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The Amish
The Amish V. A. McKusick The Old Order Amish are widely known because of their old-fashioned social and technological practices and characteristic dress (Figs. I-4). They represent both a religious isolate and a genetic isolate. Their religion is of a fundamentalist variety known generically as anabaptist, that is, they oppose infant baptism. Economically they are capitalists living on individual family farms. A strong sense of mutual collaboration exists among the Amish, however, as illustrated by barn-raisings, and in many other ways.
All the Amish are rural-living and most earn their living by farming. Some partially acculturated groups are still referred to as Amish, but in this discussion Amish refers to Old Order Amish, as defined above. They do not own automobiles but depend on the horse-and-buggy for local transportation, and most use only horse-drawn agricultural equipment. They do not have electricity in their farm buildings. They have no radios, television, nor telephones. These practices, as well as their stylized dress differing from that of their neighbours derive from their basic tenet stated in the 12th Chapter of Romans: ‘Be ye not conformed to this world, but be ye transformed. . .’ Based on the same tenet, they do not purchase commercial insurance on their property, because of the yoking with non-Amish that this would represent, and usually do not enter into business partnerships with non-Amish. Furthermore, they rigidly shun members of their own group, even close relatives, who, once baptized, leave the group or are excommunicated for failure to subscribe to the Meinung (doctrine). The Amish prefer their own schools, being particularly opposed to consolidated schools. Thus in heavily Amish parts of the country one sees many one-room parochial Amish schools. They do not educate beyond the legal minimum required by the state; that is, a grammar school education. A high-school truancy case involving Amish was carried to the U.S. Supreme Court, with the verdict in their favour. If there is one characteristic which distinguishes the Old Order Amish from other varieties of ‘plain people’-and of course there are other distinctive features-it is the practice of holding their religious services in the home, by rotation. All other plain sects, such as the Dunkards and conservative Mennonites (so called after the Frisian religious reformer Menno Simons), have meeting houses. The Old Order Amish originated in the Canton of Berne in Switzerland in 1693 as an offshoot of the older and more extensive Mennonite movement. Jacob Ammann, a Mennonite bishop, concluded that the Mennonites were too worldly. He acquired converts from among Bernese Swiss who during the previous century had left Berne to go to Alsace-Lorraine and the Palatinate. The Amish began coming to the United States about 1730, and most of the Amish of eastern Pennsylvania are descended from prerevolutionary immigrants. Immigration continued until about 1850 but later immigrants settled in western VictorA.
McKusick,M.D.,F.R.C.P.
Was born in Parkman, Maine, in 192 1, He is a graduate of Johns Hopkins University, and has been on the faculty of the medical school there since 1947. Ha was appointed Professor of Medicine in 1960 and in 1973 became chairman of the Department of Medicine and Physician-in-Chief of the Johns Hopkins Hospital, Apart from genetic studies of the Amish, his scientific work has been in heritable disorders of connective tissues, on mapping the chromosomes of man, and on the nosology of genetic disease. Endeevour, ( 0 Pergamon
52
New Series Volume 4. NO. 2.1980 Press. Printed in Great Britain)
Pennsylvania, Ohio, and points west. In some of these areas, descendants of pre-revolutionary immigrants were already living and the separate immigrant streams fused to some extent in these areas. Today the Old Order Amish number over 75,000 persons. Over 80 per cent of these live in Pennsylvania, Indiana, and Ohio and over 50 per cent live in three areas: Lancaster County (Pa.), Holmes County (Ohio), and Lagrange-Elkhart Counties (Indiana). The unit of Amish society is the church district. The size of the church district is determined by how many people can be accommodated in a farmhouse for religious services and how far one can conveniently travel by horse-andbuggy to attend it. The districts are ruled over by lay clergy called bishops, preachers, and deacons who are chosen by lot. The Amish are useful for both sociologic and genetic studies. Although the main focus of our own studies has been genetic, and that is the focus also of this article, aspects of sociologic interest are obvious. For example, their labour-intensive form of agriculture is a model that is becoming increasingly rare in developed countries. Their child-rearing practices are worth study. The child is
introduced to work early, and families are large and tightly knit. It is a memorable experience to visit an Amish family at mealtime in the large farm kitchen. Amish schooling is limited largely to the 3R’s plus geography and German. The Amish are tri-lingual: they speak the Pennsylvania Dutch dialect at home and children often know little else until they go to school. Adults speak English, and they are acquainted with the high German of the Luther Bible, which they use in religious services. The health care system of the Amish is eclectic. They, of course, do not have their own physicians. Although first babies are born in hospitals, Lancaster County Amish prefer to have later babies at home. Osteopathic physicians in that area attend deliveries at home. Although they do not hesitate to use local physicians or go to a distance to large medical centres, they tend to be attracted to fringe practitioners. The way the Amish care for their physically and mentally handicapped and for their aged is also a useful object of study. By special Act of Congress some years ago, they were exempted from Social Security payments because they ‘take care of their own’. When they retire older usually into a small move persons house (‘Grossdaddyhaus’) often attached to the big house which they previously occupied and which in this process they turn over to one of the younger sons who operates the farm. The Amish are of particular usefulness for many types of genetic studies, for the following reasons: They are a closed population. They do not proselytize and almost no new blood has been added to the groups since the immigrations. Gene flow is entirely centrifugal. Although a fair number of persons leave the groups each generation, the birth rate has been consistenly so high that the Amish have grown,
