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American Journal of Medical Genetics Part C (Semin. Med. Genet.) 121C:1 – 4 (2003) I N T R O D U C T I O N Medical Genetic Studies in the Amish: Historical Perspective Medical genetics studies in the Amish began in 1962, when two events sparked the interest of one of the authors (V.A.M.). As a member of the faculty committee advising the Johns Hopkins Press, he was asked to read the manuscript Amish Society submitted by John Hostetler. It was apparent that many characteristics of Amish society made it an excellent community in which to study genetic traits, particularly recessive conditions. In the preface to the 1978 book, Medical Genetic Studies of the Amish, he writes: Actually, my medical genetic interest in the Amish had been piqued a few months earlier in 1962 by Dr. Clair A. Francomano received her M.D. from Johns Hopkins University School of Medicine. She completed training in Internal Medicine and in Clinical and Molecular Genetics at Johns Hopkins. She is now a Senior Investigator at the National Institute on Aging, National Institutes of Health, where she directs a clinical and laboratory research program on skeletal dysplasias and hereditary disorders of connective tissue. Dr. McKusick is university professor of medical genetics in the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore. His studies of the Old Order Amish began in 1963. His description of cartilage-hair hypoplasia was published in 1965. Reports of his group and others up to 1978 were collected in his Medical Genetic Studies of the Amish: Selected Papers Assembled, with Commentary (Baltimore: Johns Hopkins University Press, 1978). Dr. Leslie Biesecker received his M.D. from the University of Illinois. He received pediatrics training at the University of Wisconsin and Medical and Molecular Genetics training at the University of Michigan. He is a senior investigator at the National Human Genome Research Institute at the NIH in Bethesda, MD. He directs a clinical and laboratory research program in the molecular genetics of birth defects. *Correspondence to: Clair A. Francomano, M.D., Laboratory of Genetics, National Institute on Aging, 333 Cassell Dr., Suite 3000, Baltimore, MD 21224. E-mail: [email protected] DOI 10.1002/ajmg.c.20001 ß 2003 Wiley-Liss, Inc. an article about a country doctor, David Krusen, who had an extensive practice among the Amish in Lancaster County, Pennsylvania. He indicated to the author of the article—in a slick-paper, pharmaceutical company ‘‘throw-away’’— that achondroplasia is frequent among the Amish. On the basis of this tip, dwarfism was the first entity we studied systematically among the Amish, and my first field trip, with visits to Amish homes, was made in the company of Dr. Krusen. [McKusick, 1978] The early studies on dwarfism in the Amish, which was, in fact, not achondroplasia, led to the recognition of two recessive conditions: Ellis-van Creveld syndrome [McKusick et al., 1964a], which had been previously reported [Ellis and van Creveld, 1940], and cartilage-hair hypoplasia [McKusick et al., 1965], a newly recognized disorder that was eventually given the formal name of metaphyseal chondrodysplasia, McKusick type. Systematic investigations were undertaken on a number of other disorders, including mental retardation, neurologic conditions, and deafness [Mengel et al., 1969]. Several disorders were initially described in publications resulting from this work, including the Troyer [Cross and McKusick, 1967a], Mast [Cross and McKusick, 1967b], and Amish microcephaly syndromes [Kelley et al., 2002]. In addition, much was learned about previously described genetic conditions, includ- Several disorders were initially described in publications resulting from this work, including the Troyer, Mast, and Amish microcephaly syndromes. ing ataxia-telangiectasia [Ginter and Tallapragada, 1975; Rary et al., 1975; Gatti et al., 1988], epidermolysis bullosa [Cross et al., 1968], hereditary spastic paraplegia [Thurmon and Walker, 1971], and pyruvate kinase deficiency [Bowman et al., 1964], among others. Other investigators exploring genetic conditions among the Amish in the 1960s and 1970s included D. Bernard Amos, Herbert S. Bowman, Joe C. Christian, C.E. Jackson, Richard C. Juberg, Walter E. Nance, and John M. Opitz. Many of these studies were published in scientific journals and later compiled in the book Medical Genetic Studies of the Amish [McKusick, 1978]. In a paper entitled ‘‘Genetic Studies of the Amish: Background and Potentialities’’ [McKusick et al., 1964b], the authors listed 15 advantages to performing genetic studies in the Amish community (Table I). In addition to these intrinsic attributes, the Amish were surprisingly open to participation in genetic studies. It was speculated that their receptivity stemmed from approaching them as a physician, genuinely concerned about those among them who were physically and mentally handicapped [McKusick et al., 1964b]. In our experience, most Amish families have been welcoming of physicians who come with information about the disorders that affect their children or family members. The initial studies of Amish in Pennsylvania, Ohio, and Indiana were facilitated greatly by the assistance and introductions from the late John Hostetler, PhD, a rural sociologist whose parents were Old Order Amish. In Lancaster County, Pennsylvania, a local Amish liaison has worked with us and other clinical researchers for many years. She, and eventually others who followed, fulfilled a critical role for the research efforts. She personally knew many of the families, spoke the local 2 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) INTRODUCTION TABLE I. Advantages of Studying Genetics in the Amish [McKusick et al., 1964b] 1. The Old Order Amish are a defined, indeed self defined, population. 