD). This genetic disease is commonly associated with C282Y mutation of the HFE gene, commonly seen in the Northern European population. Minor reports on HHC are available from Asia, however, so far no genetic study is available from India. We prospectively studied the prevalence of C282Y mutation in CLD patients and healthy subjects in a tertiary care referral center in India.
METHODS: A total of 249 consecutive biopsy proven CLD (HBV = 112, HCV = 72, cryptogenic = 65) patients and 134 age matched healthy controls were included. Cases of secondary iron overload, pregnancy, chronic alcoholism, age <>60% was suggestive of a phenotypic presentation of HHC. C282Y mutation was studied by restriction fragment length polymorphism (RFLP) using genomic DNA. The 387 bp fragment obtained after polymerase chain reaction was digested with 10 units of endonuclease Rsa1. The mutation was detected by creation of an additional restriction site, giving rise to fragments of 247 111 and 29 bp.
RESULTS: While the mean TSI was comparable, serum ferritin was significantly higher in CLD patients compared to controls (38 +/- 16%vs 28 +/- 13%; p = not significant (NS), and 125 +/- 18 vs 42 +/- 25 ng/mL; p <>60% was detected in 24 (9.64%) patients. Only one restriction site was found for endonuclease Rsa1, giving rise to two fragments of 247 and 140 bp, suggesting absence of C282Y mutation in the HFE gene in all patients. CONCLUSIONS: Almost 10% of nonalcoholic CLD patients in India have iron overload, but this is independent of C282Y mutation of the HFE gene. Large population based studies are recommended to investigate the prevalence of this RARE DISORDER IN INDIA.

Am J Hematol. 1998 Jul;58(3):213-7.

Mutation analysis of the HFE gene associated with hereditary hemochromatosis in African Americans.

Monaghan KG, Rybicki BA, Shurafa M, Feldman GL.

Department of Medical Genetics, Henry Ford Hospital, Detroit, Michigan 48202, USA.

Homozygosity for the mutation Cys282Tyr in the HFE gene has recently been identified as a cause of hereditary hemochromatosis, a disorder resulting in the inappropriate absorption of iron. Approximately 10% of Caucasians are heterozygous for this mutation; however, the gene frequency in African Americans is unknown. A study of a control population of African Americans was performed to determine the frequency of the Cys282Tyr and His63Asp alleles in this ethnic group. The carrier frequency for each mutant allele in our African American population was 3.0%. DNA studies of four African-American hemochromatosis patients did not identify any individuals with the Cys282Tyr allele. These findings suggest that if the Cys282Tyr mutation confers susceptibility to hemochromatosis in Caucasians (as suggested by recent studies) there is an alternative mechanism for hemochromatosis in the American black population. Frequency analysis and allele map in favor of the celtic origin of the C282Y mutation of hemochromatosis.Lucotte G.International Institute of Anthropology, Paris, France.After the main hereditary hemochromatosis mutation C282Y in the HFE gene was described, we report here the C282Y frequencies for various European populations. The aim of this meta-analysis is to compile the Y allele frequencies of the C282Y mutation for 53 European populations, representing a total of 9265 unrelated people representing control samples. The most elevated values are observed in residual Celtic populations in Ireland, in the United Kingdom, and in France, in accordance with the initial hypothesis of Simon et al. (Prog. Med. Genet. 4, 135-168, 1980) concerning a Celtic origin of the hereditary hemochromatosis mutation.

Euclides, 2003.

Prevalence of C282Y and E168X HFE mutations in an Italian population of Northern European ancestry.

Salvioni A, Mariani R, Oberkanins C, Moritz A, Mauri V, Pelucchi S, Riva A, Arosio C, Cerutti P, Piperno A.

Clinica Medica, Ospedale San Gerardo, via Donizetti 106, 20052 Monza, Italy.