through that means alone, from about 8200 in 1905 to a number estimatedto be greater than 75,000 today. Then too, the Amish are a defined population; indeed, a self-definedone. Their origins in western Europe are rather well known. Their genealogic records are essentially complete back to the founding immigrants. They are consanguineous to a high degree. In every marriage contracted in the Lancaster County Amish in recent years, for example, the partners have been at least remotely related. Of the 1750 married couplesin a 1973 censusof the Lancaster County Amish, only two were not demonstrably related. The average coefficient of consanguinity is something betweenthat for first cousins and that for second cousins, namely about .026. This despite the fact that no first-cousin and niece-uncle marriages were found in 1973, and only two marriages of first-cousins-once-removed.In sufficiently frequent instances couples are related as second cousins two or three times over and as third cousins several times to make the averagecoefficient comesup to the figure cited. For example, at least one Lancaster County Amish couple is related in 42 ways! Unlike many inbred groups studied by geneticists the standard of living of the Amish is high and the standard of medical care is relatively high. That the standard of diagnostic care is high is particularly useful when one is investigating genetic diseases,including possibly new ones. Amish clannishness and a related interest in the nature of illnesses that affect their co-religionists have been an important factor in identifying multiple casesof rare and sometimes“new” genetic diseases.Becausethe Amish take care of their own, they keep defective membersof their sect at home. This facilitates identification of particular problems and their study against the background of the family. Finally, in the Amish two disadvantagesof modern man as an object of genetic study-his small family size and his mobility-are counteracted. In the case of the Amish one can collect observations and samples on a rather large number of relatives living in a limited geographic area. The pattern of immigration and of subsequent community development among the Amish bears some similarity to cloning of bacteria or cultured somatic cells. It is as though the Amish founders were“streaked out” across a latitudinal belt of America east of the Mississippi. Colonies sprang up, not to be sure from individuals, yet from a limited number of individuals, and their descendants display characteristics determined by genes carried by those founders. Thus, bioassay of the genome of the founders has beenperformed for us. Each of us, it can be estimated,carries a few ‘bad’ genes; that is, recessivegenespresent in single dose and therefore not expressed. I, for example, may carry a gene for congenital deafness, a gene for albinism, and a gene for cystic fibrosis. That our children are no more often affected by these disorders than they are follows from the rarity of most of these genes; unless we marry a close relative, our spouseis likely to have a different setof ‘bad’ genes. Genetic
disorders
of the Amish
Someof the genetic disorders which have beenfound in the Amish are previously recognised ones. Some of them, however, were ‘new’ genetic diseases, having not been known, or at least not recognised, until they came to light among this sect. Once described among the Amish they have usually been found in other groups as well. Thus,
studies of the Amish have contributed to genetic nosology; that is, the classification or better delineation of genetic disorders. The visibility of recessivegenetic disorders is increased among the Amish. Most ‘visible’ mutations, (that is, mutations that are evident in persons homozygous for the mutation, without resort to special biochemical or other testing) are recessive: the gene must be present in double doseto be expressed.Man shows a deficiency of autosomal (non-sex-linked) recessives relative to known autosomal dominants, if one assumesthat most visible mutations are indeed recessive and compares man with speciessuch as mouse and drosophila in which recessives predominate. The reason for this is that a recessivemutation can occur in man and be lost, either by chance or becauseit has some disadvantageeven in the heterozygote, before it happensto encounter itself in a homozygous descendant.Man, unlike the experimental species, usually does not marry close. Furthermore, even if the gene does occur in double dose, chances are strong-because human families are smallthat it will be a single casein the family and therefore not recognised as a distinct disorder. In experimental species close mating and large number of progeny render any recessivemutation more visible than is the casein man.
Figure
1
Amish
father
with
three children
In the Amish the cloning phenomenon (known technically as Founder Effect), consanguinity, and large family size all collaborate in increasing the visibility of recessives.The very existence of the group itself increases that visibility. If a strange disorder occurs among children who are easily identified as Amish, even though they are in different sibships, one is likely to be impressed.The form of hereditary anaemia now called thalassaemia becauseof its frequent occurrence in the Mediterranean littoral, was not discovered there but was recognised first in Detroit in the 1920s by a pediatrician-haematologist T. B. Cooley. He could not help but be impressed with the likely distinctiveness of the disorder that occurred in Greek and Italian children. The Amish likewise illustrate the usefulness of ‘groupness’, or ethnic extraction, in the identification of ‘new’ entities. 53
Of the dozen or more conditions which have been identified for the first time among the Amish, a prime example is cartilage-hair hypoplasia, which will be discussedin somedetail. Disorders previously describedin non-Amish are likewise useful to study when found among the Amish, partly because they illustrate gene dynamics and the genetic structure of the populations, but also becauseone often finds in the Amish a large number of casesof the particular condition and can be quite certain that all cases are produced by the self-same gene. In medical genetics as practiced in the general population, genetic heterogeneity is a leading fact of life. In a given series of casesone may unwittingly be comparing apples and oranges, that is, cases caused by fundamentally different mutations. Six-fingered dwarfism is one of the previously known, although rare, disorders encountered quite frequently amongthe Amish (figure 2).
Figure 2 Nine-year-old Amish boy with ‘six-fingered dwarfism’ (Ellis-van Creveld syndrome) who has undergone cardiac surgery for atrial septal defect. Extra fingers have been removed. Amish children are dressed like their elders.
The Ellis-van hypoplasia
Creveld
syndrome
and cartilage-hair
When my colleaguesand I first undertook genetic studies among the Amish, we were told that achondroplastic dwarfism was unusually frequent among them. A priori it seemedunlikely that this was truly achondroplasia because we knew by that time (1962) that achondroplasia is a very specific form of dwarfism inherited as an autosomal dominant, whereasin an inbred group such as the Amish, 54
one expects to find recessive disorders in increased numbers, not dominant disorders. At least, one does not expect to find a large number of cases of a dominant disorder that has severelyreduced reproductive fitness as is the casewith achondroplasia. In the event, it proved to be recessivedwarfism that was frequent among the Amish, in fact two forms of recessivedwarfism. One was a form first described in 1942 by Ellis and van Creveld, professors of paediatrics in Edinburgh and Amsterdan, respectively, and known as the Ellis-van Creveld (EvC) syndrome, or ‘sixfingereddwarfism’ (Fig. 4). About 50 casesofthis condition had been reported up to the time of our initial report in 1964, and at one fell swoop we were able to double the world’s literature on the disorder by reporting more than 50 casesamong the Amish. We have now observed 89 cases among the Amish (figure 5). The secondform of dwarfism was a previously unknown variety in which fine, sparse, silky hair was combined with the problem in skeletal growth. Cartilage-hair hypoplasia (CHH) was the designation selectedfor the condition.
