Download Medical genetic studies in the Amish: Historical perspective

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. Inheritance in epidermolysis bullosa letalis. J Med
Genet 5:189–196.
Egeland JA, Gerhard DS, Pauls DL, Sussex JN,
Kidd KK, Allen CR, Hostetter AM,
Housman DE. 1987. Bipolar affective disorders linked to DNA markers on chromosome 11. Nature 325:783–787.
Ellis RWB, van Creveld S. 1940. A syndrome
characterized by ectodermal dysplasia, polydactyly, chondro-dysplasia and congenital
morbus cordis: report of three cases. Arch
Dis Child 15:65–84.
Gatti RA, Berkel I, Roder E, White R, Yoder F.
1988. Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature
336:577–580.
Ginns EI, St. Jean P, Philibert RA, Galdzicka M,
Damschroder-Williams P, Thiel B, Long
RT, Ingraham LJ, Dalwaldi H, Marray
MA, Ehlert M, Paul S, Remortel BG,
Patel AP, Anderson MC, Shaio C, Lau E,
Dysmarskaia I, Martin BM, Stubblefield B,
Falls KM, Carulli JP, Keith TP, Fann CS,
Paul SM, Remortel BG, Patel AP, Anderson
MCH, Shaio C, La E, Dymarskaia I,
Martin BM, Stubblefield B, Falls KM,
Carulli JP, Keith TP, Fann CSJ, Lacy LG,
Allen CR, Hostetter AM, Elston RC,
Schork NJ, Egeland JA, Paul SM. 1998.
4
AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)
A genome-wide search for chromosomal
loci linked to mental health wellness in
relatives at high risk for bipolar affective
disorder among the Old Order Amish.
Proc Natl Acad Sci USA 95:15531–
15536.
Ginter DN, Tallapragada R. 1975. Ataxia-telangiectasia. Birth Defects Orig Artic Ser 11(2):
408–409.
Hsueh WC, Mitchell BD, Schneider JL, St. Jean
PL, Pollin TI, Ehm MG, Wagner MJ, Burns
DK, Sakul H, Bell CJ, Shuldiner AR. 2001.
Genome-wide scan of obesity in the Old
Order Amish. J Clin Endocrinol Metab
86:1199–1205.
Hsueh WC, St. Jean PL, Mitchell BD, Pollin TI,
Knowler WC, Ehm MG, Bell CJ, Sakul H,
Wagner MJ, Burns DK, Shuldiner AR.
2003. Genome-wide and fine-mapping
linkage studies of type 2 diabetes and glucose
traits in the Old Order Amish: evidence for
a new diabetes locus on chromosome 14q11
and confirmation of a locus on chromosome
1q21-24. Diabetes 52:550–557.
Johnston JJ, Kelley RI, Crawford TO, Morton
DH, Agarwala AR, Koch T, Schaffer AA,
Francomano CA, Biesecker LG. 2000. A
novel nemaline myopathy in the Amish
caused by a mutation in troponin T. Am J
Hum Genet 67:814–821.
Kelley RI, Robinson D, Puffenberger EG, Strauss
KA, Morton DH. 2002. Amish lethal
microcephaly: a new metabolic disorder
with severe congenital microcephaly and
2-ketoglutaric aciduria. Am J Med Genet
112:318–326.
Kelsoe JR, Ginns EI, Egeland JA, Gerhard DS,
Goldstein AM, Bale SJ, Pauls DL, Long RT,
Kidd KK, Conte G, Houseman DE, Paul
SM. 1989. Re-evaluation of the linkage
relationship between chromosome 11p loci
and the gene for bipolar affective disorder in
the Old Order Amish. Nature 342:238–
243.
McKusick VA. 1978. Preface. In: McKusick
VA, editor. Medical genetic studies of the
Amish. Selected papers. Baltimore: Johns
Hopkins University Press. p ix–x.
McKusick VA, Egeland JA, Eldridge R, Krusen
DE. 1964a. Dwarfism in the Amish I. The
Ellis-van Creveld syndrome. Bull Johns
Hopkins Hosp 115:306–336.
McKusick VA, Hostetler JA, Egeland JA. 1964b.
Genetic studies of the Amish: background
and potentialities. Bull Johns Hopkins Hosp
115:203–222.
McKusick VA, Eldridge R, Hostetler JA,
Ruangwit U, Egeland JA. 1965. Dwarfism
in the Amish. II. Cartilage-hair hypoplasia.
Bull Johns Hopkins Hosp 116:285–286.