BACKGROUND AND OBJECTIVES: In Italy, the prevalence of C282Y is lower than in Northern European countries. We hypothesized a higher prevalence of C282Y in Northern than in Southern Italian populations. We previously identified a nonsense mutation (E168X) in hemochromatosis probands originating from a region in the north-west of Italy. We aimed to define the prevalence of C282Y and E168X in that region and the origin of the E168X mutation by haplotype analysis.
DESIGN AND METHODS: Six-hundred and six blood donors were investigated for C282Y, H63D, S65C and E168X mutations by polymerase chain reaction (PCR)-restriction assays. Three hundred were also tested for rare HFE and TFR2 mutations by reverse-hybridization test strips. D6S265, D6S105 and D6S1281 microsatellites were analyzed to define E168X 6p-associated haplotypes.
RESULTS: One C282Y homozygote, thirteen C282Y/ H63D compound heterozygotes, four E168X heterozygotes and three E168X/H63D compound heterozygotes were found. The allele frequencies of C282Y, H63D, S65C, and E168X were 4.7%, 14.9%, 0.74% and 0.58%, respectively.
INTERPRETATION AND CONCLUSIONS: The prevalence of C282Y in the region investigated was much higher than that previously reported in Italy. This finding is probably due to the heavy Celtic component of this north-western population and suggests that in populations of Northern Italian descent screening studies for hemochromatosis could be cost-effective. The prevalence of E168X in this region, although low, suggests that the mutation probably originated here many years ago and its frequency increased as a result of a local founder effect. Given its severity, we suggest that the E168X mutation should be searched for in all hemochromatosis patients of Northern ancestry with an incomplete HFE genotype.

Frequency of the HFE gene mutations in five Italian populations.

Candore G, Mantovani V, Balistreri CR, Lio D, Colonna-Romano G, Cerreta V, Carru C, Deiana L, Pes G, Menardi G, Perotti L, Miotti V, Bevilacqua E, Amoroso A, Caruso C.

Gruppo di Studio sull'Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Universita di Palermo, Palermo, Italy.

Genetic hemochromatosis is an autosomal recessive disorder characterized by iron overload and a variety of clinical manifestations such as liver cirrhosis and arthropathy. It is the most common genetic disease of northern European populations. The principal gene responsible for hereditary hemochromatosis, designated HFE, is located on chromosome 6 in the HLA region. The single point mutation 845A, changing cysteine at position 282 to tyrosine (C282Y), in this gene has been identified as the main genetic basis of hereditary hemochromatosis. Two other mutations, 187G, a histidine to aspartate at amino acid 63 (H63D), and 193T, a serine to cysteine at amino acid 65 (S65C), appear to be associated with milder forms of hereditary hemochromatosis. There is a high prevalence of the C282Y mutation in northern European populations, whereas in those of the Mediterranean basin the prevalence seems low and almost absent in Far East countries. This mutation seems usually to occur on the ancestral haplotype 7.1. Accordingly, a Celtic origin of this mutation has been suggested. The aim of this study was to determine the frequency of HFE gene mutations in five geographic regions in Italy. Samples were tested for C282Y, H63D, and S65C mutations of the HFE gene according to methods of each laboratory and the results were standardized with the exchange of typed samples between the different laboratories. In addition, C282Y-positive DNA samples were typed for D6S105 allele 8 and HLA-A3 by ARMS-PCR. We have found that the allele frequency of the C282Y mutation decreases from northeast Italy (Friuli, 6%) to northwest Italy (Piedmont, 4.8%) and to central Italy (Emilia-Romagna, 1.7%). However, this mutation is lacking in the two regions of the Mediterranean basin's center (Sicily and Sardinia). Accordingly, a significant difference in the frequency of the mutation was observed between these Italian regions (P = 0.07 x 10(-3)). In contrast, no difference was observed in allele frequency of H63D in the five Italian regions. Finally, as regards the S65C mutation a very low frequency was observed in Friuli, Emilia-Romagna, and Sardinia, whereas in Sicily and Piedmont we have not found this mutation. In conclusion, these data are consistent with the hypothesis that the C282Y mutation occurred in Caucasian populations of Celtic origin, whereas the H63D mutation is more ancient as demonstrated by the ubiquitous distribution.

Frequency of hemochromatosis C282Y and H63D mutations in Sardinia.

Melis MA, Cau M, Congiu R, Ruvoletto L, Cao A, Galanello R.

Dipartimento di Scienze Biomediche e Biotecnologie, Sezione Clinica e Biologia dell'Eta Evolutiva, Universita degli studi di Cagliari, Ospedale Regionale per le Microcitemie ASL, 8 Cagliari, Italy.