Fourteen-year-old Amish boy shown with physician from Figure 3 Dr McKusick’s group. The boy is dwarfed and has dislocated ocular lenses, a disorder called the Weill-Marchesani syndrome.
Both of these disorders, EvC and CHH, illustrate pleiotropism, that is, multiple effects of a single gene mutation. Each of them is a syndrome (which means literally ‘running together’). Personsunfamiliar with genetic principles often think of gene linkage as being the basis of such syndromes, rather than pleiotropism, but linkage is rarely, if ever, the cause.The gene-determinedbiochemical defect in neither of these two disorders is known. In recessively inherited conditions such as these, an enzyme deficiency is suspected.Whatever the nature of the basic defect it must be of a type that can lead to derangementin
several aspects of development and function, with the clinical consequences observed. EvC is characterised consistently by six fingers and short-limbed dwarfism. Furthermore, the fingernails are poorly developed, the teeth are abnormal, and in over half of cases a cardiac malformation, most often atria1 septal defect, is also present.
Furthermore, the severity of the dwarfing and hair changes is widely variable. In addition to pleiotropism and variability, these disorders illustrate a third cardinal principle of clinical genetics, genetic heterogeneity; that is, the same or nearly the same condition due to different genetic causes. Obviously if dwarfism were considered only one condition, confusion in prognostication, genetic counselling and management would be likely to occur. Among the Amish the Ellis-van Creveld syndrome occurs only in those of Lancaster County (or recently from Lancaster County). We have observed a total of 45 sibships, each with at least one member affected with this disorder. That it is an autosomal recessive is supported by the fact that the parents are normal in the case of all except one of these sibships (in which an afflicted man is married to a cousin of some sort and has two affected children out of seven). Segregation analysis shows close agreement of ‘observed’ with ‘expected’ incidence under the recessive hypothesis. Thus, both parents of each of the sibships (apart from the one mentioned above) must be heterozygous carriers. (Incidentally, the carriers show no discernible abnormality.) When one has a “founder population” such as this, in which an ordinarily rare gene is found in high frequency, it is plausible to conclude that only one of the immigrant founders carried the gene. If in tracking back the ancestry of all 90 parents of the 45 sibships one finds one but only one founder couple common to all, then the presumption is strong that one or the other of that specific couple (or both) “imported the gene” in to the U.S.A. In the genealogies only one couple was found to be ancestral to all 90 parents of affected sibships: this was Samuel King, who immigrated in 1744, and his wife (Fig. 61. ,iOiO 20000 3O@iOOO alJ0io0io0 ~Orn000
Figure 4 The Amish madonna. An Amish mother her child who has’six-fingered dwarfism’ (Ellis-van syndrome).
is shown Creveld
with
Both EvC and CHH also illustrate the principle of variability. Because of differences in genetic background against which the single major gene mutation is operating in and because of differences in different individuals, environmental circumstances under which individuals develop and live, considerable variability from case to case is observed. In a series of unrelated cases drawn from a non-Amish population one is uncertain how much of the variability is due to the fact that two or more different gene mutations are represented among the cases. In the Amish, where we have observed 90 cases of EvC, all clearly determined by the same gene, there still is considerable variability. As mentioned, congenital heart malformation occurs in only about half the cases. The pleiotropic effects of the cartilage-hair hypoplasia gene include, in addition to the cartilage and hair abnormalities, a defect of the immune system, such that many of these patients have particularly severe viral infections. Chickenpox in this condition may be a fatal illness, but even this feature is highly variable. In the more than 100 cases of CHH we have now observed among the Amish, many appear to have a normal immune system.
600000m 7oioooii ~onm00[7 ~UU.0 lomoo ~~nucln000nm00000 :~00000i000000mn 13monoiiio ~~iU.iUi~O ~~iiO0 X5~~~(-J~O($O~ ~~0000iii 18@00lii6 ~~iOOOOr3b~ 20m0000 m @ q +
~‘rnUclC ~~@UrnOU0@ ~~E!l0OWtl0@ ~~oooiaioio ~~OOiouOOOion ~~i00000000000 ~~ioOOOuOO!Il ~~ocltliocl@ooio ~~iOiOOtiOO ~~00i00000 ~~oioooioooi ~~oc~ioo 3~iOClU.O -tloii ~~00000.0 ~~lii0i00. ~~00000000m00 =ioo =ooioom ~~oooio DilYGOTlC TWINS ~~oonoooi STILL BOW4 ~AFFECrED -0iooomo DE@x 43q 000m
Figure 5 Distribution of 86 casesof the Ellis-van Creveld syndrome in 43 sibshipsof Lancaster County, Pennsylvania. The addition of two more affected sibships brings the total count to 89 cases in 45 sibships.
We estimate that the frequency of the Ellis-van Creveld syndrome in the Lancaster County Amish is not less than 50 per 10,000 births, which gives a frequency of the gene of 55
about .066 (when the effect of consanguinity is taken into account). This means,furthermore, that about 12.3per cent of all Lancaster County Amish are carriers of the EvC gene. Interestingly, and probably significantly, 12.5 per cent of the Lancaster County Amish carry the surname King (Table 1). A gene that came from Samuel King (and/or his wife) has persisted in the Lancaster County Amish population in about the same frequency as the family name which Samuel King alone introduced into the population. TABLE Lancaster
County,
1 DISTRIBUTION Pennsylvania
OF FAMILY
NAMES*
Holmes
County,
Ohio -
Stoltzfus King Fisher Beiler Esch, Esh LaPP Zook
25.7 12.6 11.1 10.7 6.5 6.4 5.4 78.4
Miller Yoder Troyer Raber Hershberger Schlabach Weaver Mast Beachy
27.6 15.3 10.4 5.6 5.5 4.3 3.7 3.5 2.7 78.6
*Each community now numbers about 13,000. Each of the top 7 names in the Lancaster community was derived from a single immigrant founder. Several of the names in Holmes County likewise had a unique origin.