2. It is a closed population; gene flow is almost exclusively centrifugal. 3. The western European origins of the population are well known. 4. Genealogic records are extensive. 5. The standard of living is high. 6. The standards of medical care are relatively high. 7. An interest in illness is evident. 8. There is a high coefficient of inbreeding due to the relatively small number of founder couples. 9. The illegitimacy rate is apparently low. 10. The Amish are interested in and knowledgeable about the health of their relatives. They seek out information on rare disorders shared by other Amish families. 11. Socio-economic and occupational circumstances are notably uniform. 12. Because of constraints on transportation, the Amish are relatively immobile. 13. Most Amish families are large, with an average of seven to nine children. 14. Children with birth defects or genetic disorders are usually kept at home rather than institutionalized. 15. The existence of several Amish isolates makes comparisons of sub-populations possible. dialect of Pennsylvania Dutch, and could address the families in their own language, introduce the visiting doctors and explain the purpose of the visit, and assist in navigating through the back roads of Lancaster County. Most importantly, she was intimately familiar with local customs and the views and opinions held by many families, and acted as a buffer between the ‘‘English’’ world of the researchers and the quiet, sometimes isolated world of the Amish. Sara Fisher filled this role for many years and was joined by Sadie Beiler and others. Ms. Fisher’s knowledge of the community was facilitated by her prior job as a schoolteacher in one of the local oneroom Amish schoolhouses. She had also worked as a typist for the Messenger, the Amish monthly newsletter that details the births, deaths, and marriages in the Amish community across the country. She had a remarkable memory, a detailed knowledge of the local families, and a fabulous sense of humor that greatly enhanced the field trips for all participants. Medical genetics studies entered a new era when D. Holmes Morton, MD, and his wife, Caroline, came to Lancaster County to establish the Clinic for Special Children. Dr. Morton, a pediatrician with an interest in metabolic genetics, came to Lancaster expressly to provide care for the children among the Amish with rare genetic disorders. He called his clinic the Clinic for Special Children to reflect the views of the community that children who are born with these disorders are a special gift to the family from God. He has been warmly embraced by the community, who donated the land and helped to build the clinic (in the tradition of a barn raising) for him and his staff and hold an annual auction to support the clinic. Efforts by Dr. Morton and his colleagues have led to the description of a new microcephaly syndrome [Kelley et al., 2002] and its causative gene [Rosenberg et al., 2002]; recognition of glutaric aciduria type I as a common cause of episodic encephalopathy and spastic paralysis [Morton et al., 1991; Strauss et al., 2003] and the common mutation in the Amish [Biery et al., 1996]; identification of the troponin T1 gene as the cause of nemaline myopathy in the Amish [Johnston et al., 2000]; and many other accomplishments [Morton et al., 2003; Puffenberger, 2003]. To a large degree, the advantages of studying genetic disease in the Amish (and other Anabaptist communities) are as true today as they were in 1964. In the mid-1980s, studies in the Amish were pivotal to identification of the gene for cystic fibrosis [Tsui et al., 1985]. Recent studies have found the genes causing cartilage-hair hypoplasia To a large degree, the advantages of studying genetic disease in the Amish (and other Anabaptist communities) are as true today as they were in 1964. [Ridanpaa et al., 2001], Ellis-van Creveld syndrome [Ruiz-Perez et al., 2000], McKusick-Kaufman syndrome [Stone et al., 2000], and Troyer syndrome [Patel et al., 2002], phenotypes that were described in the early studies. As interest in identifying genes contributing to complex or multifactorial traits has burgeoned in the last decade, interest in the Amish population for dissecting these disorders has increased. One of the earliest studies focused on ethnic variability in glucose tolerance and insulin secretion in Rimoin [1969]. More recently, Dr. Alan Shuldiner has spearheaded a large effort to find genes contributing to type II diabetes [Hsueh et al., 2003], and he and others have searched for genes contributing to obesity [Hsueh et al., 2001; Platte et al., 2003]. The history of the search for genes contributing to manic depressive illness in the Amish [Egeland et al., INTRODUCTION 1987; Kelsoe et al., 1989; Ginns et al., 1998] shows that genetic research in