Mengel MC, Konigsmark BW, McKusick VA.
1969. Two types of congenital recessive
deafness. Eye Ear Nose Throat Monthly
48:301–305.
Morton DH, Bennett MJ, Seargeant LE, Nichter
CA, Kelley RI. 1991. Glutaric aciduria type
I: a common cause of episodic encephalopathy and spastic paralysis in the Amish of
Lancaster County, Pennsylvania. Am J Med
Genet 41:89–95.
Morton DH, Morton C, Straus KA, Robinson
DL, Puffenberger EG, Hendrickson C,
Kelley RI. 2003. Pediatric medicine and
the genetic disorders of the Amish and
Mennonite populations of Pennsylvania.
Am J Med Genet (Semin Med Genet)
121.
Patel H, Cross H, Proukakis C, Hershberger R,
Bork P, Ciccarelli FD, Patton MA, McKusick
VA, Crosby AH. 2002. SPG20 is mutated in
Troyer syndrome, an hereditary spastic
paraplegia. Nat Genet 31:347–348.
Platte P, Papanicolaou GP, Johnston J, Klein CM,
Doheny KF, Pugh EW, Roy-Gagnon M-H,
Stunkard AJ, Francomano CA, Wilson AF.
2003. A study of linkage and association of
BMI in the Old-Order Amish. Am J Med
Genet (Semin Med Genet) 121.
Puffenberger EG. 2003. Genetic heritage of the
Old-Order Mennonites of South Western
Pennsylvania. Am J Med Genet (Semin Med
Genet) 121.
Rary JM, Bender MA, Kelly TE. 1975. A
14/14 marker chromosome lymphocyte
clone in ataxia-telangiectasia. J Hered 66:
33–35.
Ridanpaa M, van Eenannaam H, Pelin K,
Chadwick R, Johnson C, Yuan B, van
Venrooij W, Pruijn G, Salmela R, Rockas S,
Makitie O, Kaitila I, de la Chapelle A. 2001.
Mutations in the RNA component of
RNase MRP cause a pleiotropic human
disease, cartilage-hair hypoplasia. Cell 104:
195–203.
INTRODUCTION
Rimoin DL. 1969. Ethnic variability in glucose
tolerance and insulin secretion. Arch Int
Med 124:695–700.
Rosenberg MJ, Agarwala R, Bouffard G, Davis J,
Fiermonte G, Hilliard MS, Koch TG,
Kalikin LM, Makalowska I, Morton DH,
Petty EM, Weber JL, Palmieri F, Kelley
RI, Schäffer AA, Biesecker LG. 2002.
Mutant deoxynucleotide carrier is associated
with congenital microcephaly. Nat Genet
32:175–177.
Ruiz-Perez VL, Ide SE, Strom TM, Lorenz B,
Wilson D, Woods K, King L, Francomano
C, Freisinger P, Spranger S, Marino B,
Dallapiccola B, Wright M, Meitinger T,
Polymeropoulos MH, Goodship J. 2000.
Mutations in a gene in Ellis-van Creveld
syndrome and Weyers acrodental dysplasia.
Nat Genet 24:283–286.
Stone DL, Slavotinek A, Bouffard GG, BanerjeeBasu S, Baxevanis AD, Barr M, Biesecker
LG. 2000. Mutation of a gene encoding a
putative chaperonin causes McKusick-Kaufman syndrome. Nat Genet 25:79–82.
Straus KA, Puffenberger EG, Robinson DL,
Morton DH. 2003. Type I glutaric aciduria,
part 1: natural history of 77 patients. Am J
Med Genet (Semin Med Genet) 121.
Thurmon TF, Walker BA. 1971. Two distinct
types of autosomal dominant spastic paraplegia. In: The clinical delineation of birth
defects. IV. The nervous system. New York:
National Foundation—March of Dimes.
p 216–218.
Tsui LC, Buchwald M, Barker D, Braman JC,
Knowlton R, Schumm JW, Eiberg H,
Mohr J, Kennedy D, Plavsic N, Zsiga
M, Markiewicz D, Akots G, Brown V,
Helms C, Gravius T, Parker C, Rediker K,
Donis-Keller H. 1985. Cystic fibrosis locus
defined by a genetically linked polymorphic
DNA marker. Science 230:1054–1057.
Weijer C, Goldsand G, Emanuel EJ. 1999.
Protecting communities in research: current
guidelines and limits of extrapolation. Nat
Genet 23:275–280.
Clair A. Francomano*
Victor A. McKusick
Leslie G. Biesecker