Figure 6 Thedescentof both parents of the first 26 sibships identified as having the Ellis-van Creveld syndrome is traced to Samuel King and his wife. The same descent is demonstrable for the rest of the 90 parents of the 45 affected sibships identified to date.
56
The high EvC gene frequency in the Lancaster County Amish is largely due to Founder Effect-cloning phenomenon, if you will. Consanguineous matings of the closenesspracticed in the Lancaster County community account for only a small proportion of the cases,perhaps 14 per cent. Given the high gene frequency the other cases would have occurred with zero consanguinity. Our studies have led to the conclusion that the Amish do not represent one big homogeneous isolate, but rather several moderately separate isolates, or demes (the word demerefers to a local consanguinealgroup or endogamous community). Part of the evidence for separate deme formation among the Amish-for example, that the Lancaster County community is one deme, the Holmes County (Ohio) community another, and so on-is of at least four types: (i) the history of the immigrations and subsequentseparation of the groups; (ii) the distribution of family names in the separate communities; (iii) the distribution of blood groups in the separatecommunities; and (iv) the distribution of recessive genetic disorders in the different groups. As an example of the last the unprecedentedly high frequency of EvC among the Lancaster County Amish is a mark of their distinctiveness. Characteristic recessivedisorders are found in each of the other Amish demes. As shown in the table, only eight names account for almost 80 per cent of the 13,000 individuals in each of two Amish communities, but it is a completely different set of eight family names.This is all the more remarkable in view of the fact that each of the eight top Lancaster County names was derived from a single founder. The name Stoltzfus is carried by one fourth of all Lancaster County Amish and derives from a single founder, Nicholas Stoltzfus, who immigrated in 1766. Obviously he contributed disproportionately to the present gene poolanother illustration of Founder Effect.
Blood groups studies show that among the Lancaster County Amish almost three-fourths of the population is blood type A ascontrasted with the frequency of blood type A of 50 per cent in the Canton of Berne and 54 per cent in Holmes County (Ohio) Amish. Contrariwise, only 11 per cent of Lancaster County Amish are blood type 0, which has a frequency of 39 per cent in Berneseand 34 per cent in Holmes County Amish. Again this is presumably an expression of Founder Effect. If, for example, Nicholas Stoltzfus was homozygous for the blood group A gene,this would account in considerable part for the high frequency of blood type A now. A role may have beenplayed also by Random Genetic Drift-the chance transmission to the next generation of genesin different proportions from those existing in the parent population, a phenomenon especially likely to occur when groups are small. Cartilage-hair hypoplasia is much more generalisedin its distribution among the Amish than is EvC and someother disorders. Casesof CHH have beenidentified in all Amish communities. This must mean that many of the immigrant founders were carriers of the gene, which had achieved rather wide distribution in the parent population before the immigration, and indeed, probably before the founding of the Amish sectin 1693. The gene for cartilage-hair hypoplasia is rare in the general population, with one notable exception; the condition has a relatively high frequency in Finland, where more than 40 caseshave been observed. It is unlikely that there is any genealogic connection betweenthe Finns and the Amish. Much more likely is that an independent, but possibly identical mutation occurred sometime in the past in ancestors of the Finns and that the gene has achieved a relatively high frequency among them becauseof historicodemographic circumstances similar to those that occurred among the Amish. A large area of present day Finland was populated by a rather small number of immigrants who, using the analogy previously applied, were ‘streaked out’ over this extensive area. Groups sprung up which remained isolated, partly becauseof distance and partly becauseof language, from Germanic,neighbours on the one side and Siavic neighbours on the other. Chromosomal
peculiarities
The traits we have been discussing up to this point are Mendelian ones, autosomal recessive ones for the most part. Chromosomal peculiarities can likewise be studied among the Amish. For example; we reasonedthat sincethe
number of patronyms is limited among the Amish, since in our society the Y chromosomeand patronym are inherited together in males; sincemost of the Amish patronyms were derived from a single ancestor; and finally since the Y chromosomevaries in length from male to male, it might be possible to demonstrate a characteristic Stoltzfus Y, King Y or Fisher Y chromosome.Indeed,in the courseof doing a large number of karyotypes, males of the surname Beiler were found to have an unusually small Y chromosome, missing part of the long arm. Missing is most of the part that in other males shows fluourescencewhen stained with quinacrine, so that Amish males of the name Beiler do not show the F body which usually is a marker of malenessin interphase(resting) cells, such asbuccal mucosal cells. Amish maleswidely separatedin the pedigreewere found always to have the small Y chromosome if they had the name Beiler. All of them could be shown to be descendent from the samefounder of that name. Someof them still spell their name Beiler, while others spelled it Byler. Furthermore, the samesmall Y chromosome was found in persons of the name Beyeler who had immigrated from Berne about 1900 and even in persons of the name Beiler still living in Switzerland. Someconditions which are not genetically determinedto a significant extent have been usefully studied among the Amish. Cancer of the cercix is a case in point. In the Hoimes County (Ohio) Amish a Pap smearsurvey initiated in the early 1950s showed an unusually low frequency of carcinoma of the cervix in Amish women ascomparedwith non-Amish women of that area and other areas of the United States.This despitethe lack of circumcision and the grand multiparity of Amish women-two factors that usually predispose to cervical cancer. The observation is, however, consistent with the hypothesis of an infectious, that is venereal factor in cervical cancer. The finding reminds us that the Amish representa social isolate as well as a geneticisolate. Being a closed population and a chaste one; one might expect a low frequency of cervicai carcinoma if by good fortune the agent was not introduced with the original founders. Bibliography Hostetler, J. A., Amish Society, 2nd ed. Johns Hopkins University Press, Baltimore, 1968. McKusick, V. A. (ed) Medical Genetic Studies of the Amish: Selected Papers.Johns Hopkins University Press,Baltimore 1978. Idem Genetic nosology: three approaches.Am. J. Hum. Genet., 30,105, 1978.