Hereditary hemochromatosis (HH) is one of the most common autosomal recessive disorders of iron metabolism among Caucasians, and it is associated with C282Y mutation of the HFE gene in populations of Celtic origins. A second mutation, H63D, shows a very high widespread frequency, although its role in iron metabolism is still inconclusive. There are no data on the frequencies of these two mutations in Sardinia, an island in the Mediterranean sea that has not been invaded by Celtic peoples. We examined 836 chromosomes from Sardinian subjects and tested for the mutation by restriction enzyme digestion of PCR products. Among the 836 analyzed chromosomes, we found a C282Y allele frequency of 0.0036 and an H63D allele frequency of 0.173. These data could explain the observed rarity of HH in Sardinia. The high allele frequency of H63D and the rarity of HH in Sardinia is suggestive that this mutation is not a major contributor to this disease.

Haemochromatosis gene mutations in a clustered Italian population: evidence of high prevalence in people of Celtic ancestry.

Pozzato G, Zorat F, Nascimben F, Gregorutti M, Comar C, Baracetti S, Vatta S, Bevilacqua E, Belgrano A, Crovella S, Amoroso A.

Dipartimento di Medicina Clinica & Neurologia, Unita Operativa Medicina Clinica, Universita degli Studi di Trieste, Trieste, Italy.

Hereditary haemochromatosis is an inherited disorder characterised by an excessive iron absorption from the diet and is associated with several HFE gene mutations. One hypothesis is that these genetic mutations originated in the Celtic populations. The aim of this study is to determine the frequency of HFE gene mutations in a clustered Italian population of Celtic ancestry (Cimbri, Asiago plateau). One hundred and forty-nine consecutive unrelated blood donors (31 females and 118 males) were enrolled in this study. A family investigation was performed in each case to identify the ethnic origin of the individuals. The analysis of HFE gene mutations was performed by PCR amplification followed by digestion with RsaI and DpnII restriction enzymes. At least one HFE gene mutation was identified in 49 individuals (32.9%) of the studied population. The allele frequencies of the C282Y and H63D were respectively 0.037 and 0.144. When we considered only the 103 individuals with relatives born in Asiago, the prevalence of the HFE mutations rose from 32.9 to 39.8%; the allele frequencies of the C282Y and H63D were respectively 0.048 and 0.174. The mean serum iron and ferritin levels were significantly higher in individuals with the HFE mutations than in normal cases. This study indicates that the prevalence of the HFE gene mutations is surprisingly high in Italians with Celtic ancestry. This could suggest the need to perform large mass studies in selected areas of the country to detect the affected patients and prevent the disease in homozygous individuals.

Frequency analysis and allele map in favor of the celtic origin of the C282Y mutation of hemochromatosis.

Lucotte G.

International Institute of Anthropology, Paris, France.

After the main hereditary hemochromatosis mutation C282Y in the HFE gene was described, we report here the C282Y frequencies for various European populations. The aim of this meta-analysis is to compile the Y allele frequencies of the C282Y mutation for 53 European populations, representing a total of 9265 unrelated people representing control samples. The most elevated values are observed in residual Celtic populations in Ireland, in the United Kingdom, and in France, in accordance with the initial hypothesis of Simon et al. (Prog. Med. Genet. 4, 135-168, 1980) concerning a Celtic origin of the hereditary hemochromatosis mutation.


European Neurology 2006; 55: 57-58. Trygve Holmoy

A Norse Contribution to the History of Neurological Diseases

Trygve Holmøy

Department of Neurology
Ullevål University Hospital
NO–0047 Oslo (Norway)
Tel. +47 22 119 101
Fax +47 23 073 510

Key Words
Multiple sclerosis - Medical history - Norse saga

Multiple sclerosis (MS) is prevalent in areas with many inhabitants of Scandinavian descent, and a ‘Viking gene’ hypothesis has been suggested for the dissemination of the disease. It is therefore relevant to search Norse sagas
for descriptions of clinical pictures which could have been MS. The saga of Bishop Thorlak describes a woman named Halldora, who suffered from transient paresis between 1193 and 1198. The diagnosis is uncertain, but the story shows that symptoms associated with MS were known in Iceland at the end of the 11th century.