the Amish is not immune from problems that plague complex genetics in general, and psychiatric genetics in particular. This rich history and the many successful ongoing studies of Amish and other Anabaptist communities in North America (e.g., Mennonites and Hutterites) are a testament to the generosity of those communities, and the vision and hard work of the early proponents of this research. However, genetics research is not the same enterprise it was in 1964. Formal requirements for the protection of human subjects and concerns about the protection of communities [Weijer et al., 1999] have changed the landscape of family studies in the Amish. Whereas in the past it was sufficient for the investigators to treat the community with respect and sensitivity, today detailed Institutional Review Board (IRB) protocols and informed consent are required. Although these regulatory approaches may assure a certain kind of protection for the Amish, they are no substitute for respect and sensitivity. There have been unfortunate examples of researchers entering the community without its support. In these cases, a researcher should expect to be treated coldly and fail to meet the research goals. In spite of the infrequent use of telephones, word travels fast among the Amish, and the community is capable of making a determination that cooperation is not in their best interests. A frequent misconception among the ‘‘English’’ is that the Amish and Mennonite cultures are monolithic and uniform because of their consistent outward appearance and customs. In fact, the community represents substantial variance in their opinions regarding the utility and appropriateness of genetics research, appropriate clinical uses for genetics, and their involvement in modern technically oriented health care. In our studies (L.G.B. and C.A.F.), a large majority of families whom we visited agreed to participate in research following an explanation of the study during a house call. In spite of that high uptake, a significant portion of the AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) families declined to participate, suggesting that we were interfering with God’s will, developing technological health care that would not clearly benefit Amish children, and other reasons. Any researchers who treat Amish persons as anything but intelligent and thoughtful individuals are likely to fail in their research endeavors. In the more than 40 years since this research has started, there have been notable changes among the Amish as well. These days it is not unheard of In the more than 40 years since this research has started, there have been notable changes among the Amish as well. to reach an Amish farmer on his cell phone. In addition, the pressure of encroaching suburbs is slowly eroding the farmland of Lancaster County, causing families to disperse to settlements farther west where land is less expensive and where cities do not loom. But one attribute has not changed, which is a people who strongly value a communitarian spirit that itself springs from their deeply held religious beliefs. The primary reason why the Amish share medical information with each other and with doctors and researchers is a commitment to help those in need and to provide the most help to those in greatest need. This is another manifestation of their attitude and commitment to the special children who are the subjects of this research. This cultural value is most readily recognized in the Lancaster community by the barn raisings that follow the unfortunately frequent barn fires. Without hesitation, families put aside their own needs and rally to those with greater needs. The willingness of the community to share medical and genealogic information must be reciprocated by a commitment of the medical and research communities to provide improved medical care to those studied in this community who are affected by the disorders. Furthermore, researchers must endeavor to avoid 3 perturbing or altering the culture that makes the Amish unique. There can be no greater manifestation of this commitment than the Clinic for Special Children. Dr. Morton and his colleagues are unwavering in their commitment to the advancement of knowledge and the application of this advanced and appropriate medical care for the special children. By respecting the culture of the Amish, physicians and geneticists can improve the health of the special children, provide new insights into genetics and biology, and preserve the unique cultural heritage of these generous and peaceful people. REFERENCES Biery BJ, Stein DE, Morton DH, Goodman SI. 1996. Gene structure and mutations of glutaryl-coenzyme A dehydrogenase: impaird association of enzyme subunits that is due to an A421V substitution causes glutaric academia type I in the Amish. Am J Hum Genet 59:1006–1011. Bowman HS, McKusick VA, Dronamraju KR. 1964. Pyruvate kinase deficient hemolytic anemia in an Amish isolate. Am J Hum Genet 17:1–8. Cross HE, McKusick VA. 1967a. The Troyer syndrome: a recessive form of spastic paraplegia with distal muscle wasting. Arch Neurol 16:473–485. Cross HE, McKusick VA. 1967b. The Mast syndrome: a recessively inherited form of presenile dementia with motor disturbances. Arch Neurol 16:1–13. Cross HE, Wells RS, Esterly JR. 1968. 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