001~7162/60/0062-0057/$02.00/0
57
All the Amish are rural-living and most earn their living by farming. Some partially acculturated groups are still referred to as Amish, but in this discussion Amish refers to Old Order Amish, as defined above. They do not own automobiles but depend on the horse-and-buggy for local transportation, and most use only horse-drawn agricultural equipment. They do not have electricity in their farm buildings. They have no radios, television, nor telephones. These practices, as well as their stylized dress differing from that of their neighbours derive from their basic tenet stated in the 12th Chapter of Romans: ‘Be ye not conformed to this world, but be ye transformed. . .’ Based on the same tenet, they do not purchase commercial insurance on their property, because of the yoking with non-Amish that this would represent, and usually do not enter into business partnerships with non-Amish. Furthermore, they rigidly shun members of their own group, even close relatives, who, once baptized, leave the group or are excommunicated for failure to subscribe to the Meinung (doctrine). The Amish prefer their own schools, being particularly opposed to consolidated schools. Thus in heavily Amish parts of the country one sees many one-room parochial Amish schools. They do not educate beyond the legal minimum required by the state; that is, a grammar school education. A high-school truancy case involving Amish was carried to the U.S. Supreme Court, with the verdict in their favour. If there is one characteristic which distinguishes the Old Order Amish from other varieties of ‘plain people’-and of course there are other distinctive features-it is the practice of holding their religious services in the home, by rotation. All other plain sects, such as the Dunkards and conservative Mennonites (so called after the Frisian religious reformer Menno Simons), have meeting houses. The Old Order Amish originated in the Canton of Berne in Switzerland in 1693 as an offshoot of the older and more extensive Mennonite movement. Jacob Ammann, a Mennonite bishop, concluded that the Mennonites were too worldly. He acquired converts from among Bernese Swiss who during the previous century had left Berne to go to Alsace-Lorraine and the Palatinate. The Amish began coming to the United States about 1730, and most of the Amish of eastern Pennsylvania are descended from prerevolutionary immigrants. Immigration continued until about 1850 but later immigrants settled in western VictorA.
McKusick,M.D.,F.R.C.P.
Was born in Parkman, Maine, in 192 1, He is a graduate of Johns Hopkins University, and has been on the faculty of the medical school there since 1947. Ha was appointed Professor of Medicine in 1960 and in 1973 became chairman of the Department of Medicine and Physician-in-Chief of the Johns Hopkins Hospital, Apart from genetic studies of the Amish, his scientific work has been in heritable disorders of connective tissues, on mapping the chromosomes of man, and on the nosology of genetic disease. Endeevour, ( 0 Pergamon
52
New Series Volume 4. NO. 2.1980 Press. Printed in Great Britain)
Pennsylvania, Ohio, and points west. In some of these areas, descendants of pre-revolutionary immigrants were already living and the separate immigrant streams fused to some extent in these areas. Today the Old Order Amish number over 75,000 persons. Over 80 per cent of these live in Pennsylvania, Indiana, and Ohio and over 50 per cent live in three areas: Lancaster County (Pa.), Holmes County (Ohio), and Lagrange-Elkhart Counties (Indiana). The unit of Amish society is the church district. The size of the church district is determined by how many people can be accommodated in a farmhouse for religious services and how far one can conveniently travel by horse-andbuggy to attend it. The districts are ruled over by lay clergy called bishops, preachers, and deacons who are chosen by lot. The Amish are useful for both sociologic and genetic studies. Although the main focus of our own studies has been genetic, and that is the focus also of this article, aspects of sociologic interest are obvious. For example, their labour-intensive form of agriculture is a model that is becoming increasingly rare in developed countries. Their child-rearing practices are worth study. The child is
introduced to work early, and families are large and tightly knit. It is a memorable experience to visit an Amish family at mealtime in the large farm kitchen. Amish schooling is limited largely to the 3R’s plus geography and German. The Amish are tri-lingual: they speak the Pennsylvania Dutch dialect at home and children often know little else until they go to school. Adults speak English, and they are acquainted with the high German of the Luther Bible, which they use in religious services. The health care system of the Amish is eclectic. They, of course, do not have their own physicians. Although first babies are born in hospitals, Lancaster County Amish prefer to have later babies at home. Osteopathic physicians in that area attend deliveries at home. Although they do not hesitate to use local physicians or go to a distance to large medical centres, they tend to be attracted to fringe practitioners. The way the Amish care for their physically and mentally handicapped and for their aged is also a useful object of study. By special Act of Congress some years ago, they were exempted from Social Security payments because they ‘take care of their own’. When they retire older usually into a small move persons house (‘Grossdaddyhaus’) often attached to the big house which they previously occupied and which in this process they turn over to one of the younger sons who operates the farm. The Amish are of particular usefulness for many types of genetic studies, for the following reasons: They are a closed population. They do not proselytize and almost no new blood has been added to the groups since the immigrations. Gene flow is entirely centrifugal. Although a fair number of persons leave the groups each generation, the birth rate has been consistenly so high that the Amish have grown,
through that means alone, from about 8200 in 1905 to a number estimatedto be greater than 75,000 today. Then too, the Amish are a defined population; indeed, a self-definedone. Their origins in western Europe are rather well known. Their genealogic records are essentially complete back to the founding immigrants. They are consanguineous to a high degree. In every marriage contracted in the Lancaster County Amish in recent years, for example, the partners have been at least remotely related. Of the 1750 married couplesin a 1973 censusof the Lancaster County Amish, only two were not demonstrably related. The average coefficient of consanguinity is something betweenthat for first cousins and that for second cousins, namely about .026. This despite the fact that no first-cousin and niece-uncle marriages were found in 1973, and only two marriages of first-cousins-once-removed.In sufficiently frequent instances couples are related as second cousins two or three times over and as third cousins several times to make the averagecoefficient comesup to the figure cited. For example, at least one Lancaster County Amish couple is related in 