Pearce [1] has reviewed the history of multiple sclerosis (MS) back to 1822. The disease could be much older [2] , but reliable sources are scarce. Since MS is frequent among people of Scandinavian descent, it has been suggested that its dissemination may be linked with the Vikings’ voyages [3] . We have therefore reviewed the Norse sagas to find evidence of MS in medieval Norway and Iceland. However, most sagas are focused on feuds and struggles for power, and not much is written about women’s health. Nevertheless, Biskupa Sogur, the bishops’ sagas, contains several accounts of diseases and afflictions [4] . Poser [3] discussed whether Halla, who was blind and deaf for two weeks between 1293 and 1323 and miraculously cured, suffered from MS [4] . Bishop Thorlak died in 1193. In 1199, the Elder Book of Portents, which contains accounts of the earliest miracles performed by Thorlak, was read aloud at the Allting by his successor [5] . Among the tales of convulsions, burns, bad beer and other abominations cured by Thorlak, we find this story:
There was a young woman named Halldora. She fell ill of a serious disease and had to keep to her bed and even be cared for in bed. She could not walk and could hardly sit, and her limbs were almost without strength; she had to be carried everywhere. She often suffered great pain, which caused her much distress. She was tended by her loving family, who were greatly worried about her condition. In spite of the many prayers offered for her, her symptoms
only improved for a short while. When she had lain in bed for almost three years, it became more and more usual to make vows to Bishop Thorlak, whose holiness was talked of in every home.
Then one of the men said, ‘I believe it will be a sign of Bishop Thorlak’s miraculous power if he were to cure Halldora, who has lain in bed for three years.’ Many people agreed that the bishop would be able to obtain this favour from God if he wished. This happened on the Vestmanna Islands. A married woman whose word was reliable dreamt that a man in a black cloak came to her, and she understood that this was the holy Bishop Thorlak. He said,
‘Tell her of this revelation and tell her that she must go to Skalholt if she wishes to be cured.’ (…) When it became possible to leave the islands, Halldora began her journey and was carried to Skalholt on a stretcher. As soon as she saw the church at Skalholt her heart became lighter than it had been since she fell ill. She arrived several days before the church festival and grew better every day. Many people came to the festival, and Bishop Paul told them to pray for her. (…) The day after the festival she went to the Allting and offered up a gold ring, and a few days later she rode to the Allting, where the whole assembly of the Ting could see that she was completely cured.
Halldora was cured after Thorlak’s death in 1193 and before the Elder Book of Portents was read out in 1199, and is probably over 100 years older than the cure of Halla. The story was written down a few years after it had occurred and then read aloud publicly at the Allting by Bishop Paul [6] , which makes it likely that the core content is truthful. It served as evidence of one of the miracles for which Thorlak was canonized. Nothing more is known about Halldora. The paralysis apparently lasted too long to be compatible with the usual course of a neurological disorder. However, there were short periods of improvement.
It is possible that the symptoms were exaggerated in order to dramatise the saint’s healing power, and that the actual course of the disease corresponded more to relapsing-remitting MS, chronic infl ammatory demyelinating polyradiculoneuropathy or a neuromuscular transmission disorder. Hysteria is always suspected when miraculous cures occur, but in such cases the improvement is usually sudden and not spread over several days [7] .
Although it is impossible to make a precise diagnosis, the saga does show that temporary paralysis was well known in medieval Iceland.

The excerpt from Thorlaks Saga was translated into English by Alison Arderne Olsen at The Norwegian Ministry of Foreign Affairs.

1 Pearce JM: Historical descriptions of multiple sclerosis. Eur Neurol 2005; 54: 49–53.
2 Medaer R: Does the history of multiple sclerosis go back as far as the 14th century? Acta Neurol Scand 1979; 60: 189–192.
3 Poser CM: Viking voyages: the origin of multiple sclerosis? An essay in medical history. Acta Neurol Scand Suppl 1995; 161: 11–22.
4 Anonymous: Thorlaks Saga; in Biskupa Sogur. Editiones Arna Magnaenae C, ch. 120, series A, vol 13.2. Copenhagen, Jon Helgason, 1978.
5 Anonymous: Den gamle jærtegnsbok om Biskop Thorlak. Odense, Odense University Press, 1984, pp 54–55.
6 Anonymous: Pauls Saga; in Biskupa Sogur. Copenhagen, Icelandic Literary Society, 1858, pp 127–148.
7 Ziegler J: Practitioners and saints: medical men in canonization processes in the thirteenth to fifteenth centuries. Soc Hist Med 1999; 12: 191–225.

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