42 ways! Unlike many inbred groups studied by geneticists the standard of living of the Amish is high and the standard of medical care is relatively high. That the standard of diagnostic care is high is particularly useful when one is investigating genetic diseases,including possibly new ones. Amish clannishness and a related interest in the nature of illnesses that affect their co-religionists have been an important factor in identifying multiple casesof rare and sometimes“new” genetic diseases.Becausethe Amish take care of their own, they keep defective membersof their sect at home. This facilitates identification of particular problems and their study against the background of the family. Finally, in the Amish two disadvantagesof modern man as an object of genetic study-his small family size and his mobility-are counteracted. In the case of the Amish one can collect observations and samples on a rather large number of relatives living in a limited geographic area. The pattern of immigration and of subsequent community development among the Amish bears some similarity to cloning of bacteria or cultured somatic cells. It is as though the Amish founders were“streaked out” across a latitudinal belt of America east of the Mississippi. Colonies sprang up, not to be sure from individuals, yet from a limited number of individuals, and their descendants display characteristics determined by genes carried by those founders. Thus, bioassay of the genome of the founders has beenperformed for us. Each of us, it can be estimated,carries a few ‘bad’ genes; that is, recessivegenespresent in single dose and therefore not expressed. I, for example, may carry a gene for congenital deafness, a gene for albinism, and a gene for cystic fibrosis. That our children are no more often affected by these disorders than they are follows from the rarity of most of these genes; unless we marry a close relative, our spouseis likely to have a different setof ‘bad’ genes. Genetic
disorders
of the Amish
Someof the genetic disorders which have beenfound in the Amish are previously recognised ones. Some of them, however, were ‘new’ genetic diseases, having not been known, or at least not recognised, until they came to light among this sect. Once described among the Amish they have usually been found in other groups as well. Thus,
studies of the Amish have contributed to genetic nosology; that is, the classification or better delineation of genetic disorders. The visibility of recessivegenetic disorders is increased among the Amish. Most ‘visible’ mutations, (that is, mutations that are evident in persons homozygous for the mutation, without resort to special biochemical or other testing) are recessive: the gene must be present in double doseto be expressed.Man shows a deficiency of autosomal (non-sex-linked) recessives relative to known autosomal dominants, if one assumesthat most visible mutations are indeed recessive and compares man with speciessuch as mouse and drosophila in which recessives predominate. The reason for this is that a recessivemutation can occur in man and be lost, either by chance or becauseit has some disadvantageeven in the heterozygote, before it happensto encounter itself in a homozygous descendant.Man, unlike the experimental species, usually does not marry close. Furthermore, even if the gene does occur in double dose, chances are strong-because human families are smallthat it will be a single casein the family and therefore not recognised as a distinct disorder. In experimental species close mating and large number of progeny render any recessivemutation more visible than is the casein man.
Figure
1
Amish
father
with
three children
In the Amish the cloning phenomenon (known technically as Founder Effect), consanguinity, and large family size all collaborate in increasing the visibility of recessives.The very existence of the group itself increases that visibility. If a strange disorder occurs among children who are easily identified as Amish, even though they are in different sibships, one is likely to be impressed.The form of hereditary anaemia now called thalassaemia becauseof its frequent occurrence in the Mediterranean littoral, was not discovered there but was recognised first in Detroit in the 1920s by a pediatrician-haematologist T. B. Cooley. He could not help but be impressed with the likely distinctiveness of the disorder that occurred in Greek and Italian children. The Amish likewise illustrate the usefulness of ‘groupness’, or ethnic extraction, in the identification of ‘new’ entities. 53
Of the dozen or more conditions which have been identified for the first time among the Amish, a prime example is cartilage-hair hypoplasia, which will be discussedin somedetail. Disorders previously describedin non-Amish are likewise useful to study when found among the Amish, partly because they illustrate gene dynamics and the genetic structure of the populations, but also becauseone often finds in the Amish a large number of casesof the particular condition and can be quite certain that all cases are produced by the self-same gene. In medical genetics as practiced in the general population, genetic heterogeneity is a leading fact of life. In a given series of casesone may unwittingly be comparing apples and oranges, that is, cases caused by fundamentally different mutations. Six-fingered dwarfism is one of the previously known, although rare, disorders encountered quite frequently amongthe Amish (figure 2).
Figure 2 Nine-year-old Amish boy with ‘six-fingered dwarfism’ (Ellis-van Creveld syndrome) who has undergone cardiac surgery for atrial septal defect. Extra fingers have been removed. Amish children are dressed like their elders.
The Ellis-van hypoplasia
Creveld
syndrome
and cartilage-hair
When my colleaguesand I first undertook genetic studies among the Amish, we were told that achondroplastic dwarfism was unusually frequent among them. A priori it seemedunlikely that this was truly achondroplasia because we knew by that time (1962) that achondroplasia is a very specific form of dwarfism inherited as an autosomal dominant, whereasin an inbred group such as the Amish, 54
one expects to find recessive disorders in increased numbers, not dominant disorders. At least, one does not expect to find a large number of cases of a dominant disorder that has severelyreduced reproductive fitness as is the casewith achondroplasia. In the event, it proved to be recessivedwarfism that was frequent among the Amish, in fact two forms of recessivedwarfism. One was a form first described in 1942 by Ellis and van Creveld, professors of paediatrics in Edinburgh and Amsterdan, respectively, and known as the Ellis-van Creveld (EvC) syndrome, or ‘sixfingereddwarfism’ (Fig. 4). About 50 casesofthis condition had been reported up to the time of our initial report in 1964, and at one fell swoop we were able to double the world’s literature on the disorder by reporting more than 50 casesamong the Amish. We have now observed 89 cases among the Amish (figure 5). The secondform of dwarfism was a previously unknown variety in which fine, sparse, silky hair was combined with the problem in skeletal growth. Cartilage-hair hypoplasia (CHH) was the designation selectedfor the condition.
Fourteen-year-old Amish boy shown with physician from Figure 3 Dr McKusick’s group. The boy is dwarfed and has dislocated ocular lenses, a disorder called the Weill-Marchesani syndrome.
Both of these disorders, EvC and CHH, illustrate pleiotropism, that is, multiple effects of a single gene mutation. Each of them is a syndrome (which means literally ‘running together’). Personsunfamiliar with genetic principles often think of gene linkage as being the basis of such syndromes, rather than pleiotropism, but linkage is rarely, if ever, the cause.The gene-determinedbiochemical defect in neither of these two disorders is known. In recessively inherited conditions such as these, an enzyme deficiency is suspected.Whatever the nature of the basic defect it must be of a type that can lead to derangementin
several aspects of development and function, with the clinical consequences observed. EvC is characterised consistently by six fingers and short-limbed dwarfism. Furthermore, the fingernails are poorly developed, the teeth are abnormal, and in over half of cases a cardiac malformation, most often atria1 septal defect, is also present.
Furthermore, the severity of the dwarfing and hair changes is widely variable. In addition to pleiotropism and variability, these disorders illustrate a third cardinal principle of clinical genetics, genetic heterogeneity; that is, the same or nearly the same condition due to different genetic causes. Obviously if dwarfism were considered only one condition, confusion in prognostication, genetic counselling and management would be likely to occur. Among the Amish the Ellis-van Creveld syndrome occurs only in those of Lancaster County (or recently from Lancaster County). We have observed a total of 45 sibships, each with at least one member affected with this disorder. That it is an autosomal recessive is supported by the fact that the parents are normal in the case of all except one of these sibships (in which an afflicted man is married to a cousin of some sort and has two affected children out of seven). Segregation analysis shows close agreement of ‘observed’ with ‘expected’ incidence under the recessive hypothesis. Thus, both parents of each of the sibships (apart from the one mentioned above) must be heterozygous carriers. (Incidentally, the carriers show no discernible abnormality.) When one has a “founder population” such as this, in which an ordinarily rare gene is found in high frequency, it is plausible to conclude that only one of the immigrant founders carried the gene. If in tracking back the ancestry of all 90 parents of the 45 sibships one finds one but only one founder couple common to all, then the presumption is strong that one or the other of that specific couple (or both) “imported the gene” in to the U.S.A. In the genealogies only one couple was found to be ancestral to all 90 parents of affected sibships: this was Samuel King, who immigrated in 1744, and his wife (Fig. 61. ,iOiO 20000 3O@iOOO alJ0io0io0 ~Orn000
Figure 4 The Amish madonna. An Amish mother her child who has’six-fingered dwarfism’ (Ellis-van syndrome).
is shown Creveld
with
Both EvC and CHH also illustrate the principle of variability. Because of differences in genetic background against which the single major gene mutation is operating in and because of differences in different individuals, environmental circumstances under which individuals develop and live, considerable variability from case to case is observed. In a series of unrelated cases drawn from a non-Amish population one is uncertain how much of the variability is due to the fact that two or more different gene mutations are represented among the cases. In the Amish, where we have observed 90 cases of EvC, all clearly determined by the same gene, there still is considerable variability. As mentioned, congenital heart malformation occurs in only about half the cases. The pleiotropic effects of the cartilage-hair hypoplasia gene include, in addition to the cartilage and hair abnormalities, a defect of the immune system, such that many of these patients have particularly severe viral infections. Chickenpox in this condition may be a fatal illness, but even this feature is highly variable. In the more than 100 cases of CHH we have now observed among the Amish, many appear to have a normal immune system.
600000m 7oioooii ~onm00[7 ~UU.0 lomoo ~~nucln000nm00000 :~00000i000000mn 13monoiiio ~~iU.iUi~O ~~iiO0 X5~~~(-J~O($O~ ~~0000iii 18@00lii6 ~~iOOOOr3b~ 20m0000 m @ q +
~‘rnUclC ~~@UrnOU0@ ~~E!l0OWtl0@ ~~oooiaioio ~~OOiouOOOion ~~i00000000000 ~~ioOOOuOO!Il ~~ocltliocl@ooio ~~iOiOOtiOO ~~00i00000 ~~oioooioooi ~~oc~ioo 3~iOClU.O -tloii ~~00000.0 ~~lii0i00. ~~00000000m00 =ioo =ooioom ~~oooio DilYGOTlC TWINS ~~oonoooi STILL BOW4 ~AFFECrED -0iooomo DE@x 43q 000m
Figure 5 Distribution of 86 casesof the Ellis-van Creveld syndrome in 43 sibshipsof Lancaster County, Pennsylvania. The addition of two more affected sibships brings the total count to 89 cases in 45 sibships.
We estimate that the frequency of the Ellis-van Creveld syndrome in the Lancaster County Amish is not less than 50 per 10,000 births, which gives a frequency of the gene of 55
about .066 (when the effect of consanguinity is taken into account). This means,furthermore, that about 12.3per cent of all Lancaster County Amish are carriers of the EvC gene. Interestingly, and probably significantly, 12.5 per cent of the Lancaster County Amish carry the surname King (Table 1). A gene that came from Samuel King (and/or his wife) has persisted in the Lancaster County Amish population in about the same frequency as the family name which Samuel King alone introduced into the population. TABLE Lancaster
County,
1 DISTRIBUTION Pennsylvania
OF FAMILY
NAMES*
Holmes
County,
Ohio -
Stoltzfus King Fisher Beiler Esch, Esh LaPP Zook
25.7 12.6 11.1 10.7 6.5 6.4 5.4 78.4
Miller Yoder Troyer Raber Hershberger Schlabach Weaver Mast Beachy
27.6 15.3 10.4 5.6 5.5 4.3 3.7 3.5 2.7 78.6
*Each community now numbers about 13,000. Each of the top 7 names in the Lancaster community was derived from a single immigrant founder. Several of the names in Holmes County likewise had a unique origin.
Figure 6 Thedescentof both parents of the first 26 sibships identified as having the Ellis-van Creveld syndrome is traced to Samuel King and his wife. The same descent is demonstrable for the rest of the 90 parents of the 45 affected sibships identified to date.
56
The high EvC gene frequency in the Lancaster County Amish is largely due to Founder Effect-cloning phenomenon, if you will. Consanguineous matings of the closenesspracticed in the Lancaster County community account for only a small proportion of the cases,perhaps 14 per cent. Given the high gene frequency the other cases would have occurred with zero consanguinity. Our studies have led to the conclusion that the Amish do not represent one big homogeneous isolate, but rather several moderately separate isolates, or demes (the word demerefers to a local consanguinealgroup or endogamous community). Part of the evidence for separate deme formation among the Amish-for example, that the Lancaster County community is one deme, the Holmes County (Ohio) community another, and so on-is of at least four types: (i) the history of the immigrations and subsequentseparation of the groups; (ii) the distribution of family names in the separate communities; (iii) the distribution of blood groups in the separatecommunities; and (iv) the distribution of recessive genetic disorders in the different groups. As an example of the last the unprecedentedly high frequency of EvC among the Lancaster County Amish is a mark of their distinctiveness. Characteristic recessivedisorders are found in each of the other Amish demes. As shown in the table, only eight names account for almost 80 per cent of the 13,000 individuals in each of two Amish communities, but it is a completely different set of eight family names.This is all the more remarkable in view of the fact that each of the eight top Lancaster County names was derived from a single founder. The name Stoltzfus is carried by one fourth of all Lancaster County Amish and derives from a single founder, Nicholas Stoltzfus, who immigrated in 1766. Obviously he contributed disproportionately to the present gene poolanother illustration of Founder Effect.
Blood groups studies show that among the Lancaster County Amish almost three-fourths of the population is blood type A ascontrasted with the frequency of blood type A of 50 per cent in the Canton of Berne and 54 per cent in Holmes County (Ohio) Amish. Contrariwise, only 11 per cent of Lancaster County Amish are blood type 0, which has a frequency of 39 per cent in Berneseand 34 per cent in Holmes County Amish. Again this is presumably an expression of Founder Effect. If, for example, Nicholas Stoltzfus was homozygous for the blood group A gene,this would account in considerable part for the high frequency of blood type A now. A role may have beenplayed also by Random Genetic Drift-the chance transmission to the next generation of genesin different proportions from those existing in the parent population, a phenomenon especially likely to occur when groups are small. Cartilage-hair hypoplasia is much more generalisedin its distribution among the Amish than is EvC and someother disorders. Casesof CHH have beenidentified in all Amish communities. This must mean that many of the immigrant founders were carriers of the gene, which had achieved rather wide distribution in the parent population before the immigration, and indeed, probably before the founding of the Amish sectin 1693. The gene for cartilage-hair hypoplasia is rare in the general population, with one notable exception; the condition has a relatively high frequency in Finland, where more than 40 caseshave been observed. It is unlikely that there is any genealogic connection betweenthe Finns and the Amish. Much more likely is that an independent, but possibly identical mutation occurred sometime in the past in ancestors of the Finns and that the gene has achieved a relatively high frequency among them becauseof historicodemographic circumstances similar to those that occurred among the Amish. A large area of present day Finland was populated by a rather small number of immigrants who, using the analogy previously applied, were ‘streaked out’ over this extensive area. Groups sprung up which remained isolated, partly becauseof distance and partly becauseof language, from Germanic,neighbours on the one side and Siavic neighbours on the other. Chromosomal
peculiarities
The traits we have been discussing up to this point are Mendelian ones, autosomal recessive ones for the most part. Chromosomal peculiarities can likewise be studied among the Amish. For example; we reasonedthat sincethe
number of patronyms is limited among the Amish, since in our society the Y chromosomeand patronym are inherited together in males; sincemost of the Amish patronyms were derived from a single ancestor; and finally since the Y chromosomevaries in length from male to male, it might be possible to demonstrate a characteristic Stoltzfus Y, King Y or Fisher Y chromosome.Indeed,in the courseof doing a large number of karyotypes, males of the surname Beiler were found to have an unusually small Y chromosome, missing part of the long arm. Missing is most of the part that in other males shows fluourescencewhen stained with quinacrine, so that Amish males of the name Beiler do not show the F body which usually is a marker of malenessin interphase(resting) cells, such asbuccal mucosal cells. Amish maleswidely separatedin the pedigreewere found always to have the small Y chromosome if they had the name Beiler. All of them could be shown to be descendent from the samefounder of that name. Someof them still spell their name Beiler, while others spelled it Byler. Furthermore, the samesmall Y chromosome was found in persons of the name Beyeler who had immigrated from Berne about 1900 and even in persons of the name Beiler still living in Switzerland. Someconditions which are not genetically determinedto a significant extent have been usefully studied among the Amish. Cancer of the cercix is a case in point. In the Hoimes County (Ohio) Amish a Pap smearsurvey initiated in the early 1950s showed an unusually low frequency of carcinoma of the cervix in Amish women ascomparedwith non-Amish women of that area and other areas of the United States.This despitethe lack of circumcision and the grand multiparity of Amish women-two factors that usually predispose to cervical cancer. The observation is, however, consistent with the hypothesis of an infectious, that is venereal factor in cervical cancer. The finding reminds us that the Amish representa social isolate as well as a geneticisolate. Being a closed population and a chaste one; one might expect a low frequency of cervicai carcinoma if by good fortune the agent was not introduced with the original founders. Bibliography Hostetler, J. A., Amish Society, 2nd ed. Johns Hopkins University Press, Baltimore, 1968. McKusick, V. A. (ed) Medical Genetic Studies of the Amish: Selected Papers.Johns Hopkins University Press,Baltimore 1978. Idem Genetic nosology: three approaches.Am. J. Hum. Genet., 30,105, 1978.
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